Learn / FMK
Every FMK condition
299 diseases, deficiencies, toxicities and drug mechanisms harvested from every FMK deck — the ones sprinkled through a single bullet as much as the ones with their own slide. Pick what you're given and what you have to name, or let it cycle; distractors come from the same category so you have to discriminate (hypoketotic vs. ketotic hypoglycemia, which GSD, which urea-cycle enzyme…). Every answer shows the whole card with the lecture and slide.
299 shown
Carbohydrate 18
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Alcohol-induced (alcoholic) hypoglycemia FMK 03.4 · slide 17, 19, 24, 25; FMK 03.1 slide 12, 24; FMK 04.4 slide 26 NADH is HIGH → everything PILES UP on the NADH side: Pyruvate→Lactate, OAA→Malate → GNG blocked → hypoglycemia |
Ethanol oxidation (ADH + ALDH) → ↑↑ NADH/NAD⁺ ratio | Excess NADH drives pyruvate → lactate (LDH) and OAA → malate (MDH), depleting both key gluconeogenic substrates so a fasting, glycogen-depleted binge drinker cannot make glucose. | ↑ NADH, lactate, malate ↓ pyruvate, oxaloacetate, glucose |
Acquired | confusion, seizures, diaphoresis, tachycardia after a binge in a fasting individual (e.g., 34-year-old, glucose 38 mg/dL after 24 h without food) | ↓ glucose, ↑ lactate, ↑ anion-gap metabolic acidosis | IV dextrose + thiamine (thiamine BEFORE glucose in chronic alcoholics) |
| Carbohydrate malabsorption / osmotic diarrhea FMK 01.6 · slide ~19 Any undigested disaccharide -> large intestine -> osmotic diarrhea + CO2, CH4, H2 |
Brush-border enzyme deficiency (lactase, sucrase), transporter limits (SGLT-1, GLUT-5, GLUT-2 overloaded, saturated or genetically deficient), or mucosal damage | Undigested/unabsorbed sugars pass to the colon, pull water osmotically, and are fermented by bacteria into CO2, CH4 and H2. | ↑ Undigested disaccharides/sugars in gut lumen; colonic gas ↓ Absorbed monosaccharides |
Acquired | Osmotic diarrhea, bloating, flatulence, cramping | Hydrogen breath test (oral tolerance test) positive | Remove offending carbohydrate |
| Essential fructosuria FMK 03.4 · slide 8, 23, 25 Fructo KINASE deficiency → Fructose not KIDNAPPED (benign) |
Fructokinase | Fructose is not phosphorylated so it is not trapped in cells and simply accumulates in blood and urine — benign. | ↑ fructose (blood and urine) |
AR | asymptomatic, benign | positive copper-reduction (reducing sugar) test, negative glucose oxidase test | None required |
| Fanconi-Bickel syndrome (GLUT2 deficiency) FMK 02.3 · slide 15 GLUT2 = pancreas, liver, kidney; deficiency = Fanconi-Bickel |
GLUT2 glucose uniporter (pancreas, liver, kidney) | Loss of GLUT2 traps glucose/galactose in hepatocytes and proximal tubule cells and impairs pancreatic glucose sensing, causing glycogen storage and renal tubular losses. | ↑ Glycogen in liver and kidney ↓ GLUT2 transport |
AR | Hepatomegaly, fasting hypoglycemia with postprandial hyperglycemia, renal Fanconi syndrome (glucosuria, phosphaturia), rickets, growth failure | Glucosuria, aminoaciduria, phosphaturia | |
| G6PD deficiency (incl. favism) FMK 03.1 · slide 03.1: 19, 20, 21, 22, 23, 25; 08.4: 26; handout G6PD A⁻ (African): self-limiting because young RBCs have near-normal enzyme; Mediterranean: severe, near-zero activity in all RBCs |
Glucose-6-phosphate dehydrogenase (rate-limiting HMP shunt enzyme) | RBCs cannot generate NADPH (no other source), so glutathione stays oxidized, H₂O₂ accumulates, hemoglobin denatures into Heinz bodies and rigid RBCs are removed by the spleen → episodic hemolysis under oxidant stress. | ↑ H₂O₂, oxidized glutathione (GSSG), Heinz bodies ↓ NADPH, reduced glutathione (G-SH) |
XR | episodic hemolytic anemia after triggers (infections most common, fava beans/favism, sulfa antibiotics, primaquine/chloroquine, high-dose aspirin, nitrofurantoin), jaundice, dark urine (hemoglobinuria), splenomegaly, neonatal jaundice (1–4 days); most common enzyme deficiency worldwide (>400 million), protective against falciparum malaria | Heinz bodies + bite cells on smear, ↑ unconjugated bilirubin, G6PD enzyme assay (may be falsely normal during acute hemolysis because young RBCs have more enzyme) | Remove trigger, supportive care, transfusion if severe |
| Galactokinase deficiency FMK 03.4 · slide 11, 12, 23, 25, 26 Galactokinase only = CATARACT only (milder) |
Galactokinase | Galactose is not phosphorylated and is instead reduced by aldose reductase to galactitol, an osmotically active polyol trapped in lens fibers that swells the lens and denatures crystallins. | ↑ galactose, galactitol (lens) |
AR | early infantile oil-droplet cataracts, failure to track objects, photophobia; NO liver disease or intellectual disability | galactosuria (reducing sugar) | Dietary restriction of galactose and lactose; cataracts may reverse if treated early |
| Galactosemia (GALT deficiency) FMK 01.2 · slide 01.2: 10; 03.4: 10, 11, 12, 23, 24, 25, 26 GALT deficiency = GALT of all problems (liver, brain, kidneys, eyes, sepsis); E. coli neonatal sepsis = classic clue |
Galactose-1-phosphate uridyltransferase (GALT) | Galactose-1-phosphate cannot be converted to UDP-galactose and accumulates as a direct toxin in liver, brain, kidney and lens; galactose is also shunted to galactitol by aldose reductase. | ↑ Galactose-1-phosphate, galactose, galactitol ↓ UDP-galactose (from galactose) |
AR | days after starting milk: vomiting, poor feeding, jaundice, hepatomegaly, failure to thrive; E. coli neonatal sepsis (galactose impairs WBC function), cataracts, intellectual disability if untreated | Reduced RBC GALT activity, reducing substance in urine | Exclude galactose/lactose from diet |
| GLUT1 deficiency (epileptic disorder) FMK 02.3 · slide 02.3: 15; 02.1: 6 GLUT1 = BBB; deficiency = epileptic disorder |
GLUT1 glucose uniporter (most cells, mainly across the blood-brain barrier) | Deficient GLUT1 limits facilitated diffusion of glucose across the BBB, starving the brain of glucose and causing seizures. | ↓ Brain/CSF glucose |
AD | Infantile-onset epilepsy, developmental delay, movement disorder | Low CSF glucose with normal blood glucose | Ketogenic diet |
| Hereditary fructose intolerance (secondary hyperuricemia) FMK 08.1 · slide 08.1: 19; 03.4: 6, 8, 23, 24, 25, 26 Listed with von Gierke as 'unrelated metabolic diseases with secondary purine overproduction' |
Aldolase B deficiency | Fructose-1-phosphate is trapped, sequestering phosphate and depleting ATP; the resulting AMP degradation drives secondary purine breakdown and uric acid overproduction. | ↑ Fructose-1-phosphate, uric acid ↓ Intracellular phosphate and ATP |
AR | Hypoglycemia, vomiting, hepatomegaly after fructose/sucrose ingestion; hyperuricemia/gout as a secondary purine-overproduction state (per lecture) | reducing sugar in urine, negative glucose oxidase, elevated LFTs, hypoglycemia | Avoid fructose, sucrose, sorbitol |
| Hexokinase deficiency FMK 02.1 · slide 22 |
Hexokinase | Impairing the very first step shuts down all of glycolysis; RBCs are most affected because they have no alternate energy source. | ↓ glucose-6-phosphate, ATP in RBCs |
AR | rare cause of hemolytic anemia | ||
| High-fructose diet: NAFLD, hyperuricemia and metabolic syndrome FMK 03.4 · slide 7 |
Fructose bypasses PFK-1 regulation (fructokinase/aldolase B entry) | Unregulated glycolytic flux generates excess acetyl-CoA → de novo lipogenesis and VLDL export, while fructokinase ATP consumption drives AMP degradation to uric acid. | ↑ triglycerides (liver, VLDL), uric acid ↓ ATP (transient hepatic) |
Acquired | non-alcoholic fatty liver disease, insulin resistance, metabolic syndrome, gout risk, dyslipidemia with sugary beverages/HFCS | hypertriglyceridemia, ↑ uric acid | |
| Lactose intolerance (lactase deficiency) FMK 01.2 · slide 01.2: 10; 01.6: ~20 Undigested disaccharide -> osmotic diarrhea + CO2/CH4/H2 |
Lactase (brush-border alpha-glucosidase/disaccharidase) | Without lactase, lactose is not split into glucose + galactose, passes to the colon where it draws water osmotically and is fermented by bacteria. | ↑ Undigested lactose in gut lumen; bacterial H2, CH4, CO2 gas ↓ Lactase |
Acquired | Osmotic diarrhea, bloating, cramping, flatulence after dairy; ~70% of global population lactose intolerant past infancy | Positive hydrogen breath test (oral tolerance test), stool osmotic gap, acidic stool | Avoid lactose, lactase supplements |
| PFK-1 deficiency (Tarui disease, GSD VII) FMK 02.1 · slide 22 |
Phosphofructokinase-1 (muscle/RBC isoform) | Block at the rate-limiting glycolytic step backs up fructose-6-P and glycogen in muscle and starves RBCs of ATP; AMP catabolism raises uric acid. | ↑ fructose-6-phosphate, glycogen in muscle, uric acid ↓ ATP |
AR | exercise-induced cramps and myopathy, hemolytic anemia, gout | high fructose-6-P, hyperuricemia | |
| Post-infectious (temporary) carbohydrate malabsorption FMK 01.6 · slide ~19 |
Transient mucosal damage after GI infection | Infection damages mucosal cells, temporarily reducing lactase/sucrase and transporter activity. | ↑ Undigested sugars in gut ↓ Brush-border enzymes |
Acquired | Transient diarrhea and bloating after enteric infection | ||
| Pyruvate carboxylase deficiency FMK 03.1 · slide 12 Any condition that depletes OAA or pyruvate (entry points to GNG) → hypoglycemia + lactic acidosis |
Pyruvate carboxylase (biotin-dependent) | Pyruvate cannot be carboxylated to OAA, so pyruvate accumulates as lactate, gluconeogenesis fails and TCA anaplerosis is lost (↓ OAA → ↓ TCA flux in brain). | ↑ pyruvate, lactate, ammonia ↓ oxaloacetate, glucose |
AR | lactic acidosis, hypoglycemia, hyperammonemia, neurologic deficits | ↑ lactate, ↓ glucose, ↑ NH₃ | |
| Pyruvate dehydrogenase complex (PDHC) deficiency FMK 02.1 · slide 16, 24 |
PDH E1α subunit | Pyruvate cannot enter the TCA cycle as acetyl-CoA, so it is shunted to lactate (and alanine) and the brain is starved of TCA-derived energy. | ↑ pyruvate, lactate ↓ acetyl-CoA, ATP in brain |
XD | infancy: lactic acidosis, neurodegeneration, neurologic deficits | ↑ lactate, ↑ pyruvate | Ketogenic diet (ketones bypass PDH) |
| Pyruvate kinase (PK) deficiency FMK 02.1 · slide 02.1: 10, 22, 24, 25; 08.4: handout |
Pyruvate kinase (RBC isoform) | PEP cannot be converted to pyruvate so RBCs, which have no mitochondria and depend entirely on glycolysis, run out of ATP; Na⁺/K⁺-ATPase fails, cells swell and are hemolyzed prematurely. | ↑ PEP and upstream glycolytic intermediates ↓ ATP in RBCs |
AR | most common glycolytic enzyme deficiency; jaundice, pallor, splenomegaly, mild–severe hemolytic anemia (Hb 6–10), may need transfusions; heterozygotes resistant to P. falciparum malaria | echinocytes (burr cells), ↑ reticulocytes, ↑ unconjugated bilirubin | transfusions in severe cases |
| Sucrose intolerance (sucrase-isomaltase deficiency) FMK 01.6 · slide ~20 |
Sucrase-isomaltase (brush-border alpha-glucosidase) | Without sucrase-isomaltase, sucrose (and alpha-1,6 branch products) is not hydrolyzed to glucose + fructose and is fermented in the colon. | ↑ Undigested sucrose in colon; H2/CH4/CO2 gas ↓ Sucrase-isomaltase |
AR | Osmotic diarrhea, bloating, cramping after sucrose; congenital (rare, prevalent in Inuit of Greenland) or acquired from small-intestinal inflammation | Positive hydrogen breath test after sucrose load | Sucrose restriction, enzyme (sacrosidase) supplementation |
Glycogen 6
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Andersen disease (GSD Type IV) FMK 03.6 · slide 22 |
Branching enzyme (4:6 transferase) | Glycogen cannot be branched, producing abnormal poorly soluble amylopectin-like glycogen that damages the liver. | ↑ abnormal unbranched glycogen (polyglucosan) in liver and muscle |
AR | cirrhosis, progressive hepatic failure, death in early childhood | ||
| Cori disease (GSD Type III) FMK 03.6 · slide 22, 25, 30 'Cori = Cuts off at branches' |
Debranching enzyme (4:4 transferase + amylo-α-1,6-glucosidase) | Phosphorylase stops 4 residues from each branch and the stubs cannot be removed, so limit dextrin accumulates; gluconeogenesis is intact so hypoglycemia is milder than GSD I. | ↑ limit dextrin (abnormal glycogen with short outer chains) |
AR | milder fasting hypoglycemia, hepatomegaly, growth retardation, possible muscle weakness | elevated liver enzymes, mild hypoglycemia, abnormal glycogen structure | |
| Hers disease (GSD Type VI) FMK 03.6 · slide 22, 23, 26, 30 'Hers is Her Liver' |
Liver glycogen phosphorylase | Only hepatic glycogenolysis is impaired; gluconeogenesis is intact and compensates, so course is mild. | ↑ glycogen in liver |
AR | mild fasting hypoglycemia, hepatomegaly, growth retardation; generally benign, no cardiac/severe muscle involvement | mild hypoglycemia | |
| McArdle disease (glycogen storage disease type V) FMK 01.2 · slide 01.2: 10; 03.6: 22, 25, 26, 29, 30 McArdle = Muscle |
Muscle glycogen phosphorylase (myophosphorylase) | Muscle cannot mobilize glycogen during exercise so glycogen (normal structure) accumulates and no lactate is produced; liver phosphorylase is intact so blood glucose stays normal. | ↑ Glycogen in skeletal muscle ↓ Glucose-1-phosphate from muscle glycogen during exercise |
AR | exercise intolerance, muscle cramps, myoglobinuria after strenuous exercise, 'second wind' at 8–10 min (switch to blood glucose + FFA) | no rise in blood lactate during forearm exercise test, ↑ CK, normal blood glucose | aerobic warm-up, pre-exercise oral glucose (sucrose 20–40 g) |
| Pompe disease (GSD Type II) FMK 03.6 · slide 22, 24, 29, 30; Lysosomal lecture (Pompe, IOPD, LOPD pages) 'Pompe PUMPS are broken' / 'Pompe Pumps Poorly' — heart pump + muscle pump fail; only LYSOSOMAL GSD |
Lysosomal acid α-1,4-glucosidase (acid maltase, GAA gene) | Glycogen accumulates inside lysosomes of cardiac, smooth and skeletal muscle; lysosomes swell and rupture, replacing myofibrils with glycogen and debris; cytosolic glycogen metabolism is normal so blood glucose is normal. | ↑ glycogen in lysosomes of heart, muscle, liver |
AR | infantile-onset (IOPD): massive cardiomegaly (92% by 4 months), profound hypotonia/'floppy infant', head lag, feeding problems, macroglossia, moderate hepatomegaly, respiratory failure, death by ~10 months untreated; late-onset (LOPD): limb-girdle pattern weakness, early diaphragm/respiratory weakness, restrictive lung disease, heart relatively spared | normal blood glucose, ↑ CK/CPK, GAA enzyme assay on dried blood spot, GAA genetic testing | Enzyme replacement therapy with recombinant α-glucosidase (alglucosidase alfa / Myozyme); gene therapy in trials |
| Von Gierke disease (GSD type I; secondary hyperuricemia) FMK 08.1 · slide 08.1: 19; 03.6: 22, 23, 29, 30; FMK 03.1 slide 12, 21, 22, 23 Listed with hereditary fructose intolerance as 'unrelated metabolic diseases with secondary purine overproduction' |
Glucose-6-phosphatase deficiency | Glucose-6-phosphate cannot be dephosphorylated, so it is shunted into the HMP pathway raising ribose-5-P/PRPP and purine synthesis, while lactic acidosis competitively reduces renal urate excretion — both raise uric acid. | ↑ Glucose-6-phosphate, glycogen, lactate, uric acid ↓ Free glucose (fasting hypoglycemia) |
AR | Severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia/gout, hyperlipidemia | hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia/hypertriglyceridemia | Frequent oral glucose/cornstarch; allopurinol for hyperuricemia |
Lipid 23
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Abetalipoproteinemia FMK 04.4 · slide 12, 28 Pharmacologic parallel: MTP inhibitor lomitapide — same mechanism, therapeutic intent |
Microsomal triglyceride transfer protein (MTP) | Without MTP, lipid cannot be loaded onto apo B-48/B-100 so no chylomicrons or VLDL are assembled; lipid and fat-soluble vitamins accumulate in enterocytes/hepatocytes instead of being secreted. | ↑ lipid in enterocytes and hepatocytes ↓ chylomicrons, VLDL, LDL, plasma cholesterol/TAG, vitamin E (and other fat-soluble vitamins) |
AR | fat malabsorption, steatorrhea, vomiting, failure to thrive, vitamin E deficiency (ataxia, areflexia) | acanthocytes on smear, very low cholesterol and TAG | |
| Alcoholic ketoacidosis (AKA) FMK 03.4 · slide 17, 21, 26 |
↑ NADH + low insulin/high glucagon after binge with poor nutrition | Impaired gluconeogenesis keeps insulin low and glucagon high, driving lipolysis and ketogenesis; the high NADH shifts acetoacetate to β-hydroxybutyrate. | ↑ β-hydroxybutyrate (β-OHB/acetoacetate ratio ↑↑), acetoacetate ↓ glucose, glycogen |
Acquired | chronic drinker + poor nutrition + recent binge + abstinence/withdrawal | anion-gap metabolic acidosis, ↑ ketones (nitroprusside test may be falsely negative — misses β-OHB), glucose often normal or low (unlike DKA) | IV fluids + glucose + thiamine; no insulin needed |
| Alcoholic liver disease (steatosis → hepatitis → fibrosis → cirrhosis) FMK 03.4 · slide 17, 20, 23, 25, 26; FMK 04.4 slide 26 FA β-oxidation blocked + Glycerol-3-P increased → Triglycerides accumulate |
↑ NADH/NAD⁺ from ADH/ALDH; CYP2E1-derived ROS | Excess NADH pushes DHAP → glycerol-3-P and inhibits β-oxidation (3-hydroxyacyl-CoA DH), so fatty acids are re-esterified to triglycerides and accumulate as macrovesicular steatosis; ROS from MEOS drives progression to hepatitis and cirrhosis. | ↑ NADH, triglycerides in hepatocytes, glycerol-3-phosphate, ketone bodies ↓ NAD⁺, pyridoxal phosphate (ALT), B12/folate |
Acquired | reversible fatty liver → alcoholic hepatitis (potentially reversible) → fibrosis (partially) → cirrhosis (irreversible) | AST > ALT (≥2:1), ↑ GGT (sensitive marker), ↑ bilirubin, ↑ INR, ↑ MCV (macrocytosis from B12/folate deficiency) | Abstinence; supportive care |
| CPT I deficiency FMK 05.4 · slide 18, 20; FMK 05.6 slide 18 Same shuttle, two checkpoints, two clinical pictures |
Carnitine palmitoyltransferase I (outer mitochondrial membrane, hepatic isoform; malonyl-CoA-regulated gatekeeper) | Long-chain fatty acids cannot be converted to acylcarnitine for entry into hepatic mitochondria, so fasting β-oxidation and ketogenesis fail; muscle is spared because the affected isoform is hepatic. | ↑ long-chain fatty acyl-CoA (cytosolic) ↓ acylcarnitines (low), ketones, glucose |
AR | infancy, hepatic: hypoketotic hypoglycemia, hepatomegaly triggered by fasting; muscle spared | hypoketotic hypoglycemia, low acylcarnitines | Avoid fasting; high-carbohydrate, low long-chain-fat diet; MCT oil bypasses the transport step |
| CPT II deficiency FMK 05.4 · slide 18, 20; FMK 05.6 slide 18 CPT I = outer membrane gatekeeper (malonyl-CoA); CPT II = inner membrane, regenerates acyl-CoA |
Carnitine palmitoyltransferase II (inner mitochondrial membrane, predominant muscle isoform) | Acylcarnitine enters the matrix but cannot be reconverted to fatty acyl-CoA, so muscle cannot burn long-chain fat during prolonged exercise or fasting → rhabdomyolysis. | ↑ long-chain acylcarnitines ↓ muscle fatty acyl-CoA for β-oxidation |
AR | classic adult form: recurrent exercise- or fasting-induced muscle pain, rhabdomyolysis, myoglobinuria in adolescence/adulthood; infantile form: cardiomyopathy | ↑ CK during episodes, myoglobinuria, characteristic long-chain acylcarnitine elevation | Avoid fasting, prolonged/intense exercise and cold exposure; high-carb low-LCFA diet; MCT oil |
| Diabetic ketoacidosis (DKA) FMK 05.6 · slide 2, 3, 5, 6; FMK 05.4 slide 7; FMK 04.4 slide 25 What single hormonal derangement explains every value? Insulin deficiency |
Absolute insulin deficiency (uncontrolled Type 1 diabetes) with unopposed glucagon | Without insulin, HSL-driven lipolysis floods the liver with NEFA, β-oxidation generates acetyl-CoA beyond TCA capacity (OAA diverted to gluconeogenesis), so ketone bodies are produced, exceeding buffering capacity and causing anion-gap acidosis with Kussmaul respirations. | ↑ glucose, β-hydroxybutyrate, acetoacetate, acetone, NEFA (~2 mEq/L), triglycerides, K⁺ (serum) ↓ insulin, HCO₃⁻, total body K⁺/Na⁺ |
Acquired | 14-year-old with polyuria, polydipsia, weight loss, nausea/vomiting, abdominal pain, confusion, deep rapid (Kussmaul) breathing, fruity breath (acetone), tachycardia, hypotension | glucose 489, HCO₃ 12, anion gap 24, pH 7.22, pCO₂ 20, β-OHB 8.3, Na 128, K 5.8, TG 519, urine glucose 4+ and ketones 4+ | insulin, IV fluids, potassium |
| Dysbetalipoproteinemia (Type III hyperlipoproteinemia) FMK 04.4 · slide 29 |
Apo E2/E2 genotype | Apo E2 binds hepatic remnant receptors poorly, so chylomicron and VLDL remnants (IDL) accumulate. | ↑ chylomicron remnants, VLDL remnants (IDL) ↓ functional apo E |
AR | palmar xanthomas, premature atherosclerosis | ↑ remnants/IDL (↑ cholesterol and TAG) | |
| Familial chylomicronemia / LPL deficiency (Type I hyperlipoproteinemia) FMK 04.4 · slide 18, 29; FMK 05.1 slide 23 |
Lipoprotein lipase (LPL) or its cofactor apo C-II | Without LPL activity, TAG cannot be stripped from chylomicrons (and VLDL), so chylomicrons persist in fasting plasma; particles are too large to enter the intima so atherosclerosis risk is NOT increased. | ↑ chylomicrons, triglycerides ↓ FFA delivery to tissues |
AR | recurrent pancreatitis, eruptive xanthomas, lipemia retinalis, lipemic serum | fasting chylomicron-TAG >1000 mg/dL | Dietary fat restriction (NOT statins — statins don't touch chylomicron-TAG) |
| Familial hypercholesterolemia (FH) FMK 01.2 · slide 01.2: 12, 14; 05.1: 12, 23; FMK 04.4 slide 29 Five LDLR mutation classes: null, transport, binding, internalization, recycling |
LDL receptor (LDLR gene, 19p13.2), >2,000 mutations; Class I null, II transport defect (most common), III binding defect (ApoB cannot bind), IV internalization defect, V recycling defect | Defective LDL receptors cannot clear LDL from plasma, so LDL-C rises markedly and cholesterol deposits in vessel walls (foam cells -> fatty streaks -> fibrous plaques) and tendons. | ↑ Plasma LDL cholesterol; cholesterol in vessel walls, tendons, periorbital skin ↓ Functional LDL receptors |
AD | Premature atherosclerosis and coronary disease, tendon xanthomas, xanthelasma; 1:250 heterozygous (most common single-gene disorder) | Markedly elevated LDL-C | Statins (block HMG-CoA reductase), PCSK9 inhibitors |
| Gallstones (cholesterol cholelithiasis) FMK 05.1 · slide 2, 14 |
Disrupted cholesterol : bile-acid : phospholipid ratio in bile | Stones form when bile's cholesterol/bile-acid/phospholipid ratio is disrupted — not from too much cholesterol alone; fibrates raise stone risk by increasing biliary cholesterol secretion. | ↑ cholesterol in bile (supersaturation) ↓ bile acids relative to cholesterol |
Acquired | severe RUQ pain after a fatty meal (case: Elena, 54, on a statin) | ||
| Hypertriglyceridemia (pancreatitis risk; metabolic syndrome) FMK 01.2 · slide 12 TG > 500 = pancreatitis risk |
Excess plasma triglycerides (>500 mg/dL) | Very high triglyceride-rich lipoproteins are hydrolyzed by pancreatic lipase to toxic free fatty acids that injure acinar cells, causing pancreatitis. | ↑ Serum triglycerides |
Acquired | Pancreatitis risk when TG >500 mg/dL, seen in metabolic syndrome, eruptive xanthomas | Triglycerides >500 mg/dL, lipemic serum | Fibrates, omega-3 fatty acids, dietary fat restriction |
| Hypertriglyceridemia and hepatic steatosis from excess VLDL secretion FMK 04.4 · slide 25, 26 |
Sustained ↑ hepatic TAG synthesis/VLDL secretion (fed state, high-carbohydrate diet, high FFA flux, ethanol, high insulin/glucagon ratio) | Excess acetyl-CoA from carbohydrate and circulating FFA is esterified to TAG faster than it can be exported, producing hypertriglyceridemia and fatty liver. | ↑ triglycerides (plasma VLDL and hepatocytes) |
Acquired | fatty liver, hypertriglyceridemia in overfeeding, uncontrolled DM, alcohol use | ↑ TAG; NEFA fed very low → starved 0.7–0.8 → uncontrolled DM ~2 mEq/L | |
| LCAT deficiency (fish-eye disease) FMK 04.4 · slide 30 |
Lecithin:cholesterol acyltransferase | Cholesterol on HDL cannot be esterified, so discoid HDL never matures and free cholesterol deposits in the cornea. | ↑ free (unesterified) cholesterol ↓ cholesteryl esters on HDL, mature HDL |
AR | corneal opacities | low HDL | |
| MCAD deficiency FMK 05.4 · slide 2, 5, 18, 19; FMK 05.6 slide 16, 18 Hypoglycemia + absent ketones = block in fatty acid oxidation (vs starvation: hypoglycemia + HIGH ketones) |
Medium-chain acyl-CoA dehydrogenase (first step of β-oxidation for C6–C10 fatty acids) | Fatty acid oxidation stalls at medium-chain length so the fasting liver cannot make acetyl-CoA for ketogenesis or ATP for gluconeogenesis, producing hypoketotic hypoglycemia; most common inherited FAO disorder. | ↑ medium-chain acylcarnitines (C8 octanoylcarnitine), medium-chain fatty acids ↓ ketone bodies, acetyl-CoA, glucose, ATP |
AR | infant/toddler unmasked by fasting stress (viral illness with vomiting, overnight fast): lethargy, vomiting, hepatomegaly, seizures, coma, sudden death (case: 14-month-old, glucose 32, ketones trace/negative) | hypoketotic hypoglycemia (inappropriately low/absent urine ketones), acylcarnitine profile with ↑ C8 on newborn screen (tandem MS) | Avoid prolonged fasting; IV dextrose during acute illness; newborn screening |
| Neonatal respiratory distress syndrome (surfactant/DPPC deficiency) FMK 01.2 · slide 01.2: 12; 04.1: 10, 23 L/S ratio > 2 = lungs ready |
Dipalmitoylphosphatidylcholine (DPPC) lung surfactant deficiency in preterm infants | Immature type II pneumocytes make too little DPPC surfactant, so alveolar surface tension is high and alveoli collapse. | ↓ DPPC (lecithin) surfactant |
Acquired | Preterm neonate with tachypnea, grunting, retractions, cyanosis shortly after birth | Low lecithin:sphingomyelin ratio in amniotic fluid (<2), ground-glass CXR | Antenatal steroids, exogenous surfactant, CPAP |
| Primary (systemic) carnitine deficiency FMK 05.4 · slide 18, 21; FMK 05.6 slide 18 LOW free carnitine → transporter defect; normal-to-high specific acylcarnitine species → enzyme block downstream |
OCTN2 plasma-membrane carnitine transporter | Impaired cellular carnitine uptake plus renal carnitine wasting means fatty acyl-CoA can never be converted to acylcarnitine — the shuttle has no vehicle — so long-chain FAO fails in liver, heart and muscle. | ↑ fatty acyl-CoA (cytosol), lipid in heart/muscle ↓ plasma free carnitine (very low), acylcarnitines (low overall), ketones, glucose |
AR | infancy to early childhood: hypoketotic hypoglycemia, hepatomegaly, hypotonia; progresses to dilated cardiomyopathy and skeletal myopathy (cardiac phenotype distinguishes it) | very low plasma free carnitine; acylcarnitine profile low overall (vs high specific species in MCAD/CPT) | High-dose oral L-carnitine — most directly treatable FAO disorder; can reverse cardiomyopathy if started early |
| Refsum disease FMK 05.6 · slide 19 |
Phytanoyl-CoA hydroxylase (peroxisomal α-oxidation) | Branched-chain phytanic acid (from dietary chlorophyll) cannot be α-oxidized and accumulates in nerve, retina and skin. | ↑ phytanic acid |
AR | retinitis pigmentosa, peripheral neuropathy, ataxia, anosmia | ↑ phytanic acid | Diet-manageable (avoid phytanic acid / chlorophyll-rich foods) |
| SCAD deficiency FMK 05.6 · slide 15, 18 |
Short-chain acyl-CoA dehydrogenase | Short-chain fatty acyl-CoAs cannot be dehydrogenated; often clinically silent because most energy has already been extracted from longer chains. | ↑ short-chain acylcarnitines (C4; textbook: ethylmalonic acid) |
AR | often mild or asymptomatic | acylcarnitine profile | |
| Tangier disease FMK 04.4 · slide 24, 30; FMK 05.1 slide 23 Low HDL alone does not always predict atherosclerosis risk in this disorder — an important nuance |
ABCA1 transporter | No cholesterol efflux to nascent pre-β HDL, so HDL cannot mature and is rapidly degraded; cholesteryl esters accumulate in macrophages. | ↑ cholesteryl esters in macrophages (tonsils, liver, spleen, nerves) ↓ plasma HDL |
AR | large orange-yellow tonsils, hepatosplenomegaly, peripheral neuropathy, premature atherosclerosis despite normal LDL | ↓↓ HDL with normal-to-low LDL | |
| Trans-fat induced dyslipidemia FMK 01.2 · slide 01.2: 12; 04.1: 6, 23 Trans = acts saturated; omega-3 competes with arachidonic acid for the same enzymes |
Dietary trans fatty acids | Trans acyl chains pack like saturated fat despite the double bond, and trans-fat intake is linked to increased cardiovascular disease and type 2 diabetes risk. | ↑ LDL cholesterol ↓ HDL cholesterol |
Acquired | increased cardiovascular disease and type 2 diabetes risk | Increased LDL, decreased HDL | Dietary avoidance |
| VLCAD deficiency FMK 05.6 · slide 15, 18 Unifying pattern of mitochondrial FAO disorders: fasting HYPOKETOTIC hypoglycemia |
Very-long-chain acyl-CoA dehydrogenase | Very-long-chain fatty acids cannot begin mitochondrial β-oxidation, causing MCAD-like fasting hypoketotic hypoglycemia plus energy failure in heart and muscle. | ↑ very-long-chain acylcarnitines (C14–C18; textbook) ↓ ketones, glucose, ATP in heart/muscle |
AR | MCAD-like hypoketotic hypoglycemia plus cardiomyopathy and rhabdomyolysis | acylcarnitine profile on newborn screen | |
| X-linked adrenoleukodystrophy (X-ALD) FMK 05.6 · slide 13, 19 |
ABCD1 transporter — defective VLCFA import across the peroxisomal membrane | VLCFAs cannot enter the peroxisome for β-oxidation and accumulate in myelin and adrenal cortex, causing demyelination and adrenal failure. | ↑ very-long-chain fatty acids ↓ adrenal steroids (Addison disease) |
XR | progressive demyelination, adrenal insufficiency (Addison disease) | ↑ plasma VLCFA | |
| Zellweger syndrome FMK 04.1 · slide 04.1: 13; 05.6: 13, 19 Plasmalogens are made in peroxisomes (vinyl-ether at sn-1) |
Peroxisome biogenesis (PEX genes) | Absent functional peroxisomes prevents plasmalogen synthesis (and very-long-chain fatty acid oxidation), causing neurologic and cardiac dysfunction. | ↑ Very-long-chain fatty acids ↓ Plasmalogens (ether phospholipids) |
AR | neurologic problems, cardiac problems, hypotonia, craniofacial dysmorphism, early death | Elevated plasma VLCFA |
Amino acid 18
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Albinism (oculocutaneous albinism type 1, OCA1) FMK 07.2 · slide 5, 11, 12, 15, 27 Hypopigmentation + photophobia; albinism = melanin not made, PKU = melanin inhibited |
Absent/defective copper-requiring tyrosinase (tyrosine → L-DOPA → DOPA-quinone in melanocytes) | Defective melanin synthesis inside melanocytes — a true synthesis defect, unlike PKU's hypopigmentation which is competitive inhibition of tyrosinase by excess Phe. | ↓ Melanin in skin, hair, eyes |
AR | Partial or complete absence of pigment in skin, hair, eyes; photophobia; vision defects (melanin needed for retinal/optic nerve development) | ||
| Alkaptonuria FMK 07.2 · slide 07.2: 5, 10, 12, 15, 27; 07.1: 25 Dark-on-standing urine (vs cabbage odor in tyrosinemia I); arthritis at 40 |
Homogentisate oxidase deficiency (homogentisate → maleylacetoacetate block in tyrosine degradation) | Homogentisic acid accumulates, is excreted in urine where it oxidizes to a dark pigment, and deposits over decades as black pigment in cartilage and collagenous tissue. | ↑ Homogentisic acid |
AR | Urine darkens on standing (especially with alkalinization), ochronosis (black pigment in cartilage/connective tissue), early-onset arthritis of large joints; symptom onset ~age 40 | Homogentisic aciduria — urine darkens on standing/alkalinization | Dietary restriction of phenylalanine and tyrosine |
| BH₄-deficient hyperphenylalaninemia (dihydropteridine reductase / DHPR deficiency, variant PKU) FMK 07.2 · slide 07.2: 2, 6, 8, 12, 27; 07.1: 25, 26 One cofactor, three hydroxylases: diet controls one, this defect silences three |
Dihydropteridine reductase (DHPR), which regenerates tetrahydrobiopterin (BH₄) from BH₂ | BH₄ cannot be recycled, starving phenylalanine hydroxylase AND tyrosine hydroxylase AND tryptophan hydroxylase, so dopamine/norepinephrine/epinephrine and serotonin synthesis fail even when dietary Phe control normalizes phenylalanine. | ↑ Phenylalanine (unless diet-restricted); BH₂ ↓ BH₄; dopamine, norepinephrine, epinephrine, serotonin |
AR | Infant on a perfect low-Phe diet with normal Phe still develops truncal hypotonia, stiff limbs, movement disorder, difficulty swallowing, seizures — progressive neurologic decline despite biochemical improvement | Phe falls on diet yet neurologic symptoms progress | Poor response to low-Phe diet alone |
| Carbamoyl phosphate synthetase I (CPS-I) deficiency FMK 07.1 · slide 18, 19 Low citrulline like OTC but NO orotic acid |
Carbamoyl phosphate synthetase I (mitochondrial, rate-limiting urea cycle enzyme requiring N-acetylglutamate) | Ammonia cannot be incorporated into carbamoyl phosphate, so urea synthesis fails at its first step and ammonia accumulates without orotic acid spillover. | ↑ Ammonia ↓ Carbamoyl phosphate, citrulline (low), urea |
AR | Rare neonatal hyperammonemia (lethargy, vomiting, seizures, coma) | Hyperammonemia, LOW citrulline, low/normal orotic acid | Protein restriction, nitrogen scavengers |
| Citrullinemia (argininosuccinate synthetase deficiency) FMK 07.1 · slide 19, 32 Sky-high citrulline → look downstream at argininosuccinate synthetase |
Argininosuccinate synthetase (cytosolic; citrulline + aspartate → argininosuccinate) | Block downstream of citrulline formation causes citrulline to accumulate to very high levels while ammonia disposal fails. | ↑ Citrulline (very high), ammonia ↓ Argininosuccinate, arginine, urea |
AR | Rare neonatal hyperammonemia | Hyperammonemia with VERY HIGH citrulline; orotic acid variable | Protein restriction, nitrogen scavengers |
| Cystathioninuria FMK 07.1 · slide 28, 31, 32 Cystathioninuria = enzyme defect, benign |
Cystathioninase (cystathionine γ-lyase, downstream of CBS; B6-dependent) | Cystathionine cannot be hydrolyzed to cysteine + α-ketobutyrate, so it accumulates and spills into urine. | ↑ Cystathionine (urine) ↓ Cysteine (mild) |
AR | Generally benign — often an incidental finding | Cystathionine in urine | |
| Cystinuria FMK 07.1 · slide 7, 31, 32 COAL transporter; hexagonal crystals; a transporter defect — not an enzyme defect like homocystinuria |
Defective COAL transporter (Cystine, Ornithine, Arginine, Lysine — dibasic amino acids + cystine) in intestine and renal proximal tubule | Failure to reabsorb cystine and dibasic amino acids lets poorly soluble cystine precipitate in urine as stones. | ↑ Cystine, ornithine, arginine, lysine in urine |
AR | Recurrent kidney stones; most common inherited amino acid transport disorder (~1 in 7,000) | Hexagonal crystals on urinalysis = cystine stones | |
| Hartnup disease FMK 07.1 · slide 7 'Niacin deficiency without a niacin-poor diet'; 3 Ds |
Defective neutral amino acid transporter (gut and kidney) — tryptophan uptake impaired | Reduced tryptophan absorption limits endogenous niacin (vitamin B3) synthesis, producing pellagra-like symptoms. | ↑ Neutral amino acids in urine ↓ Tryptophan, niacin (NAD) |
AR | Pellagra-like dermatitis, diarrhea, dementia (classic triad); neurologic symptoms | Neutral aminoaciduria | Niacin supplementation |
| Histidinemia FMK 07.1 · slide 23 |
Histidase (histidine ammonia-lyase) deficiency | Histidine cannot be deaminated to urocanate on its route to glutamate/α-ketoglutarate, so histidine accumulates. | ↑ Histidine |
AR | Generally benign | Elevated plasma/urine histidine | |
| Homocystinuria (cystathionine β-synthase deficiency) FMK 07.2 · slide 07.2: 13, 15; 07.1: 28, 31, 32 Name ≠ mechanism: enzyme defect with systemic disease (vs cystinuria transporter, cystathioninuria benign); lens down, thrombosis |
Cystathionine β-synthase (B6/PLP-dependent transsulfuration enzyme: homocysteine + serine → cystathionine) | Homocysteine cannot enter transsulfuration, so it accumulates (spilling into urine) and is remethylated to excess methionine while downstream cysteine is starved; homocysteine damages connective tissue and endothelium. | ↑ Homocysteine (plasma and urine), methionine ↓ Cysteine (low plasma), cystathionine |
AR | Lens dislocation (ectopia lentis, downward), marfanoid habitus, skeletal abnormalities, intellectual disability/developmental delay, thrombosis (leading cause of death) | High urinary and plasma homocysteine, high plasma methionine, low plasma cysteine | Methionine restriction + folate and vitamin B12 supplementation (supports remethylation escape route); textbook: B6 in responsive forms, cysteine supplementation |
| Hyperammonemia FMK 07.1 · slide 2, 13, 17, 18 Brain has no urea cycle — glutamine synthetase is its only ammonia sink, so hyperammonemia hits the brain hardest |
Acquired: liver disease (viral hepatitis, hepatotoxins, liver failure with gut urease-derived ammonia reabsorption); Congenital: deficiency of any urea cycle enzyme or NAG synthase | Ammonia the liver cannot convert to urea accumulates and is neurotoxic; astrocytes swell as they buffer ammonia via glutamine synthesis (osmotic stress) → cerebral edema. | ↑ Ammonia (normal 5–35 µmol/L, can exceed 1,000), brain glutamine ↓ Urea synthesis capacity |
Acquired | Tremor, slurred speech, drowsiness, vomiting, blurred vision, lethargy, poor feeding, tachypnea, seizures → cerebral edema, coma, death; medical emergency | Blood ammonia > 35 µmol/L; normal glucose, no infection | ↓ dietary protein; replace missing enzyme; nitrogen scavengers — phenylbutyrate (→ phenylacetylglutamine) or benzoate (→ hippurate via glycine) |
| Maple syrup urine disease (MSUD) FMK 07.2 · slide 07.2: 07.2: 14, 15; 07.1: 29, 33; 02.4: 18 One complex handles all three BCAAs; odor from isoleucine, coma from leucine |
Branched-chain α-ketoacid dehydrogenase (BCKD) complex — partial or complete deficiency (a PDH-like multienzyme complex) | Oxidative decarboxylation of all three branched-chain α-ketoacids is blocked by one shared complex, so leucine, isoleucine, valine and their ketoacids accumulate simultaneously; leucine is neurotoxic. | ↑ Leucine, isoleucine, valine and their branched-chain α-ketoacids |
AR | Feeding problems, ketoacidosis, altered muscle tone, coma (from elevated leucine), maple-syrup urine odor (from isoleucine); fatal if untreated; intellectual disability if treatment delayed | Newborn screening; elevated plasma BCAAs and ketoacids; ketoacidosis | Synthetic BCAA-free formula with limited Leu/Ile/Val — enough for growth, not enough for toxicity |
| Maternal PKU syndrome FMK 07.2 · slide 7 |
High maternal phenylalanine in a pregnant PKU patient not on a restricted diet | Fetal exposure to teratogenic maternal phenylalanine levels damages development even when the fetus does not have PKU. | ↑ Maternal (and fetal) phenylalanine |
Acquired | Microcephaly and congenital heart abnormalities in the infant | Strict pre-conception and lifelong dietary Phe restriction for all PKU patients | |
| N-acetylglutamate synthase deficiency FMK 07.1 · slide 16, 18, 32 No NAG, no urea synthesis |
N-acetylglutamate synthase (makes NAG, the obligate allosteric activator of CPS-I) | Without NAG, CPS-I is inactive, so the urea cycle cannot start and congenital hyperammonemia results (mimics CPS-I deficiency). | ↑ Ammonia ↓ N-acetylglutamate; carbamoyl phosphate; urea |
AR | Congenital hyperammonemia | Hyperammonemia, low citrulline | Textbook: carglumic acid (NAG analog) |
| Ornithine transcarbamylase (OTC) deficiency FMK 07.1 · slide 07.1: 2, 15, 18, 19, 32; 08.1: 23, 26, 28, 29 Orotic aciduria WITH hyperammonemia = OTC; X-linked is 'unique' among UCDs; citrulline is your compass |
Ornithine transcarbamylase (mitochondrial urea cycle enzyme, carbamoyl phosphate + ornithine → citrulline) | Carbamoyl phosphate made by CPS-I cannot combine with ornithine, backs up, leaks to the cytosol and feeds aspartate transcarbamylase in pyrimidine synthesis, overproducing orotic acid while ammonia accumulates. | ↑ Ammonia, carbamoyl phosphate, orotic acid (orotic aciduria) ↓ Citrulline (low), urea |
XR | Most common urea cycle disorder; full-term newborn normal at birth (maternal clearance in utero), then at 24–48 h lethargy, refusal to feed, tachypnea, seizures, vomiting → coma | Elevated serum ammonia AND elevated urinary orotic acid (distinguishes from hereditary orotic aciduria, where ammonia is normal); low BUN | Protein restriction + nitrogen-scavenger drugs (phenylbutyrate, benzoate) that bypass the enzyme |
| Phenylketonuria (classic PKU) FMK 07.2 · slide 07.2: 2, 5, 6, 7, 12, 15; 07.1: 25, 26 Musty odor; diet fixes classic PKU but not DHPR deficiency |
Phenylalanine hydroxylase (PAH) deficiency (~98%; BH₄-requiring enzyme converting Phe → Tyr) | Phenylalanine cannot be hydroxylated to tyrosine, so it accumulates and is shunted to phenylketones while tyrosine becomes conditionally essential; excess Phe also competitively inhibits tyrosinase, reducing melanin. | ↑ Phenylalanine; phenylpyruvate, phenylacetate, phenyllactate in urine ↓ Tyrosine; melanin (secondary tyrosinase inhibition) |
AR | No neonatal symptoms; untreated: severe intellectual disability, developmental delay, microcephaly, seizures; fair hair, light skin, blue eyes; musty urine odor; 1:15,000, most common inborn error of amino acid metabolism | Newborn screening 24–48 h after protein feeding begins; ↑ plasma Phe; phenylketones in urine | Dietary Phe restriction started within 7–10 days of life and continued lifelong; tyrosine supplementation |
| Primary hyperoxaluria type I FMK 07.1 · slide 24 |
Deficiency of liver peroxisomal transaminase (alanine-glyoxylate aminotransferase) that converts glyoxylate back toward glycine/pyruvate | Glycine oxidized by D-amino acid oxidase to glyoxylate cannot be recycled, so glyoxylate is shunted to oxalate, which precipitates as calcium oxalate in the kidney. | ↑ Glyoxylate, oxalate |
AR | Calcium oxalate renal stones, progressive renal damage | Hyperoxaluria; calcium oxalate stones | |
| Tyrosinemia type I FMK 07.2 · slide 07.2: 5, 10, 12, 27; 07.1: 25 Cabbage odor = tyrosinemia; dark urine = alkaptonuria |
Fumarylacetoacetate hydrolase deficiency (fumarylacetoacetate → fumarate + acetoacetate block) | Block at the last step of tyrosine degradation causes toxic upstream metabolites (fumarylacetoacetate and, by textbook, succinylacetone) to accumulate and damage the liver. | ↑ Fumarylacetoacetate/maleylacetoacetate, tyrosine |
AR | Cabbage-like urine odor, severe liver disease | Cabbage-like urine odor | Textbook: nitisinone (NTBC), dietary Phe/Tyr restriction |
Nucleotide 9
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Adenosine deaminase (ADA) deficiency — SCID FMK 08.1 · slide 2, 17, 28, 29 Baby Sophia — a defect in recycling a nucleotide breakdown product wipes out the immune system. ADA deficiency = more common and more severe than PNP deficiency (T + B + NK loss). |
Adenosine deaminase (purine degradation: adenosine -> inosine) | Without ADA, adenosine and deoxyadenosine accumulate and are converted to dATP, which allosterically inhibits ribonucleotide reductase, halting synthesis of ALL dNTPs and causing developmental arrest and apoptosis of lymphocyte precursors (lymphocytes have the highest ADA activity of any cell type). | ↑ Adenosine, deoxyadenosine, dATP ↓ All deoxyribonucleotides (dNTPs) in lymphocytes; T, B, and NK cells |
AR | Severe combined immunodeficiency: recurrent infections (e.g., third pneumonia at 4 months), absent thymic shadow on chest X-ray, failure to thrive; fatal by ~age 2 if untreated | Critically low absolute lymphocyte count (T, B, and NK cells depleted); elevated dATP | Enzyme replacement (PEG-ADA), hematopoietic stem cell transplant, gene therapy |
| APRT (adenine phosphoribosyltransferase) deficiency FMK 08.1 · slide 13 APRT = Adenine; HGPRT = Hypoxanthine + Guanine |
Adenine phosphoribosyltransferase (purine salvage: adenine + PRPP -> AMP) | Adenine cannot be salvaged to AMP and is instead oxidized by xanthine oxidase to the very insoluble 2,8-dihydroxyadenine, which precipitates in the urinary tract. | ↑ Adenine, 2,8-dihydroxyadenine ↓ Salvaged AMP |
AR | 2,8-dihydroxyadenine kidney stones; much milder than HGPRT deficiency | 2,8-dihydroxyadenine crystals/stones | Allopurinol |
| Gout FMK 08.1 · slide 2, 18, 19, 20, 27, 28 Mr. Alvarez, 52: great toe at 2 AM that cannot tolerate a bedsheet = podagra. Purines -> insoluble uric acid -> crystal disease; pyrimidines -> soluble products -> no crystal disease. |
Multifactorial hyperuricemia (uric acid overproduction and/or underexcretion); humans lack urate oxidase so uric acid is the insoluble end product of purine degradation | Hyperuricemia supersaturates joint fluid, monosodium urate (MSU) crystals deposit in and around joints, and the inflammatory response to the crystals drives acute gouty arthritis; recurrent attacks lead to chronic tophaceous gout. | ↑ Uric acid / monosodium urate crystals (joints, renal collecting system) |
Acquired | Podagra (hot, swollen, exquisitely tender first MTP joint, classically waking the patient at ~2 AM), painful monoarthritis, tophi, urate nephrolithiasis (kidney stones) | Needle-shaped, negatively birefringent MSU crystals in aspirated synovial fluid under polarized light microscopy (gold standard, distinguishes from pseudogout and septic arthritis); serum uric acid above saturation (~6.5 mg/dL) | Acute: colchicine, NSAIDs (indomethacin), or glucocorticoids (prednisolone); chronic under-excretors: uricosurics (probenecid, sulfinpyrazone); chronic over-producers: allopurinol (xanthine oxidase inhibitor); rasburicase for tumor lysis syndrome |
| Hereditary orotic aciduria (UMP synthase deficiency) FMK 07.1 · slide 07.1: 15; 08.1: 22, 26, 27, 28 Orotic aciduria + hyperammonemia = OTC; orotic aciduria without hyperammonemia + megaloblastic anemia = UMP synthase deficiency |
UMP synthase (de novo pyrimidine synthesis) | Orotate cannot be converted to UMP, so orotic acid accumulates and spills into urine while the cell is starved of pyrimidine nucleotides for RNA/DNA synthesis, hitting rapidly dividing bone marrow hardest; the defect is entirely within pyrimidine synthesis, so ammonia handling is normal. | ↑ Orotic acid ↓ UMP / pyrimidines |
AR | Megaloblastic anemia unresponsive to B12/folate, failure to thrive / poor growth in infancy, orotic acid crystals in urine, normal ammonia | Massive orotic aciduria with orotic acid crystals; megaloblastic anemia; NORMAL serum ammonia (contrast with OTC deficiency) | Uridine |
| Hyperuricemia — underexcretion (primary and secondary) FMK 08.1 · slide 19, 20 Underexcretion = >90% of cases; overproduction = <10% |
Renal urate excretory defect: primary/idiopathic, or secondary to lactic acidosis, thiazide diuretics, other drug/environmental factors | Reduced renal excretion of uric acid (>90% of hyperuricemia cases); lactic acidosis competitively increases renal urate reabsorption and thiazides impair urate excretion, raising serum urate toward the crystallization threshold. | ↑ Uric acid (serum) |
Acquired | Usually asymptomatic until gout or urate nephrolithiasis develops | Elevated serum uric acid | Uricosuric agents (probenecid, sulfinpyrazone) to increase renal uric acid excretion; goal serum urate below saturation point (~6.5 mg/dL) |
| Lesch-Nyhan syndrome FMK 08.1 · slide 2, 13, 14, 28, 29 Ethan, age 3, biting his fingers and lips until they bleed with high uric acid — one missing enzyme causes both gout AND self-injury. Salvage matters most where de novo synthesis is limited (brain, marrow). |
Complete deficiency of HGPRT (hypoxanthine-guanine phosphoribosyltransferase), the purine salvage enzyme | Hypoxanthine and guanine cannot be salvaged to IMP/GMP, so they accumulate and are degraded to uric acid; unconsumed PRPP stays elevated and IMP/GMP fall, both disinhibiting GPAT and driving even more de novo purine synthesis, compounding uric acid production; brain, marrow and RBCs rely on salvage and cannot compensate. | ↑ Hypoxanthine, guanine, PRPP, uric acid ↓ Salvaged IMP and GMP (in salvage-dependent tissues: brain, bone marrow, erythrocytes) |
XR | Compulsive self-mutilation (lip and finger biting), choreoathetosis, spasticity, cognitive and developmental deficits, gouty arthritis and urolithiasis even in young children | Markedly elevated uric acid (serum and urine) | Allopurinol (addresses urate/gout only, not the neurologic features) |
| PRPP synthetase superactivity (primary hyperuricemia from overproduction) FMK 08.1 · slide 8, 12, 19 PRPP is the shared 'green light' for both purine and pyrimidine synthesis; losing the PRPP control layer drives purine overproduction |
Gain-of-function mutation in PRPP synthetase | Excess PRPP drives more flux through GPAT (the committed step of purine synthesis) because PRPP concentration is the positive driver of de novo purine synthesis, so purine overproduction leads to overproduction of uric acid. | ↑ PRPP, purine nucleotides, uric acid |
XR | Early-onset hyperuricemia, gout, uric acid stones | Elevated serum uric acid (overproducer) | Allopurinol (xanthine oxidase inhibitor) |
| Purine nucleoside phosphorylase (PNP) deficiency FMK 08.1 · slide 17, 28 Compare: ADA = T + B + NK loss (severe); PNP = predominantly T-cell loss (milder) |
Purine nucleoside phosphorylase (removes the sugar from purine nucleosides to yield the free base) | Accumulating purine nucleosides (notably deoxyguanosine -> dGTP) are toxic to T lymphocytes, causing a milder, predominantly T-cell immunodeficiency that spares B cells more than ADA deficiency. | ↑ Purine nucleosides (inosine, guanosine, deoxyguanosine/dGTP) ↓ T lymphocytes (B cells relatively spared) |
AR | Recurrent infections with predominantly T-cell immunodeficiency; milder than ADA deficiency | Low T-cell count; low serum uric acid | Supportive care, hematopoietic stem cell transplant |
| Tumor lysis syndrome (TLS) FMK 08.1 · slide 16, 19, 20 |
Massive lysis of leukemic/lymphoma cells after chemotherapy (secondary purine overproduction) | Lysis of huge numbers of tumor cells releases massive quantities of nucleic acid that are degraded to uric acid, along with intracellular potassium and phosphate, creating a life-threatening metabolic emergency. | ↑ Uric acid, potassium, phosphate ↓ Calcium |
Acquired | Acute kidney injury from urate nephropathy, hyperkalemia (arrhythmia), hyperphosphatemia, hypocalcemia after starting chemotherapy | Markedly elevated uric acid, potassium, phosphate; rising creatinine | Rasburicase (recombinant urate oxidase, first-line in TLS) rapidly degrades uric acid to soluble allantoin; hydration |
Heme 24
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Acute intermittent porphyria (AIP) FMK 08.4 · slide 2, 10, 12, 16, 18, 30; handout The 'great masquerader'; precipitants = drugs, alcohol, hormones, fasting, infection/stress; 'give glucose and hemin, avoid inducers'; before ring closure = neurovisceral |
PBG deaminase (hydroxymethylbilane synthase, HMBS) - step 3 | Heterozygotes retain ~50% HMBS activity; when CYP450 inducers, hormones or fasting deplete hepatic free heme and derepress ALAS1, the surge of ALA/PBG overwhelms the half-capacity enzyme and neurotoxic linear precursors (before ring closure) accumulate. | ↑ Porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) ↓ Hydroxymethylbilane / downstream heme (thin margin) |
AD | Severe colicky abdominal pain without peritoneal signs, nausea/vomiting, anxiety, confusion, hallucinations, seizures, peripheral motor neuropathy, tachycardia, hypertension; women after puberty; NO photosensitivity; urine colorless when voided then darkens to reddish-brown/port-wine on standing in light and air (PBG oxidizes/polymerizes nonenzymatically) | Markedly elevated urine PBG (most specific) and ALA during an attack | IV hemin (repletes heme pool, re-represses ALAS1), IV glucose/carbohydrate loading for mild attacks, stop porphyrinogenic drugs, supportive care; givosiran (siRNA against ALAS1) for recurrent attacks |
| ALA dehydratase deficiency porphyria FMK 08.4 · slide 14-15 Sits in the 'before ring closure' zone = neurovisceral only |
ALA dehydratase (porphobilinogen synthase, ALAD) - step 2 | Deficient conversion of two ALA molecules to PBG causes ALA to accumulate before tetrapyrrole ring closure, producing a neurovisceral picture like AIP without photosensitivity. | ↑ delta-Aminolevulinic acid (ALA) ↓ Porphobilinogen and downstream heme |
AR | Acute neurovisceral attacks (abdominal pain, neuropathy, psychiatric symptoms), no photosensitivity; very rare | Elevated urinary ALA with normal PBG (biochemically resembles lead poisoning) | Hemin, glucose, avoid precipitants (as for acute porphyrias) |
| Autoimmune hemolytic anemia (as cause of hemolytic jaundice) FMK 08.4 · slide 26 |
Autoantibodies against RBC surface antigens | Antibody-coated RBCs are destroyed, raising unconjugated bilirubin beyond conjugation capacity. | ↑ Unconjugated bilirubin, urobilinogen |
Acquired | Hemolytic anemia, acholuric jaundice | Elevated unconjugated bilirubin, positive direct antiglobulin (Coombs) test | |
| Breast milk jaundice FMK 08.4 · slide 29 Breast MILK jaundice = week 2, milk inhibits UGT |
A substance in breast milk that inhibits UGT1A1 | An inhibitory factor in breast milk reduces bilirubin conjugation, producing a later-onset, prolonged unconjugated hyperbilirubinemia. | ↑ Unconjugated bilirubin ↓ UGT1A1 activity (inhibited) |
Acquired | Jaundice appearing in week 2 of life and lasting longer in a well-fed breastfed infant | Unconjugated hyperbilirubinemia | Usually observation; continue breastfeeding |
| Breastfeeding jaundice FMK 08.4 · slide 29 Breastfeeding jaundice = early, not enough milk; breast milk jaundice = later, something in the milk |
Inadequate milk intake in the first week of life | Poor intake reduces stooling and increases enterohepatic reabsorption of bilirubin, exaggerating the normal physiologic pattern. | ↑ Unconjugated bilirubin ↓ Caloric/fluid intake |
Acquired | Exaggerated jaundice in the first week of life in a poorly feeding breastfed infant | Unconjugated hyperbilirubinemia | Improve feeding frequency/intake |
| Congenital erythropoietic porphyria (Gunther disease, CEP) FMK 08.4 · slide 10, 14, 17 Wrong (type I) isomer = dead end; after ring closure = cutaneous only |
Uroporphyrinogen III synthase (cosynthase) - step 4 | Without the cosynthase, hydroxymethilbilane cyclizes nonenzymatically into the symmetric type I isomer, a metabolic dead end; uroporphyrin I and coproporphyrin I accumulate in erythroid cells and skin and are photoreactive. | ↑ Uroporphyrinogen/uroporphyrin I and coproporphyrin I (type I isomers) ↓ Uroporphyrinogen III and heme |
AR | Severe cutaneous photosensitivity with blistering and mutilation from infancy, skin fragility, red-brown urine, hemolysis; erythropoietic origin | Elevated type I porphyrins in urine and RBCs; erythrodontia/fluorescence under UV | Strict sun avoidance; transfusion, marrow transplant in severe disease |
| Crigler-Najjar syndrome type I FMK 08.4 · slide 21, 28; handout Type I = no enzyme = no phenobarbital response |
Complete absence of UGT1A1 | No bilirubin glucuronidation occurs, so lipophilic unconjugated bilirubin accumulates to severe levels, crosses the blood-brain barrier and deposits in the basal ganglia. | ↑ Unconjugated bilirubin (severe) ↓ Conjugated bilirubin |
AR | Severe nonhemolytic jaundice in infancy, kernicterus, historically fatal early | Severe unconjugated hyperbilirubinemia, no response to phenobarbital | Phototherapy, plasmapheresis, liver transplant |
| Crigler-Najjar syndrome type II FMK 08.4 · slide 21, 28; handout Type II = some enzyme = phenobarbital works |
Partial UGT1A1 deficiency (residual activity) | Reduced but present bilirubin-UGT activity causes moderate unconjugated hyperbilirubinemia; residual enzyme can be induced by phenobarbital. | ↑ Unconjugated bilirubin (moderate) ↓ Conjugated bilirubin (partial) |
AR | Less severe jaundice than type I, low kernicterus risk | Moderate unconjugated hyperbilirubinemia that falls with phenobarbital | Phenobarbital (induces residual UGT1A1) |
| Dubin-Johnson syndrome FMK 08.4 · slide 21, 28; handout Dubin-Johnson = Dark liver; Rotor = normal liver |
Canalicular MRP2 (MOAT) transporter for conjugated bilirubin | Conjugation is normal but conjugated bilirubin cannot be exported across the canalicular membrane into bile, so it refluxes into plasma; pigment accumulates in hepatocytes. | ↑ Conjugated (direct) bilirubin; dark pigment in liver ↓ Biliary excretion of conjugated bilirubin |
AR | Benign conjugated hyperbilirubinemia, grossly black/darkly pigmented liver | Conjugated hyperbilirubinemia, normal liver enzymes | None needed |
| Erythropoietic protoporphyria (EPP) FMK 08.4 · slide 11, 14, 17, 30; handout EPP = marrow, childhood, painful non-blistering photosensitivity; contrast PCT = liver, adult, blisters |
Ferrochelatase - step 8 (inner mitochondrial membrane) | Inability to insert Fe2+ into protoporphyrin IX causes photoactive protoporphyrin to accumulate in erythroid cells, plasma and skin; protoporphyrin excreted via bile can injure the liver. | ↑ Protoporphyrin IX in erythrocytes, skin and bile ↓ Heme |
AD | Painful burning photosensitivity usually WITHOUT frank blistering, beginning in childhood; hepatobiliary disease/liver injury from biliary protoporphyrin in severe cases; erythropoietic (marrow) origin | Elevated free erythrocyte protoporphyrin; normal urinary porphyrins (protoporphyrin is not water-soluble) | Sun avoidance/protection; monitor liver |
| Gilbert syndrome FMK 08.4 · slide 21, 28; handout Gilbert, CN-I and CN-II are one enzyme (UGT1A1) on a severity spectrum |
UGT1A1 promoter polymorphism (~30% activity) | Mildly reduced bilirubin-UDP-glucuronosyltransferase expression slows conjugation, so unconjugated bilirubin rises modestly, especially when fasting, stress or illness raises bilirubin load. | ↑ Unconjugated (indirect) bilirubin, mildly ↓ Conjugated bilirubin formation (partial) |
AR | Very common (3-7%), benign, incidental mild jaundice/scleral icterus during fasting, stress or viral illness | Mild isolated unconjugated hyperbilirubinemia, normal liver enzymes | None needed |
| Hemolytic disease of the newborn (ABO/Rh incompatibility) FMK 08.4 · slide 29 Jaundice in first 24 h is always pathologic |
Maternal antibodies against fetal RBC antigens (Rh or ABO) | Maternal IgG destroys fetal/neonatal RBCs, overwhelming immature UGT1A1 with unconjugated bilirubin within the first day of life. | ↑ Unconjugated bilirubin |
Acquired | Jaundice in the FIRST 24 hours of life, anemia, kernicterus risk | Unconjugated hyperbilirubinemia, positive direct Coombs, anemia | Phototherapy, exchange transfusion, urgent workup |
| Hepatic (hepatocellular) jaundice FMK 08.4 · slide 25, 26, 30; handout AST/ALT >> ALP = hepatocellular pattern |
Damaged hepatocytes failing at uptake, conjugation and canalicular excretion simultaneously | Injured hepatocytes cannot take up, conjugate or excrete bilirubin efficiently, so both unconjugated and conjugated bilirubin rise while transaminases leak from injured cells. | ↑ Mixed conjugated and unconjugated bilirubin; conjugated bilirubin in urine |
Acquired | Jaundice with dark urine, normal-to-pale stool; causes: viral hepatitis, cirrhosis, alcoholic liver disease, drug/toxin-induced liver injury (acetaminophen, carbon tetrachloride, chloroform) | Mixed hyperbilirubinemia, bilirubinuria present, variable urine urobilinogen, AST/ALT markedly elevated out of proportion to ALP | Treat underlying liver disease; remove hepatotoxin |
| Hereditary coproporphyria (HCP) FMK 08.4 · slide 11, 14, 30; handout HCP and VP straddle both zones - the exception board-writers love |
Coproporphyrinogen oxidase - step 6 (mitochondrial) | Block in conversion of coproporphyrinogen III to protoporphyrinogen IX causes coproporphyrin to accumulate after ring closure while upstream ALA/PBG rise during derepressed ALAS1 states, giving both cutaneous and neurovisceral features. | ↑ Coproporphyrinogen/coproporphyrin III; ALA and PBG during attacks ↓ Protoporphyrinogen IX and heme |
AD | Acute neurovisceral attacks (abdominal pain, neuropathy, psychiatric symptoms) precipitated by barbiturates/ethanol/drugs PLUS photosensitive skin lesions | Elevated urinary ALA/PBG in attacks; elevated fecal/urinary coproporphyrin III | Hemin, glucose, avoid precipitating drugs, sun protection |
| Hereditary spherocytosis (as cause of hemolytic jaundice) FMK 08.4 · slide 26 |
RBC membrane skeleton proteins (spectrin/ankyrin) | Spherical, poorly deformable RBCs are trapped and destroyed in the spleen, producing extravascular hemolysis and unconjugated hyperbilirubinemia. | ↑ Unconjugated bilirubin, urobilinogen |
AD | Hemolytic anemia, jaundice, splenomegaly, pigment gallstones | Elevated unconjugated bilirubin, spherocytes on smear | |
| Intrahepatic cholestasis FMK 08.4 · slide handout |
Impaired canalicular secretion of conjugated bilirubin within the liver | Bilirubin is conjugated normally but poorly secreted into bile, so conjugated bilirubin regurgitates back into the blood. | ↑ Conjugated bilirubin in plasma and urine ↓ Bilirubin in bile |
Acquired | Jaundice, dark urine, pruritus | Conjugated hyperbilirubinemia, cholestatic enzyme pattern (ALP/GGT) | Treat underlying cause |
| Kernicterus (bilirubin encephalopathy) FMK 08.4 · slide 20, 28, 29; handout Unconjugated = lipophilic = crosses BBB |
Free unconjugated bilirubin exceeding albumin-binding capacity crossing the immature blood-brain barrier | Lipophilic unconjugated bilirubin crosses the neonatal blood-brain barrier and deposits in the basal ganglia, causing irreversible neuronal injury. | ↑ Unconjugated bilirubin in basal ganglia ↓ Albumin binding capacity (relative) |
Acquired | Neonatal lethargy, hypotonia then hypertonia, seizures, irreversible neurologic injury; risk in severe physiologic jaundice, Crigler-Najjar I, hemolytic disease of the newborn, or drug displacement from albumin | Markedly elevated unconjugated bilirubin | Prevent with phototherapy or exchange transfusion |
| Physiologic neonatal jaundice FMK 08.4 · slide 29; handout Day 1 jaundice = pathologic; day 2-3 = physiologic |
Developmentally immature UGT1A1 at birth (not a mutation) | Low bilirubin-UGT activity for ~2 weeks after birth, combined with increased RBC turnover (fetal hemoglobin breakdown, short neonatal RBC lifespan), raises unconjugated bilirubin transiently. | ↑ Unconjugated bilirubin ↓ Conjugated bilirubin (transient) |
Acquired | Affects ~60% of term and ~80% of preterm infants; appears day 2-3 of life, resolves within 1-2 weeks; jaundice in the first 24 hours is NEVER physiologic | Unconjugated hyperbilirubinemia | Phototherapy (blue light converts bilirubin to water-soluble photoisomers such as lumirubin, excreted without conjugation); exchange transfusion if severe; sometimes phenobarbital to induce UGT |
| Porphyria cutanea tarda (PCT) FMK 08.4 · slide 11, 14, 17, 18; handout Chronic hepatic porphyria; after ring closure = cutaneous; PCT = hepatic/adult/blistering vs EPP = marrow/childhood/non-blistering |
Uroporphyrinogen decarboxylase (UROD) - step 5 (cytosol) | Severe (often acquired) deficiency of hepatic UROD prevents decarboxylation of uroporphyrinogen III to coproporphyrinogen III; accumulated uroporphyrin is cyclic and photoactive (Soret band), producing skin damage on light exposure without neurovisceral attacks. | ↑ Uroporphyrin(ogen) in liver, plasma, urine and skin ↓ Coproporphyrinogen III and heme |
Acquired | Most common porphyria; onset 4th-5th decade; painful blisters and skin fragility on sun-exposed skin (dorsal hands), hyperpigmentation, hypertrichosis, tea/red-brown urine; associated with hepatitis C, alcohol, estrogen, iron overload/hemochromatosis, phenytoin; no acute attacks | Markedly elevated urinary uroporphyrin; urine fluoresces coral-pink under Wood's (UV) lamp | Therapeutic phlebotomy (reduces hepatic iron), low-dose hydroxychloroquine, treat HCV, avoid alcohol/estrogen, sun protection |
| Post-hepatic (obstructive) jaundice FMK 08.4 · slide 22, 25, 27, 30; handout Dark urine + pale stool = obstruction; ALP/GGT >> AST/ALT = cholestatic pattern |
Mechanical obstruction of bile flow downstream of a normally functioning liver | Conjugated bilirubin is made correctly but cannot reach the intestine; it backs up into plasma and is filtered into urine, while no pigment reaches the gut so no stercobilin or urobilinogen forms. | ↑ Conjugated (direct) bilirubin in plasma and urine; bile salts in skin ↓ Stercobilin in stool, urobilinogen in urine |
Acquired | Jaundice, dark urine, pale/clay-colored (acholic) stool, pruritus; causes: gallstones in common bile duct, pancreatic head cancer, cholangiocarcinoma, primary sclerosing/biliary cholangitis, biliary atresia in infants | Conjugated hyperbilirubinemia, marked bilirubinuria, absent urine urobilinogen, ALP/GGT markedly elevated out of proportion to AST/ALT | Relieve obstruction (ERCP/stone removal, surgery) |
| Pre-hepatic (hemolytic) jaundice FMK 08.4 · slide 25, 26, 30; handout Pre-hepatic: up unconjugated, normal urine, up urobilinogen; chronic hemolysis can make pigment gallstones |
Excess RBC breakdown exceeding hepatic conjugation capacity; liver itself is normal | Overproduction of unconjugated bilirubin outpaces UGT1A1 conjugation; unconjugated bilirubin is albumin-bound and not filtered into urine, while a normal liver/gut converts more substrate into urobilinogen. | ↑ Unconjugated (indirect) bilirubin in plasma; urobilinogen in urine and stool |
Acquired | Jaundice with normal urine color ('acholuric jaundice'), normal or dark stool, anemia; causes: hemolytic anemias (G6PD deficiency, sickle cell disease, hereditary spherocytosis, pyruvate kinase deficiency, autoimmune hemolysis), ineffective erythropoiesis | Elevated unconjugated bilirubin, no bilirubinuria, increased urine urobilinogen, normal AST/ALT/ALP | Treat underlying hemolysis |
| Rotor syndrome FMK 08.4 · slide 28 Rotor = Regular-looking liver (distinguishes from Dubin-Johnson) |
Defective hepatic storage / OATP transport of bilirubin | Impaired hepatocyte uptake/storage of bilirubin allows conjugated bilirubin to escape into plasma despite normal conjugation, without hepatic pigment deposition. | ↑ Conjugated (direct) bilirubin ↓ Hepatic bilirubin uptake/storage |
AR | Benign conjugated hyperbilirubinemia, liver NOT pigmented | Conjugated hyperbilirubinemia, normal liver enzymes | None needed |
| Variegate porphyria (VP) FMK 08.4 · slide 11, 14, 30; handout HCP and VP straddle both zones (acute + cutaneous) |
Protoporphyrinogen oxidase - step 7 (mitochondrial) | Failure to oxidize protoporphyrinogen IX to protoporphyrin IX causes protoporphyrinogen and coproporphyrinogen to accumulate after ring closure, with ALA/PBG accumulation during induced attacks, so both photosensitivity and acute attacks occur. | ↑ Protoporphyrinogen IX and coproporphyrinogen; ALA and PBG during attacks ↓ Protoporphyrin IX and heme |
AD | Acute neurovisceral attacks precipitated by drugs (barbiturates, ethanol) plus cutaneous blistering photosensitivity | Elevated urinary ALA/PBG in attacks; elevated fecal protoporphyrin and coproporphyrin; characteristic plasma fluorescence peak | Hemin, glucose, avoid precipitating drugs, sun protection |
| X-linked sideroblastic anemia FMK 08.4 · slide 9 ALAS2 = erythroid, X-linked, iron-regulated (IRE/IRP); ALAS1 = liver, heme-repressed, drug-induced |
ALAS2 (erythroid-specific ALA synthase; X-linked gene) | Loss of erythroid ALA synthase activity blocks the first step of heme synthesis in marrow precursors, so iron delivered to mitochondria cannot be incorporated into heme and accumulates as ring sideroblasts. | ↑ Iron in erythroblast mitochondria (ring sideroblasts) ↓ Heme / hemoglobin in erythroid cells |
XR | Microcytic anemia, iron overload; a hematology disorder, NOT a porphyria | Ring sideroblasts on marrow Prussian-blue stain, microcytic anemia, elevated iron/ferritin | Pyridoxine (B6) trial, since ALAS is PLP-dependent |
Lysosomal 11
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Fabry disease FMK 04.1 · slide 04.1: 18, 19; Protein: n/a (Fabry page) The only X-linked sphingolipidosis — all the rest are autosomal recessive |
α-Galactosidase A | α-Galactosidase deficiency causes globosides (ceramide trihexoside) to accumulate in vascular endothelium, kidney, nerves and skin. | ↑ Globosides (ceramide trihexoside) ↓ α-Galactosidase |
XR | males symptomatic in early childhood: inability to sweat, acroparesthesias (hand/foot pain), heat/cold intolerance, angiokeratomas, whorl keratopathy (vision unaffected), renal failure, strokes, ventricular hypertrophy (more common in females), mitral valve prolapse/regurgitation, fibrosis → arrhythmia; cardiovascular disease is the most common cause of death | Enzyme replacement | |
| Farber disease FMK 04.1 · slide 18, 19 One missing enzyme, one accumulated lipid (one step up the degradation chain) |
Ceramidase | Ceramidase block leaves ceramide undegraded in lysosomes. | ↑ Ceramide ↓ Ceramidase |
AR | hoarse cry, subcutaneous nodules, joint deformity | ||
| Gaucher disease FMK 01.2 · slide 01.2: 12; 04.1: 18, 19, 24; Protein: n/a (Gaucher page; histology page) Sphingolipidoses: Niemann-Pick (sphingomyelinase), Gaucher (glucocerebrosidase) |
Glucocerebrosidase (beta-glucosidase) deficiency | Glucocerebroside cannot be cleaved and accumulates in macrophages (Gaucher cells) in liver, spleen, and bone. | ↑ Glucocerebroside ↓ Glucocerebrosidase |
AR | fatigue, thrombocytopenia (easy bruising), anemia, hepatosplenomegaly, neurologic degeneration, osteopenia, pathologic bone crises, avascular necrosis; GBA carriers at increased risk of Parkinson-like tremor in 50s–60s | bone marrow: Gaucher cells with striated 'crumpled/wrinkled tissue paper' cytoplasm, nucleus pushed to periphery | Enzyme replacement (imiglucerase) |
| Hunter syndrome (MPS Type II) FMK Protein Targeting & Lysosomal Disorders · slide n/a (Hunter pages) Hunter: X-linked, no corneal clouding (a hunter needs to see) |
Iduronate sulfatase (IDS gene) | Dermatan and heparan sulfate accumulate in lysosomes; X-linked so males are affected and female carriers usually asymptomatic. | ↑ dermatan sulfate, heparan sulfate ↓ iduronate sulfatase |
XR | presents at 2–4 years: milder Hurler-like features, aggressive behavior, progressive developmental delay, hearing impairment, thickened heart wall, NO corneal clouding, vision loss from optic nerve pressure, nodular skin lesions (pebbling sign) | urine screen for dermatan sulfate and heparan sulfate | Enzyme replacement therapy (Elaprase) — does not cross BBB |
| Hurler syndrome (MPS I) FMK 01.2 · slide 01.2: 10; Protein: n/a (Hurler pages) |
Lysosomal GAG-degrading enzymes (Hurler: alpha-L-iduronidase) | GAGs dermatan sulfate and heparan sulfate cannot be degraded and accumulate in lysosomes of connective tissue, cornea, heart and brain; only ~20% enzyme activity is needed to be symptom-free, most patients have <1%. | ↑ Glycosaminoglycans (heparan sulfate, dermatan sulfate) ↓ alpha-L-iduronidase (Hurler) |
AR | normal at birth; progressive coarse facial features (short upturned nose, flat face, prominent forehead, large head, thick lips, large tongue), finger contractures/claw hand, corneal clouding (ground glass), glaucoma, retinal disease, chronic rhinitis/otitis media, cardiomyopathy (most common cause of death), hydrocephalus, developmental delay, gibbus deformity, abnormal clavicles, hip dysplasia, joint stiffness, growth retardation; Hurler most severe (0% enzyme), Hurler-Scheie intermediate, Scheie mildest (no cognitive delay) | urine screen for dermatan sulfate and heparan sulfate | Enzyme replacement, hematopoietic stem cell transplant |
| I-cell disease (mucolipidosis II) FMK 01.2 · slide 01.2: 10; Protein: n/a (LSD overview page) I-cell = Inclusion cell; misrouted enzymes |
N-acetylglucosamine-1-phosphotransferase (fails to add mannose-6-phosphate tag) - misrouted lysosomal enzymes | Lysosomal enzymes lacking the mannose-6-phosphate tag are secreted instead of delivered to lysosomes, so undigested substrates accumulate in inclusion bodies. | ↑ Oligosaccharides, GAGs, lipids in lysosomal inclusions ↓ Lysosomal enzymes inside lysosomes (elevated in plasma) |
AR | Coarse facial features, skeletal abnormalities, clouded corneas, restricted joint movement, early death | High plasma lysosomal enzyme levels | |
| Krabbe disease FMK 04.1 · slide 04.1: 19; Protein: n/a (Krabbe page; histology page) |
Galactosylceramidase (GALC) | GALC deficiency causes galactosylceramide (and psychosine) accumulation that kills oligodendrocytes and destroys myelin. | ↑ Galactosylceramide (galactocerebroside) ↓ Galactosylceramidase (GALC) |
AR | infantile onset in first 6 months, life expectancy ~2 years: failure to thrive, muscle weakness, restlessness/irritability, fevers without infection, optic atrophy/blindness, deafness, seizures, loss of milestones, decerebrate posturing | brain histology: large multinucleated globoid cells in white matter | enzyme replacement therapy |
| Metachromatic leukodystrophy FMK 04.1 · slide 19 Sulfatides = brain and kidney lipid; lose the sulfatase, lose the myelin |
Arylsulfatase A | Arylsulfatase A deficiency causes sulfatide accumulation, destroying central and peripheral myelin. | ↑ Sulfatides (sulfated galactocerebroside) ↓ Arylsulfatase A |
AR | demyelination, mental regression, psychiatric changes | ||
| Niemann-Pick disease FMK 01.2 · slide 01.2: 12; 04.1: 16, 19; Protein: n/a (Niemann-Pick page); FMK 04.4 slide 20, 30 No man PICKs his nose with his SPHINGER (sphingomyelinase) |
Sphingomyelinase (acid sphingomyelinase) deficiency | Deficient sphingomyelinase cannot cleave sphingomyelin to ceramide + phosphorylcholine, so sphingomyelin accumulates in monocyte/macrophage cells. | ↑ Sphingomyelin ↓ Sphingomyelinase |
AR | hepatosplenomegaly, rapid neurodegeneration fatal in early childhood (type A), milder with minimal neural involvement and longer survival (type B) | Reduced sphingomyelinase activity; foam cells | enzyme replacement therapy (sphingolipidoses) |
| Tay-Sachs disease FMK 04.1 · slide 04.1: 18, 19, 23; Protein: n/a (Tay-Sachs page; Think-Pair-Share) The 7-month-old case: Hex A missing, GM2 ganglioside piling up; no hepatosplenomegaly |
Hexosaminidase A | Hexosaminidase A block leaves GM2 ganglioside piling up in neurons, one step up the degradation chain. | ↑ GM2 ganglioside ↓ Hexosaminidase A |
AR | onset ~6 months, life expectancy 3–5 years; muscle weakness progressing to paralysis, convulsions/seizures, cherry-red spot on macula, NO contractures, NO hepatosplenomegaly | Absent hexosaminidase A activity; cherry-red spot on fundoscopy | enzyme replacement therapy (sphingolipidoses managed with ERT; lifespan depends on age of diagnosis) |
| Wolman disease FMK 04.4 · slide 20, 30 |
Lysosomal acid lipase | LDL is endocytosed normally but its cholesteryl esters and TAG cannot be hydrolyzed in the lysosome, so lipid is trapped there (LDL-receptor pathway intact). | ↑ cholesteryl esters and triglycerides in lysosomes ↓ free cholesterol released from lysosome |
AR | lysosomal storage disease correlate of LDL lysosomal hydrolysis; textbook: infantile hepatosplenomegaly, adrenal calcification |
Mitochondrial 6
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Ischemia-reperfusion injury FMK 02.4 · slide 22; FMK 02.1 slide 23 |
ETC stops without O₂; burst of ROS when O₂ returns | Ischemia depletes ATP (Na⁺/K⁺-ATPase failure, cell swelling, Ca²⁺ influx, lactic acidosis); reperfusion causes a sudden ROS burst (superoxide, hydroxyl radical) that damages proteins, lipids and DNA and may exceed the ischemic injury. | ↑ lactate, AMP, NADH, ROS, Ca²⁺ ↓ ATP |
Acquired | MI/STEMI (PCI reperfusion), ischemic stroke (tPA window, penumbra vs core), organ transplant (cold storage, antioxidants) | ↑ lactate | timely reperfusion (benefit outweighs injury), cold storage/antioxidants in transplant; ROS defense by SOD, catalase, glutathione peroxidase |
| Lactic acidosis (Type A and Type B) FMK 02.4 · slide 13, 17; FMK 02.1 slide 15, 21 |
OXPHOS failure (hypoxia or ETC/mitochondrial dysfunction) | When the ETC is blocked or O₂ is absent, NAD⁺ is not regenerated, NADH/NAD⁺ rises and LDH reduces pyruvate to lactate, producing an anion-gap metabolic acidosis. | ↑ lactate, NADH ↓ ATP, NAD⁺ |
Acquired | Type A (hypoxic): hemorrhagic shock, cardiac arrest, severe anemia, CO poisoning, PE, MI; Type B (metabolic): cyanide/ETC poisons, mitochondrial disease (MELAS), thiamine deficiency, metformin (renal failure), liver failure, sepsis | serum lactate >2 mEq/L (normal <1), anion gap >12, ↓ pH | treat underlying cause; lactate tracks severity and recovery (O₂ debt) |
| Leber hereditary optic neuropathy (LHON) FMK 02.4 · slide 6, 21 |
Complex I subunit mutations (ND1, ND4, ND6 most common) | mtDNA Complex I subunit mutations cause energy failure in the highly ATP-dependent retinal ganglion cells/optic nerve. | ↓ ATP in retina/optic nerve |
Mitochondrial | painless subacute bilateral (may be sequential) vision loss in young adults (M>F, ages 15–35), central scotoma, color vision loss | ||
| MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like episodes) FMK 02.4 · slide 17, 21, 25 Name is the mnemonic: Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like episodes |
mtDNA m.3243A>G in mt-tRNA^Leu (most common) | A mt-tRNA mutation impairs mitochondrial translation of OXPHOS subunits, causing energy failure in brain and muscle with lactate accumulation. | ↑ lactate (blood and CSF) ↓ ATP |
Mitochondrial | childhood/young-adult onset, exercise intolerance, muscle weakness, stroke-like episodes, seizures, migraine-like headaches | ↑ blood and CSF lactate, abnormal MRI | Supportive; CoQ10, riboflavin |
| MERRF (Myoclonic Epilepsy with Ragged Red Fibers) FMK 02.4 · slide 21 Ragged red = mitochondrial aggregates |
mtDNA m.8344A>G in mt-tRNA^Lys (most common) | mt-tRNA^Lys mutation impairs OXPHOS subunit synthesis; mitochondrial aggregates accumulate in muscle fibers (ragged red). | ↑ mitochondrial aggregates in muscle (ragged-red fibers), lactate ↓ ATP |
Mitochondrial | myoclonus (hallmark), epilepsy, ataxia, hearing loss | ragged-red fibers on Gomori trichrome stain | |
| Primary mitochondrial disease / mitochondrial myopathy (general pattern) FMK 02.4 · slide 6, 21, 24, 26; FMK 02.1 slide 23 Common thread: maternal inheritance, high-energy organs, lactic acidosis, exercise intolerance; don't assume maternal — POLG/ANT are Mendelian |
Mutations in mtDNA (maternal) or nuclear DNA encoding ETC/TCA proteins (e.g., POLG, ANT defects — Mendelian) | Defective OXPHOS causes organs to fail in proportion to their ATP dependence (brain > heart > skeletal muscle > retina > kidney > liver); heteroplasmy above ~70–80% mutant load produces symptoms. | ↑ lactate, NADH ↓ ATP |
Mitochondrial | exercise intolerance, myopathy, seizures, stroke-like episodes, encephalopathy, cardiomyopathy, arrhythmia, vision loss, Fanconi syndrome/renal tubular acidosis, hepatopathy, fatty liver, neuropathy; maternal family history, males affected but do not transmit | ↑ lactate | supportive |
Vitamin 11
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Beriberi (wet and dry) FMK 02.4 · slide 18; FMK 02.1 slide 16 |
Thiamine deficiency | Thiamine deficiency impairs PDH and TCA energy production in heart and peripheral nerves. | ↑ lactate ↓ thiamine, ATP |
Acquired | wet beriberi: dilated cardiomyopathy, high-output heart failure; dry beriberi: peripheral neuropathy | ↑ lactate | thiamine |
| Folate (folic acid) deficiency FMK 07.1 · slide 23, 28, 32 FIGlu = folate |
Folate (tetrahydrofolate) deficiency | Histidine catabolism requires folate to accept the formimino group of N-formiminoglutamate (FIGlu); when folate is low, FIGlu accumulates and spills into urine; folate is also needed for homocysteine remethylation. | ↑ Urinary FIGlu; plasma homocysteine ↓ Folate / THF |
Acquired | Hyperhomocysteinemia | Urinary FIGlu excretion test after histidine load; elevated homocysteine | Folate |
| Hyperhomocysteinemia (acquired; B6/B12/folate deficiency) FMK 07.1 · slide 27, 28, 29, 32 B6 = transamination + transsulfuration; B12 = methionine synthase + methylmalonyl-CoA mutase; folate = FIGlu + remethylation |
Deficiency of folate, vitamin B6, or vitamin B12 — cofactors for methionine synthase (B12, N⁵-methyl-THF) and cystathionine β-synthase (B6) | Impaired remethylation (B12/folate) or transsulfuration (B6) of homocysteine raises plasma homocysteine, an independent risk factor for cardiovascular disease and stroke. | ↑ Plasma homocysteine ↓ Folate, B6, and/or B12 |
Acquired | Increased risk of cardiovascular disease and stroke | Elevated plasma homocysteine inversely proportional to folate, B6, B12 status | Folate, B6, B12 repletion |
| Korsakoff syndrome FMK 03.4 · slide 22, 25; FMK 02.4 slide 18 Korsakoff = Confabulation + Amnesia |
Untreated thiamine deficiency (chronic) | Untreated Wernicke encephalopathy progresses to permanent damage of memory circuits. | ↓ thiamine |
Acquired | anterograde amnesia, confabulation; irreversible in 80% | thiamine (prevention); largely irreversible | |
| Pellagra (niacin / vitamin B3 deficiency) FMK 07.1 · slide 7, 30 The 3 Ds: dermatitis, diarrhea, dementia |
Niacin (vitamin B3) deficiency — dietary, or secondary to tryptophan malabsorption (Hartnup) | Tryptophan is the precursor for endogenous NAD synthesis; niacin/tryptophan shortage impairs NAD-dependent metabolism in skin, gut and brain. | ↓ Niacin / NAD |
Acquired | Dermatitis, diarrhea, dementia | Niacin | |
| Scurvy (vitamin C deficiency) FMK 06.4 · slide 9, 13, 34 Fe²⁺ + vitamin C = hydroxylase cofactors (intracellular); Cu²⁺ + lysyl oxidase = cross-linking (extracellular) |
Ascorbate (vitamin C) deficiency → prolyl and lysyl hydroxylase cannot keep Fe²⁺ reduced | Fe²⁺ cofactor of the hydroxylases is oxidized to inactive Fe³⁺ during catalysis and needs ascorbate to be regenerated; without it collagen is under-hydroxylated, cannot form enough interchain H-bonds, and the triple helix is thermally unstable and degrades. | ↓ Hydroxyproline/hydroxylysine in collagen; vitamin C |
Acquired | Bleeding gums, poor wound healing, fragile blood vessels | Vitamin C repletion | |
| Steatorrhea and fat-soluble vitamin (A, D, E, K) deficiency FMK 04.4 · slide 10, 28 Board tip: isolated fat-soluble vitamin deficiency with normal diet → search for pancreatic, biliary or enterocyte-level fat malabsorption |
Poor digestion (cystic fibrosis, no pancreatic lipase) or malabsorption (short bowel syndrome, celiac disease, bile acid deficiency, chylomicron assembly defect) | Vitamins A, D, E, K all require mixed-micelle incorporation and chylomicron packaging, so any upstream defect (lipase, bile salts, chylomicron assembly) takes all four down together. | ↑ fecal fat ↓ vitamins A, D, E, K |
Acquired | vitamin A → night blindness; vitamin D → rickets/osteomalacia; vitamin E → ataxia, areflexia, peripheral neuropathy; vitamin K → bleeding | ↑ fecal fat, elevated PT (vitamin K) | |
| Thiamine (vitamin B₁) deficiency FMK 02.4 · slide 16, 18, 25; FMK 03.1 slide 17, 24; FMK 03.4 slide 22; FMK 02.1 slide 16 THIAMINE FIRST — before glucose |
TPP cofactor for PDH, α-ketoglutarate dehydrogenase, branched-chain α-keto acid dehydrogenase, transketolase | Without TPP, PDH and α-KG dehydrogenase stall so pyruvate is diverted to lactate and TCA flux (NADH/ATP) drops, causing energy failure in high-demand neurons and heart. | ↑ pyruvate, lactate ↓ acetyl-CoA, NADH, ATP |
Acquired | Wernicke encephalopathy (confusion, ataxia, ophthalmoplegia), Korsakoff syndrome, wet beriberi (dilated cardiomyopathy, high-output failure), dry beriberi (peripheral neuropathy); alcohol use disorder/malnutrition | ↑ lactate, ↑ pyruvate; ↓ erythrocyte transketolase activity (TPP effect) | IV thiamine BEFORE glucose |
| Vitamin D deficiency: rickets (child) / osteomalacia (adult) FMK 05.1 · slide 2, 15, 24; FMK 04.4 slide 10 Liver = storage form (25-OH, what we measure); kidney = active form (calcitriol) |
Deficient vitamin D (7-dehydrocholesterol/UV-B → D3 → liver 25-OH → kidney 1,25-(OH)₂ calcitriol); or fat malabsorption of dietary D | Inadequate calcitriol reduces intestinal calcium absorption (calbindin), so a continuously forming collagen matrix is not mineralized, giving soft fracture-prone bone; growth-plate deformity only in children. | ↑ unmineralized osteoid ↓ 25-OH-D3 / calcitriol, Ca²⁺ |
Acquired | soft, fracture-prone bone; growth-plate deformity in children; case: outdoor patient with 'critically low' vitamin D (bile-acid/fat malabsorption link) | ↓ Ca²⁺, variable PTH, ↓ 25-OH-D3 (storage form measured) | vitamin D/calcitriol |
| Wernicke encephalopathy FMK 03.4 · slide 19, 22, 23, 25; FMK 02.4 slide 18 WE = OCA: Ophthalmoplegia, Confusion, Ataxia |
Thiamine deficiency → PDH / α-KG dehydrogenase / transketolase failure | Chronic alcohol use (poor nutrition, impaired absorption) depletes thiamine, blocking mitochondrial energy production and causing neuronal necrosis in high-metabolic-demand regions. | ↑ pyruvate, lactate ↓ thiamine, ATP |
Acquired | classic triad (only ~10% have all three): confusion/altered mental status, ophthalmoplegia (lateral gaze palsy), ataxia | ↓ erythrocyte transketolase activity | IV thiamine before or with glucose; glucose first can precipitate/worsen encephalopathy |
| Zinc deficiency / pyridoxal kinase defect seizures (incl. preeclampsia) FMK 07.2 · slide 22 GAD needs PLP; PLP needs pyridoxal kinase; pyridoxal kinase needs zinc |
Pyridoxal kinase (zinc-requiring enzyme that converts B6 vitamers to PLP); zinc deficiency | Without PLP, glutamate decarboxylase (GAD) cannot make GABA, the major inhibitory neurotransmitter, lowering seizure threshold. | ↓ PLP, GABA |
Acquired | Seizure disorders, notably in preeclamptic patients | Textbook: pyridoxine/PLP, zinc repletion |
Protein structure 17
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Alport syndrome FMK 06.4 · slide 19, 20, 34 IV = basement membrane (kidney, cochlea, eye): hematuria + sensorineural hearing loss |
Mutations in type IV (network-forming) collagen genes | Type IV collagen forms the basement-membrane mesh of the glomerulus, cochlea, and eye; its defect causes progressive basement-membrane failure in all three organs. | ↓ Functional type IV collagen |
XR | Progressive glomerulonephritis with hematuria, proteinuria, hypertension → end-stage renal disease, plus sensorineural hearing loss and eye involvement; onset second to fourth decades | Hematuria, proteinuria | |
| Alzheimer disease FMK 01.2 · slide 01.2: 7; 01.5: 15; 06.1: 2, 4, 12; 06.3: When Gene Regulation Fails; Conclusion Uncompetitive: binds ES complex, lowers both Km and Vmax |
Misfolded beta-sheet-rich amyloid peptides (secondary structure pathology) | Misfolded amyloid-β monomers escape ubiquitin/proteasome clearance and self-assemble into β-sheet-rich insoluble extracellular plaques, while hyperphosphorylated tau (a microtubule-stabilizing protein) forms intracellular neurofibrillary tangles. | ↑ Beta-amyloid sheet aggregates (plaques) ↓ Acetylcholine |
Acquired | Progressive dementia over years (contrasted with the weeks-long course of CJD) | Memantine (NMDA receptor uncompetitive antagonist) noted in 01.5 | |
| Amyloid diseases (general) FMK 06.1 · slide 12 Same protein — harmless folded, lethal misfolded |
Misfolded proteins that escape ubiquitin-tagged proteasomal/lysosomal clearance | Misfolding (spontaneous/age-related, genetic mutation, or abnormal proteolytic cleavage of a precursor) drives self-assembly into β-sheet-rich, insoluble fibrous aggregates that resist degradation and physically disrupt cells. | ↑ β-sheet-rich amyloid fibrils |
Acquired | Neurodegeneration (Alzheimer's, Parkinson's as examples) | ||
| Ehlers-Danlos syndrome (classic) FMK 01.2 · slide 01.2: 8; 06.4: 18, 20, 34 Collagen mutations -> OI, EDS |
Collagen mutations / defective collagen processing | Defective type V collagen (or defective collagen processing) impairs fibril assembly, weakening skin and joint connective tissue. | ↓ Normal collagen |
AD | Hyperextensible skin, joint hypermobility, easy bruising, vascular rupture in vascular type | ||
| Ehlers–Danlos syndrome, vascular type FMK 06.4 · slide 18, 20, 34 Type III = vessels |
Type III collagen gene mutation | Type III collagen is critical to vessel wall integrity, so its defect makes arteries prone to spontaneous rupture. | ↓ Functional type III collagen |
AD | Most dangerous EDS form — risk of spontaneous, potentially lethal arterial rupture; hyperextensible skin and hypermobile joints | ||
| Hemoglobin C disease FMK 06.1 · slide 26 |
β-globin structural variant (HbC; textbook: Glu6→Lys) | Qualitative hemoglobinopathy — a structurally abnormal β-globin is produced (listed alongside HbS as a qualitative hemoglobinopathy). | ↑ HbC |
AR | Listed as a qualitative hemoglobinopathy | Hemoglobin electrophoresis | |
| Hemoglobin SC disease FMK 06.1 · slide 26 |
Compound heterozygosity for HbS and HbC β-globin variants | Qualitative hemoglobinopathy with one HbS and one HbC allele; structurally abnormal hemoglobin is produced. | ↑ HbS and HbC |
AR | Listed as a qualitative hemoglobinopathy | Hemoglobin electrophoresis | |
| Marfan syndrome FMK 06.4 · slide 2, 32, 33, 34 Fibrillin scaffolds elastin — defective scaffold fails elastic tissue though elastin is normal |
FBN1 gene mutation → abnormal fibrillin-1, the microfibril scaffold for elastin | Abnormal fibrillin is incorporated into microfibrils and disrupts their formation; because tropoelastin must be deposited on this scaffold, elastic fiber integrity fails throughout the body even though elastin itself is normal. | ↓ Functional fibrillin-1 microfibrils / intact elastic fibers |
AD | Tall, long slender limbs/fingers/toes, hypermobile joints, eye involvement; progressive aortic root dilation → aortic dissection or rupture (leading cause of death) presenting as sudden chest and back pain | Imaging: aortic root dilation / dissection | |
| Methemoglobinemia FMK 06.1 · slide 06.1: 2, 24, 26; 08.4: 6 Fe²⁺ vs Fe³⁺: 'chocolate-brown' blood that extra O₂ won't fix |
Oxidation of heme iron Fe²⁺→Fe³⁺: oxidizing drugs/toxins (nitrates in well water, certain local anesthetics, dapsone), congenital NADH–cytochrome b₅ reductase deficiency, or HbM globin variants that stabilize Fe³⁺ | Ferric (Fe³⁺) methemoglobin cannot bind O₂ at all, so supplemental oxygen cannot be used by the blood that carries it. | ↑ Methemoglobin (Fe³⁺ heme) ↓ Functional Fe²⁺ hemoglobin; NADH–cytochrome b₅ reductase (congenital form) |
Acquired | Grey-blue cyanosis unresponsive to supplemental O₂, 'chocolate-brown' blood, normal-appearing lungs; classic infant after well-water (nitrate) formula | Chocolate-brown blood; cyanosis with normal pulse oximetry/lungs; methemoglobin level | Methylene blue — accelerates enzymatic reduction of Fe³⁺ back to Fe²⁺ |
| Osteogenesis imperfecta FMK 01.2 · slide 01.2: 8; 04.2: 15; 06.4: 2, 15, 16, 17, 20, 34 Collagen mutations -> OI, EDS |
Collagen (type I) mutations - structural protein | Glycine is the only residue small enough for the crowded triple-helix core every third position, so substitution prevents proper triple-helical folding of type I collagen, the principal collagen of bone. | ↓ Normal type I collagen |
AD | Type I (most common, mildest): mild bone fragility, hearing loss, blue sclerae; Type II (lethal): fractures in utero, perinatal death from pulmonary complications of underdeveloped rib cage; Type III: multiple fractures at birth, short stature, progressive kyphoscoliosis, blue sclerae; infant with multiple fractures in various stages of healing, bowed femur, thin bones, abuse ruled out | X-ray: fractures in various stages of healing, diffusely thin bones | Bisphosphonates, fracture care |
| Parkinson disease FMK 06.1 · slide 06.1: 12; 07.2: 18; 06.3: When Gene Regulation Fails; Conclusion Neurodegenerative proteinopathy example under 'When Gene Regulation Fails' |
Misfolded α-synuclein | Loss of nigral neurons that make dopamine (tyrosine → L-DOPA via BH₄-dependent tyrosine hydroxylase → dopamine via AADC) produces a movement disorder. | ↑ Intracellular α-synuclein aggregates (Lewy bodies) ↓ Dopamine |
Acquired | Neurodegenerative movement disorder (see 07.2 for dopamine loss) | Textbook: L-DOPA (crosses blood-brain barrier, decarboxylated by AADC) | |
| Prion disease (CJD) FMK 01.2 · slide 01.2: 7; 06.1: 2, 4, 13 Tertiary structure loss -> protein misfolding diseases (prions, CF dF508) |
Prion protein (PrP) misfolded from alpha-helical PrPc to beta-sheet PrPsc (tertiary structure loss) | Loss of normal tertiary fold converts PrP into a protease-resistant beta-sheet conformer that templates further misfolding and aggregates in brain. | ↑ Misfolded PrPsc aggregates |
Acquired | Rapidly progressive dementia over weeks with myoclonic jerks, bed-bound within months (58-year-old engineer); scrapie in sheep, 'mad cow' in cattle | None available — fatal | |
| Sickle cell disease (HbS) FMK 01.2 · slide 01.2: 7; 06.1: 2, 25, 26, 27, 28; 08.1: 08.1 slide 15; 07.3 'Southern Blot', 'Applications and Implications of CRISPR-Cas9'; 08.4: 26; handout Primary structure determines ALL subsequent structure; one AA change can cause disease |
Hemoglobin beta chain (HbS); single amino acid substitution (Glu6Val) altering primary structure | The surface valine creates a hydrophobic 'sticky patch' on deoxy-HbS that docks into a pocket on neighboring deoxy-HbS tetramers, forming rigid polymers that distort RBCs into sickles which occlude capillaries and hemolyze. | ↑ Polymerized deoxy-HbS fibers in RBCs ↓ Normal HbA |
AR | Vaso-occlusive crises with severe bone/abdominal pain, microinfarcts and organ ischemia, hemolytic anemia (RBC lifespan <20 days), hyperbilirubinemia; crises triggered by hypoxia/high altitude/exertion, acidosis, dehydration, ↑2,3-BPG; heterozygous trait usually asymptomatic and malaria-protective | Southern blot can detect the mutation/deletion for carrier screening and diagnosis; hemoglobin electrophoresis | Hydroxyurea, supportive care, transfusion |
| Sickle cell trait (HbAS) FMK 06.1 · slide 27 |
Heterozygous β-globin Glu6→Val mutation (one HbS allele) | Only about half the hemoglobin is HbS, so polymerization does not occur under ordinary conditions. | AR | Usually asymptomatic; confers protection against malaria | Hemoglobin electrophoresis shows both HbA and HbS | ||
| α-Thalassemia FMK 06.1 · slide 26, 29 |
Deletions/mutations in the α-globin gene cluster (chromosome 16, two α-globin genes per chromosome): α⁰ (no expression) or α⁺ (reduced) | Quantitative hemoglobinopathy with decreased production of otherwise-normal α-globin, causing imbalanced globin chain synthesis. | ↑ Unpaired β (or γ) chains ↓ α-globin |
AR | Severity depends on number of affected genes (trait vs major) | Hemoglobin electrophoresis | Transfusion with iron chelation in severe forms |
| α1-Antitrypsin (AAT) deficiency FMK 06.4 · slide 2, 27, 28, 29, 30, 34 One gene, two mechanisms: gain-of-function in liver, loss-of-function in lung; smoking is a double hit (oxidizes Met358) |
AAT gene mutation, most severe Z-variant: Glu342→Lys; AAT is the hepatocyte-made inhibitor of neutrophil elastase | Mutant AAT misfolds, polymerizes and aggregates in hepatocyte RER (toxic gain-of-function liver injury) so plasma/lung AAT falls, leaving neutrophil elastase unopposed to degrade alveolar elastin (loss-of-function panacinar emphysema); cigarette smoke oxidizes Met358, further disabling residual AAT. | ↑ Polymerized AAT in hepatocyte RER ↓ Plasma and lung α1-antitrypsin (e.g., 5.5 µM vs normal 20–40 µM); alveolar elastin |
AD | Early-onset panacinar emphysema in a non-smoker (lower lung zones), dyspnea, familial lung disease, pediatric end-stage liver failure | Low plasma AAT (5.5 µM; normal 20–40 µM) | Smoking cessation is the key prognostic factor; liver transplantation for liver failure |
| β-Thalassemia FMK 06.1 · slide 26, 29 Not an abnormal protein — too little of a normal one |
Point mutations or deletions in the single β-globin gene (chromosome 11): β⁰ (no expression) or β⁺ (reduced) | Quantitative hemoglobinopathy — β-chain production is impaired while α synthesis is normal, so unpaired α chains precipitate and damage RBC precursors. | ↑ Unpaired α-globin chains (precipitate); compensatory HbA₂ and HbF ↓ β-globin / HbA |
AR | Symptoms appear months after birth as HbF is replaced by HbA; thalassemia minor (trait, one gene) usually asymptomatic; thalassemia major (both genes) transfusion-dependent anemia | ↑HbA₂ and ↑HbF on electrophoresis | Regular transfusion with iron-chelation therapy (prevents transfusion iron overload); hematopoietic stem cell transplant |
DNA/RNA 5
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Bloom syndrome (helicase mutation) FMK 02.5 · slide 9 Helicase mutation -> Bloom (accelerated aging) |
DNA helicase (BLM, RecQ family) | Mutant helicase causes genomic instability with excessive sister-chromatid exchange, leading to accelerated aging and cancer predisposition. | ↑ Chromosomal breaks, sister chromatid exchanges ↓ Functional BLM helicase |
AR | Accelerated aging, short stature, sun-sensitive facial rash, immunodeficiency, high cancer risk | Increased sister chromatid exchange | |
| BRCA1-mutant breast cancer (PARP inhibitor synthetic lethality) FMK 02.5 · slide 14, 18, 22 PARPi + BRCA1 loss = synthetic lethality |
BRCA1 (homologous recombination repair); PARP (BER) is the drug target | PARP inhibitors block base excision repair so single-strand breaks become double-strand breaks that BRCA1-deficient cells cannot repair by homologous recombination - synthetic lethality. | ↑ Unrepaired DNA breaks in tumor cells ↓ Homologous recombination repair (BRCA1) |
AD | Hereditary breast (and ovarian) cancer | BRCA1 germline mutation | PARP inhibitors (PARPi) |
| HIV / AIDS (reverse transcriptase; nucleoside analogues; HAART) FMK 02.2 · slide 02.2: 4, 24; 03.2: 25, 27 No 3'-OH = no phosphodiester bond with next base = chain termination |
HIV reverse transcriptase (RNA-dependent DNA polymerase) - drug target; CD4+ T-cell infection | HIV, an RNA retrovirus, uses reverse transcriptase to copy its genome into proviral DNA that integrates into the host genome; host RNA polymerase then transcribes it as both mRNA and genomic RNA, and replication lyses CD4+ T cells. | ↓ CD4+ T cells |
Acquired | Opportunistic infections from CD4+ T-cell loss; transmitted by sexual contact, blood transfusion, mother-to-infant (breast feeding) | Low CD4 count, HIV RNA viral load | Nucleoside analogues zidovudine (AZT) and didanosine (ddI) lack a 3'-OH so cause chain termination; HAART = 2 reverse transcriptase inhibitors (nucleotide + non-nucleotide) + 1 HIV protease inhibitor |
| Lynch syndrome (Hereditary Non-Polyposis Colorectal Cancer, HNPCC) FMK 02.5 · slide 2, 14, 20, 22 MMR uses methylated parental strand; MLH1/MSH2/MSH6/PMS2 -> MSI -> Lynch |
Mismatch repair proteins MLH1, MSH2, MSH6, PMS2 | Mutation in MMR genes abrogates correction of replication mismatches (which normally uses the methylated parental strand as template), producing microsatellite instability and colorectal cancer. | ↑ Replication errors, microsatellite instability (MSI) ↓ Mismatch repair |
AD | Early-onset colorectal cancer (often right-sided) without polyposis, endometrial and other cancers | Microsatellite instability, loss of MMR protein on IHC | Surveillance colonoscopy, prophylactic surgery |
| Xeroderma pigmentosum (XP) FMK 02.5 · slide 2, 14, 15, 22 Thymine dimers (UV) -> NER; no NER = XP |
Nucleotide excision repair (NER) enzymes - lack of repair system for thymine dimers | UV light forms thymine dimers; without NER they persist and cause polymerase errors (misincorporation, insertions, deletions), giving a 1000x increased skin cancer risk. | ↑ UV-induced thymine dimers ↓ Nucleotide excision repair |
AR | Extreme sun sensitivity, freckling, dry skin, early multiple skin cancers, 1000x skin cancer risk | Strict sun avoidance |
Genetic 25
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| 47,XYY (Jacobs syndrome) FMK 08.5 · slide Fetal Aneuploidy; Sex Chromosome Aneuploidies 1/1,000 live-born males; random event, not passed down |
Extra Y chromosome (47,XYY) from paternal nondisjunction in meiosis II | A random paternal meiosis II error yields a YY sperm; the extra Y produces tall stature with mild behavioral/cognitive effects but normal fertility; not inherited. | Chromosomal | Phenotypically near-normal and usually undiagnosed; very tall stature (~193 cm), IQ 10-15 points below siblings, behavioral problems, normal fertility, macrodontia, flat feet, clinodactyly, wide-spaced eyes | Karyotype 47,XYY | None specific; supportive | |
| Achondroplasia FMK 04.2 · slide 15 Gonadal mosaicism: parent phenotypically normal, somatic cells test negative |
FGFR3 gain-of-function | Dominant constitutive FGFR3 signaling inhibits chondrocyte proliferation; 'de novo' recurrence in siblings is explained by germline mosaicism. | AD | short-limb dwarfism, macrocephaly, recurrence in siblings of unaffected parents | |||
| Agammaglobulinemia (BTK mutation, X-linked) FMK 01.2 · slide 8 |
Bruton tyrosine kinase (BTK) | Loss of BTK blocks B-cell maturation, so no immunoglobulins are produced. | ↓ Immunoglobulins (all classes), mature B cells |
XR | Recurrent bacterial infections after ~6 months of age (maternal IgG wanes) | Absent/low serum immunoglobulins, absent B cells | IVIG replacement |
| ALDH2 deficiency ('Asian flush', rs671) FMK 03.4 · slide 15, 21 |
Aldehyde dehydrogenase 2 (mitochondrial) polymorphism rs671 | Impaired acetaldehyde clearance after drinking causes acetaldehyde accumulation (protein/DNA adducts, mitochondrial damage), mimicking the disulfiram reaction. | ↑ acetaldehyde |
AD | facial flushing, nausea after small amounts of alcohol; ↓ risk of alcohol dependence but ↑ risk of esophageal cancer with drinking | ||
| Angelman syndrome FMK 06.3 · slide When Gene Regulation Fails; Conclusion Listed with Prader-Willi as an 'imprinting disorder'; same region, opposite parent of origin |
Genomic imprinting error: loss of maternally expressed UBE3A at 15q11-q13 (maternal deletion or paternal uniparental disomy; widely known) | The paternal UBE3A allele is imprinted/silenced in neurons, so loss of the maternal contribution leaves no functional UBE3A (an E3 ubiquitin ligase). | ↓ Maternal UBE3A expression |
Chromosomal | Severe intellectual disability, ataxia, seizures, inappropriate laughter ('happy puppet'; widely known) | Methylation-specific testing / FISH for 15q11-13 | |
| Burkitt lymphoma (t(8;14) MYC-IGH) FMK 08.2 · slide Nomenclature – Translocation of a Portion of One Chromosome Nomenclature example: translocation swaps 8q24 (region 2 band 4) with 14q32 (region 3 band 2) |
Reciprocal translocation 46,XX,t(8;14)(q24;q32) placing MYC (8q24) next to the immunoglobulin heavy chain locus IGH (14q32) | Juxtaposition of the MYC oncogene with the IGH enhancer drives constitutive MYC expression in B cells, causing a highly proliferative lymphoma. | ↑ MYC oncoprotein (overexpressed) |
Acquired | Rapidly growing jaw or abdominal mass in children/young adults; 'starry sky' histology | Karyotype 46,XX,t(8;14)(q24;q32); FISH for MYC rearrangement | |
| Chronic myeloid leukemia (CML) FMK 08.2 · slide Clinical Cytogenetics and Molecular Cytogenetics Cited as the example of molecular cytogenetics identifying specific cancer mutations |
Specific cancer mutation detected by molecular cytogenetics Philadelphia chromosome, BCR-ABL fusion) | A reciprocal translocation creates the BCR-ABL fusion tyrosine kinase that is constitutively active, driving myeloid proliferation. | ↑ Mature and maturing granulocytes |
Acquired | Leukocytosis, splenomegaly, fatigue | FISH/microarray for the specific cancer mutation; karyotype t(9;22)(q34;q11) | Tyrosine kinase inhibitors, e.g., imatinib |
| Cri-du-chat syndrome (5p-) FMK 08.5 · slide Chromosomal Deletions 1/15,000-1/50,000 live births; 'cry of the cat' |
Partial deletion of the short arm of chromosome 5 (46,XX,del(5)(p15.3)) | Loss of 5p genes causes laryngeal and neurodevelopmental abnormalities; the larger the deletion, the more severe the phenotype; mostly sporadic (only 2% from a parental balanced rearrangement). | ↓ 5p15 genes |
Chromosomal | High-pitched cat-like cry, microcephaly, growth deficiency, congenital heart disease, hypotonia, intellectual disability | Karyotype/FISH showing del(5p) | Supportive |
| Cystic fibrosis FMK 01.2 · slide 01.2: 01.2: 7; 02.3: 13, 18; 04.2: 6; 07.3: Applications and Implications of CRISPR-Cas9; 04.4: 5, 10, 28 Listed among ion-channel diseases; ABC = ATP-Binding-Cassette |
CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), an ABC-family Cl- channel; dF508 deletion causes misfolding (loss of function) | Defective CFTR chloride channel causes thick secretions in lungs and pancreas; lecture cites it as a disease whose causative allele could be replaced with a healthy variant via CRISPR-Cas9 homology-directed repair. | ↑ Thick viscous mucus in airways, pancreatic ducts ↓ Epithelial Cl- secretion |
AR | steatorrhea, failure to thrive, recurrent pulmonary infections, meconium ileus; CFTR also expressed in lungs, testes, sweat glands | Sweat chloride test; CFTR genotyping | CFTR modulators, airway clearance, pancreatic enzyme replacement |
| DiGeorge syndrome (22q11.2 deletion) FMK 08.2 · slide 08.2: Nomenclature – Addition/Deletion of a Portion of One Chromosome; 08.5: Chromosomal Deletions Classic example that karyotyping cannot detect microdeletions |
Microdeletion on the long arm of chromosome 22, region 1, band 1, sub-band 2: 46,XY,del(22)(q11.2) | Interstitial microdeletion removes genes (including TBX1) required for third/fourth pharyngeal pouch development, causing thymic and parathyroid hypoplasia and conotruncal heart defects. | ↓ T cells (thymic hypoplasia), parathyroid hormone/calcium |
Chromosomal | Micrognathia, palatal anomalies (~70%), microtia, hypocalcemia, congenital heart disease (~75%), renal anomalies (~30%), immunodeficiency, learning disorders (~80%) | Microdeletion (<5 Mb) is NOT visible on karyotype — requires FISH (targeted 22q11.2 probe) or microarray; karyotype string 46,XY,del(22)(q11.2) | Calcium/vitamin D, cardiac surgery, immune monitoring |
| Down syndrome (Trisomy 21) FMK 08.2 · slide 08.2: Clinical Cytogenetics; Nomenclature – Addition/Deletion of a Whole Chromosome; Down Syndrome (T21); 08.5: Fetal Aneuploidy; Second Trimester Screen; Level II Ultrasound; Autosomal Aneuploidies Karyotype string = total chromosomes, sex chromosomes, then abnormality: 47,XX,+21 |
Three copies of chromosome 21: ~95% free trisomy from nondisjunction (47,XX,+21 or 47,XY,+21), ~5% from an unbalanced Robertsonian translocation (46,XX,der(14;21)(q10;q10),+21) | Nondisjunction of chromosome 21 (most often an error in creation of the egg or sperm) or inheritance of a der(14;21) from a balanced carrier yields an extra dose of chromosome 21 genes. | Chromosomal | Upslanting palpebral fissures, epicanthal folds, sandal gap between toes 1-2, single palmar crease, tongue thrusting, hypotonia, thick nuchal fold, congenital heart defects in 50% (AV septal defect, tetralogy of Fallot), duodenal atresia, Hirschsprung disease, intellectual disability | First trimester: thickened nuchal translucency, absent nasal bone, abnormal ductus venosus flow, tricuspid regurgitation, low PAPP-A; Quad screen: low AFP, high beta-hCG, low estriol, high inhibin-A (81% detection); cfDNA extra chr 21 fragments; Level II ultrasound (50-60%): heart defect, short long bones, duodenal atresia, thick nuchal fold; confirm by CVS/amniocentesis karyotype | Supportive; cardiac surgery as needed | |
| Dravet syndrome FMK 04.2 · slide 15 Gonadal mosaicism: recurrence risk is real and non-zero |
SCN1A sodium channel | Dominant de novo channel mutation causes severe epilepsy; sibling recurrence reflects germline (gonadal) mosaicism in a phenotypically normal parent. | AD | severe infantile-onset epilepsy, recurrence in siblings of unaffected parents | |||
| Edwards syndrome (Trisomy 18) FMK 08.5 · slide Fetal Aneuploidy; First/Second Trimester Screen; Level II Ultrasound; Autosomal Aneuploidies 1/3,000-1/8,000 live births; Edwards = Eighteen, overlapping fingers, rocker-bottom feet |
Extra copy of chromosome 18 (47,XY,+18) | Meiotic nondisjunction yields trisomy 18; chromosome 18 has few genes but the imbalance causes growth restriction and multi-organ malformations. | Chromosomal | Intrauterine growth restriction, microcephaly, strawberry-shaped head, brain malformation, congenital heart defects, rocker-bottom feet, overlapping/clenched fingers, malformed low-set posteriorly rotated ears; 90% die before 1 year | Thickened nuchal translucency; quad screen abnormal (screened alongside T21); Level II ultrasound detects ~90%; cfDNA; karyotype 47,XY,+18 | Supportive/palliative | |
| Fragile X syndrome FMK 06.3 · slide 06.3 'When Gene Regulation Fails'; 07.3 'Southern Blot' Listed with myotonic dystrophy as a 'trinucleotide repeat expansion'; Southern = DNA (SNoW DRoP) |
CGG trinucleotide repeat expansion in FMR1 | Expanded CGG repeats become hypermethylated, silencing FMR1 transcription epigenetically — a trinucleotide repeat expansion disorder in which gene regulation fails. | ↑ CGG repeats in FMR1 ↓ FMRP (FMR1 protein) |
XD | Intellectual disability, long face, large ears, macroorchidism | Southern blot to determine the number of CGG repeats (per 07.3); PCR | |
| Klinefelter syndrome (47,XXY) FMK 08.5 · slide Fetal Aneuploidy; Sex Chromosome Aneuploidies 1/500-1/1,000 live-born males |
Extra X chromosome in a male (47,XXY); nondisjunction in meiosis II, paternal or maternal origin 50/50 | Supernumerary X causes testicular dysgenesis with low testosterone and elevated gonadotropins, plus mild cognitive effects. | ↓ Testosterone / spermatogenesis |
Chromosomal | Tall stature (~185 cm), long extremities, sparse body hair, post-pubertal small testes, infertility, gynecomastia, IQ 10-15 points below siblings, behavioral problems; breast cancer risk equal to 46,XX females (1/8); often diagnosed only at infertility workup | Karyotype 47,XXY | Testosterone replacement, fertility counseling |
| Noonan syndrome FMK 05.2 · slide 14 SOS = the GEF that turns Ras 'on' — too much SOS, too much Ras |
SOS1 (and other RAS–MAPK pathway genes, e.g., PTPN11) gain-of-function mutations | Mutant SOS1 enhances Ras GDP→GTP exchange, hyperactivating the RAS–MAPK pathway during development (a 'RASopathy'). | AD | short stature, facial dysmorphia, congenital heart defects (pulmonic stenosis), skeletal anomalies | Targeted exon sequencing identifying SOS1 or other RAS-pathway mutations | ||
| Open neural tube defects (spina bifida, anencephaly) FMK 08.5 · slide Second Trimester Screen; Level II Ultrasound AFP UP = open defect (NTD or abdominal wall); AFP DOWN = Down syndrome |
Failure of the embryonic neural tube to close completely (weeks 3-4) | Incomplete neural tube closure during the first month of pregnancy leaves brain, spine or spinal cord open, allowing fetal AFP to leak into amniotic fluid and maternal serum; folate deficiency greatly increases risk. | ↑ Alpha-fetoprotein in amniotic fluid and maternal serum ↓ Folic acid (risk factor) |
Acquired | Spina bifida (open spinal defect) or anencephaly (absent cranial vault/brain), major brain/spine birth defects | Elevated maternal serum AFP on triple/quad screen; Level II ultrasound detects ~90% | Prevention with folic acid before and during early pregnancy; postnatal surgical closure |
| Osteopetrosis (ion channel disease) FMK 02.3 · slide 13 |
Osteoclast Cl- channel (ClC-7) / proton pump - listed among ion channel diseases | Osteoclasts cannot acidify the resorption lacuna, so bone is not resorbed and becomes dense but brittle. | ↑ Bone mass ↓ Bone resorption |
Acquired | Dense brittle bones, fractures, cranial nerve palsies, pancytopenia from marrow crowding | Diffusely sclerotic bones on X-ray | |
| Patau syndrome (Trisomy 13) FMK 08.5 · slide Fetal Aneuploidy; Level II Ultrasound; Autosomal Aneuploidies 1/15,000-1/20,000 live births; Patau = Polydactyly, cleft Palate, holoProsencephaly |
Extra copy of chromosome 13 (47,XY,+13) | Meiotic nondisjunction yields trisomy 13; although chromosome 13 has few genes, the dosage imbalance causes severe midline brain and facial malformations. | Chromosomal | Holoprosencephaly (brain fails to divide into two hemispheres), microcephaly, cleft lip +/- palate, polydactyly, congenital heart defects, rocker-bottom feet; 99% die before 1 year | Thickened nuchal translucency; Level II ultrasound detects ~90%; cfDNA; karyotype 47,XY,+13 | Supportive/palliative | |
| Prader-Willi syndrome FMK 06.3 · slide When Gene Regulation Fails; Conclusion Listed with Angelman as an 'imprinting disorder' arising when epigenetic gene regulation fails |
Genomic imprinting error: loss of the paternally expressed genes at 15q11-q13 (paternal deletion or maternal uniparental disomy; widely known) | Because the maternal copy of the region is silenced by imprinting (DNA methylation), loss of the paternal contribution leaves no active copy of the genes. | ↓ Paternal 15q11-13 gene expression |
Chromosomal | Hyperphagia/obesity, hypotonia, hypogonadism, intellectual disability | Methylation-specific testing / FISH for 15q11-13 | |
| Proteus syndrome FMK 04.2 · slide 15 Somatic mosaicism: earlier mutation = more cells affected = more severe |
AKT1 somatic gain-of-function mutation | A post-zygotic AKT1 activating mutation drives overgrowth only in descendant clones of the mutant cell, so severity depends on how early the mutation occurred. | Acquired | asymmetric, progressive segmental overgrowth of tissues, variable severity | Deep NGS or single-cell methods to detect low allele burden in affected tissue | ||
| Repeat expansion disorders (e.g., Huntington disease) FMK 04.2 · slide 6 Repeat expansion = anticipation |
Tandem triplet repeat amplification (e.g., CAG in HTT for Huntington) | Expanded repeats produce polyglutamine/polyalanine toxicity (gain of function) or loss of function; repeat length grows across generations, causing anticipation. | ↑ PolyQ/polyA aggregate protein |
AD | severe, earlier onset in successive generations (anticipation); chorea and dementia in Huntington | Repeat-length testing | |
| Robertsonian translocation carrier (balanced) FMK 08.2 · slide Chromosomal Translocations; Carrier of Robertsonian Translocation; Many People Learn Their Robertsonian Translocation Carrier Status ~85% of Robertsonian translocations involve 13q14q and 14q21q; rob = balanced, der = unbalanced derivative |
Fusion of two acrocentric chromosomes (13, 14, 15, 21, 22) at their centromeres, e.g., 45,XY,rob(14;21)(q10;q10) | Long arms of two acrocentric chromosomes fuse at the centromere and the short arms are lost; no essential genetic material is gained or lost so the carrier is healthy, but meiosis produces unbalanced gametes that after fertilization by a normal gamete yield trisomic or monosomic (almost always lethal) zygotes. | Chromosomal | Usually healthy; discovered through family planning challenges (recurrent pregnancy loss, infertility, or a child with translocation Down syndrome) | Karyotype 45,XY,rob(14;21)(q10;q10) — 45 chromosomes with balanced content | ||
| Turner syndrome (45,X) FMK 08.5 · slide Fetal Aneuploidy; Sex Chromosome Aneuploidies Only monosomy compatible with life; most common cause of first-trimester loss (99% of 45,X conceptions miscarry); 1/2,500 live-born females |
Monosomy X (45,X); 70% paternal nondisjunction (father contributes no X or Y), 30% maternal | Loss of one sex chromosome leaves a single X; haploinsufficiency of X genes (e.g., SHOX) causes short stature, gonadal dysgenesis and lymphatic malformation. | ↓ Second sex chromosome |
Chromosomal | Short stature, webbed neck, shield chest with widely spaced nipples, widened carrying angle (cubitus valgus), left-sided congenital heart defect (coarctation of the aorta), cystic hygroma/hydrops fetalis in utero; most diagnosed at age 5-6 | Karyotype 45,X; cystic hygroma / increased nuchal translucency on ultrasound | Growth hormone, estrogen replacement, cardiac follow-up |
| Wolf-Hirschhorn syndrome (4p-) FMK 08.5 · slide Chromosomal Deletions 1/20,000-1/50,000 live births |
Deletion of the distal short arm of chromosome 4 (46,XX,del(4)(p16.3)) | Loss of 4p16 genes disrupts craniofacial and brain development; larger deletions give more severe phenotypes. | ↓ 4p16 genes |
Chromosomal | Cleft lip +/- palate, down-turned mouth, hypertelorism (widely spaced eyes), hypotonia, severe cognitive defects ('Greek warrior helmet' facies) | Karyotype/FISH showing del(4p) | Supportive |
Signaling 10
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Addison disease (primary adrenal insufficiency) FMK 05.1 · slide 2, 21, 25; FMK 05.6 slide 19 Elena's presentation is textbook Addison |
Primary adrenal cortical failure → ↓ cortisol + ↓ aldosterone | Loss of cortisol removes negative feedback so ACTH rises; ACTH shares the POMC precursor with MSH and cross-reacts with skin melanocortin receptors (hyperpigmentation), while aldosterone loss causes salt wasting and hypotension. | ↑ ACTH (POMC/MSH) ↓ cortisol, aldosterone |
Acquired | fatigue, orthostatic hypotension, salt craving, hyperpigmentation (darkened skin creases); also a feature of X-linked adrenoleukodystrophy | ↑↑ ACTH, ↓ cortisol | glucocorticoid + mineralocorticoid replacement |
| Androgen receptor–driven prostate cancer FMK 05.5 · slide 2, 4, 5, 21 Type I = cytoplasmic (steroid receptors: androgen, gluco/mineralocorticoid); Type II = nuclear (thyroid, retinoic acid, vitamin D) |
Androgen receptor (Type I cytoplasmic intracellular receptor) | Androgen binding moves the receptor to the nucleus where it acts as a transcription factor driving prostate cell proliferation; tumors depend on this signaling. | Acquired | prostate cancer | PSA elevation | Androgen deprivation / androgen receptor antagonists | |
| Congenital adrenal hyperplasia (21α-hydroxylase deficiency) FMK 05.1 · slide 19, 25 CAH = a block anywhere on the steroid map: what's missing downstream, what backs up upstream |
21α-hydroxylase (most common CAH, ~90%+) | Block in the glomerulosa and fasciculata branches prevents aldosterone and cortisol synthesis; precursors back up and are shunted to the androgen branch, while loss of cortisol feedback raises ACTH and hyperplasia. | ↑ 17-hydroxyprogesterone/progesterone precursors, adrenal androgens (DHEA, testosterone), ACTH ↓ cortisol, aldosterone |
AR | salt-wasting, virilization | ↓ cortisol, ↓ aldosterone | |
| Congenital hyperinsulinism (SUR / K-ATP channel loss of function) FMK 02.3 · slide 18 SUR = Sulphonyl urea Receptor, an ABC protein |
Sulfonylurea receptor (SUR1), ABC-family K+ channel subunit - loss of function | Loss of the K-ATP channel keeps beta cells depolarized, causing unregulated Ca2+ influx and constant insulin secretion. | ↑ Insulin ↓ Blood glucose |
AR | Persistent neonatal hypoglycemia, seizures | Hypoglycemia with inappropriately elevated insulin | Diazoxide (opens K-ATP), pancreatectomy |
| Cushing syndrome / Cushing disease FMK 05.1 · slide 21, 25 |
Cortisol excess — adrenal tumor (ACTH-independent, ↓ ACTH) or pituitary Cushing disease (ACTH-dependent, ↑ ACTH) | Excess cortisol is gluconeogenic, insulin-antagonizing and catabolic to muscle protein, producing hyperglycemia, central obesity and proximal weakness. | ↑ cortisol |
Acquired | truncal obesity, hypertension, proximal muscle weakness, hyperglycemia | ACTH high (pituitary) vs low (adrenal tumor) | |
| EGFR-driven lung cancer (gain-of-function) FMK 01.2 · slide 01.2: 8; 05.2: 2, 11 RTK dimerize → autophosphorylate → Grb2 (SH2) → SOS (SH3) → Ras-GTP → Raf → MEK → ERK |
EGFR receptor tyrosine kinase, activating (gain-of-function) mutation | Mutant EGFR signals without ligand, hyperactivating the Grb2–SOS–Ras–Raf–MEK–ERK (MAPK) cascade and driving uncontrolled proliferation. | Acquired | non-small cell lung cancer (classically adenocarcinoma in non-smokers) | EGFR mutation on tumor genotyping | EGFR tyrosine kinase inhibitors | |
| Hyperthyroidism FMK 05.5 · slide 2, 6 TR–RXR heterodimer: CoR off, CoA on |
Excess T3 acting on the nuclear thyroid hormone receptor (TR) | T3 binds DNA-bound TR, releasing co-repressor, pairing with RXR and recruiting co-activators to drive transcription at thyroid response elements; excess hormone over-drives metabolic gene expression. | ↑ T3/T4 |
Acquired | weight loss, heat intolerance, tachycardia, tremor, anxiety | Elevated free T4/T3 with suppressed TSH | Antithyroid drugs, beta-blockers for adrenergic symptoms |
| Hypoglycemia in counter-regulatory hormone deficiency (glucagon, epinephrine/adrenal insufficiency, cortisol) FMK 03.6 · slide 27 |
Glucagon deficiency (absent PKA cascade), epinephrine deficiency (adrenal insufficiency), cortisol deficiency | Without glucagon the PKA cascade cannot activate glycogenolysis; without epinephrine glycogen is not mobilized under stress; without cortisol gluconeogenesis and insulin counter-regulation are impaired. | ↑ glycogen (unmobilized) ↓ blood glucose during fasting/stress |
Acquired | fasting or stress hypoglycemia; patients especially sensitive to fasting or stress | hypoglycemia | |
| JAK2 V617F myeloproliferative disease FMK 05.2 · slide 2, 21 JAK-STAT = fast-acting cytokine/growth-hormone signaling; STAT has the SH2 domain |
JAK2 (Janus kinase 2) V617F gain-of-function mutation | Constitutively active JAK2 phosphorylates STATs without cytokine binding, driving continuous transcription of blood-cell production genes. | ↑ Excess blood cells (e.g., red cells in polycythemia vera) |
Acquired | myeloproliferative neoplasm (polycythemia vera, essential thrombocythemia, primary myelofibrosis), hyperviscosity, thrombosis | JAK2 V617F mutation on somatic testing; elevated cell counts | JAK inhibitors (e.g., ruxolitinib), phlebotomy for polycythemia |
| Type 2 diabetes / insulin resistance FMK 01.2 · slide 01.2: 8; 06.3: When Gene Regulation Fails; Conclusion; 02.1: 5, 6, 24, 25; FMK 03.6 slide 27 Glucose homeostasis via insulin/glucagon negative feedback (01.3) |
Insulin (peptide hormone) deficiency or insulin receptor resistance | Loss of control over protein production produces transcriptional dysregulation of metabolic genes; cited as the metabolic-disease example of failed gene regulation. | ↑ Blood glucose ↓ Insulin action |
Acquired | chronic hyperglycemia and downstream complications; early T2DM: hyperinsulinemia with excess glycogenesis; dawn phenomenon (overnight glucagon/cortisol → morning glucose rise) | Fasting glucose >=126 mg/dL, HbA1c >=6.5% | Insulin, oral hypoglycemics, lifestyle |
Neuromuscular 6
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) - FUS mutation FMK 03.5 · slide 2, 20 FUS = Fused in Sarcoma; familial ALS via RNA metabolism disruption + impaired NMD |
FUS (Fused in Sarcoma) RNA-binding protein gene | Mutant FUS loses nuclear function, accumulates in cytoplasm as toxic aggregates, sequesters nonsense-mediated decay (NMD) factors so faulty mRNAs accumulate, and induces stress granules that suppress global translation at the ER. | ↑ Cytoplasmic FUS aggregates, faulty mRNAs, stress granules ↓ Nonsense-mediated decay, global protein translation |
AD | Fatal upper and lower motor neuron degeneration: weakness, atrophy, fasciculations, spasticity, hyperreflexia | Riluzole (standard therapy, not in lecture) | |
| Duchenne muscular dystrophy FMK 07.3 · slide Applications and Implications of CRISPR-Cas9 Germline editing is illegal in >40 countries (US, China, Canada, UK); somatic editing is uncontroversial |
Frameshift/deletion mutations in the dystrophin gene | Absent dystrophin destabilizes the muscle sarcolemma leading to progressive muscle degeneration; cited as a disease whose causative allele could be corrected by CRISPR-Cas9 somatic gene editing. | ↓ Dystrophin |
XR | Proximal weakness in early childhood, Gowers sign, calf pseudohypertrophy, cardiomyopathy | Markedly elevated creatine kinase; genetic testing | Somatic CRISPR-Cas9 editing is an application under investigation |
| Migraine (ion channel disease) FMK 02.3 · slide 13 |
Neuronal Ca2+/Na+/K+ channel mutations (e.g., CACNA1A in familial hemiplegic migraine) - listed among ion channel diseases | Channel mutations increase cortical excitability, favoring cortical spreading depression and migraine. | Acquired | Recurrent unilateral throbbing headache with aura in familial forms | |||
| Myasthenia gravis FMK 05.2 · slide 9 (also FMK 04.3 slide 21) Signal transduction always begins with a receptor conformational change — no receptor, no signal (also listed under 'Anticholinesterases' in FMK 04.3 slide 21) |
Autoantibodies against the nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction | Autoimmune antibodies cause endocytosis and degradation of ACh receptors, so fewer receptors remain to open Na+ channels and generate an end-plate potential. | ↓ Functional nicotinic ACh receptors at the motor end plate |
Acquired | fatigable skeletal muscle weakness, ptosis, diplopia, weakness worsening with use and improving with rest | Improvement with acute IV edrophonium (Tensilon test); anti-AChR antibodies | Anticholinesterase inhibitors (edrophonium chloride acutely; Tensilon/Enlon/Reversol), longer-acting anticholinesterases |
| Myotonia (Cl- channelopathy) FMK 02.3 · slide 13 Cl- channels: excitability |
Skeletal muscle Cl- channel (CLCN1) - listed among ion channel diseases | Loss of muscle Cl- conductance leaves the membrane hyperexcitable, so muscle keeps firing after voluntary contraction ends. | ↓ Muscle Cl- conductance |
AD | Delayed muscle relaxation after contraction (stiffness), warm-up phenomenon | Myotonic discharges on EMG | |
| Myotonic dystrophy FMK 06.3 · slide When Gene Regulation Fails; Conclusion Listed with Fragile X as a 'trinucleotide repeat expansion' |
CTG trinucleotide repeat expansion in DMPK | Expanded CTG repeats in the 3' UTR produce toxic RNA that sequesters splicing regulators, causing mis-splicing of many transcripts; cited by the lecture as a trinucleotide repeat expansion disorder of gene regulation. | ↑ CUG-repeat RNA foci |
AD | Myotonia, muscle weakness, cataracts, frontal balding, cardiac conduction defects | Repeat-expansion testing (Southern blot / PCR) |
Cardiovascular 2
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Atherosclerosis (oxidized LDL / foam cells) FMK 04.4 · slide 22, 24 |
Macrophage scavenger receptor-A (SR-A) uptake of oxidized LDL is NOT downregulated by cholesterol | Endothelial injury/inflammation oxidizes LDL; macrophages take it up without limit via SR-A and become foam cells, forming the fatty streak. | ↑ oxidized LDL cholesteryl esters in macrophages (foam cells) |
Acquired | fatty streak → plaque; risk factors smoking, hypertension, hyperglycemia; HDL2 inversely related to risk | statins, ezetimibe, PCSK9 inhibitors, fibrates (lipid pharmacology) | |
| Myocardial infarction (troponin, CK-MB) FMK 01.2 · slide 01.2: 8; 07.2: 23 Elevated troponin I/T -> MI (key lab!) |
Cardiomyocyte necrosis releasing contractile proteins troponin I/T | Ischemic death of cardiac muscle releases troponin I/T into the serum, the key diagnostic lab for MI. | ↑ Serum troponin I/T |
Acquired | Chest pain, dyspnea, diaphoresis | Elevated troponin I/T (key lab!) |
Toxin/Drug 83
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| 2,4-Dinitrophenol (DNP) toxicity FMK 02.4 · slide 13, 14, 25 |
Uncoupler — hydrophobic weak acid that shuttles H⁺ across the inner membrane, bypassing ATP synthase | DNP dissipates the proton gradient so the ETC runs (O₂ consumed) but energy is released as heat rather than ATP. | ↑ heat ↓ ATP |
Acquired | hyperthermia (>40°C), tachycardia, diaphoresis, rapid weight loss, death; 1930s diet pill still sold online | ↑ temperature, metabolic acidosis, ↑ O₂ consumption | Cooling, supportive care |
| 5-Fluorouracil (5-FU) - thymidylate synthase inhibitor FMK 02.2 · slide 02.2: 23; 08.1: 24, 29 5-FU -> F-dUMP -> blocks TS -> no dTMP -> no DNA |
Thymidylate synthase (TS), inhibited by F-dUMP | Cells convert 5-FU to F-dUMP, which binds TS very tightly as a competitive inhibitor, so dUMP cannot be converted to dTMP and no dTTP or DNA is made. | ↑ dUMP ↓ dTMP, dTTP, DNA synthesis |
Acquired | Chemotherapy (colorectal and other cancers); adverse: myelosuppression, mucositis | ||
| 6-Mercaptopurine (6-MP) FMK 08.1 · slide 29 Listed among nucleoside analogs (5-FU, 6-MP, hydroxyurea) — 'know the step, and you know the drug's mechanism and toxicity profile' |
Purine (nucleoside) analog; inhibits de novo purine synthesis | Acts as an antimetabolite that blocks specific steps of purine nucleotide synthesis in rapidly dividing cells. | ↓ Purine nucleotides |
Acquired | Used for: ALL, IBD; toxicity greatly increased with allopurinol (xanthine oxidase metabolises 6-MP) and in TPMT deficiency; side effects: myelosuppression, hepatotoxicity | ||
| ACE inhibitors (hyperkalemia side effect) FMK 05.1 · slide 20 |
Angiotensin-converting enzyme (lung) | Blocking angiotensin II formation removes both vasoconstriction and aldosterone-driven Na⁺/volume retention and K⁺ excretion, so potassium rises. | ↑ K⁺ ↓ angiotensin II, aldosterone |
Acquired | antihypertensive; hyperkalemia is a known side effect | ↑ K⁺ | |
| Acetaminophen hepatotoxicity in chronic alcohol use (CYP2E1/NAPQI) FMK 03.4 · slide 16, 24 |
Induced CYP2E1 (MEOS) converts acetaminophen to toxic NAPQI | Chronic alcohol induces CYP2E1, so standard acetaminophen doses generate more NAPQI, which depletes glutathione and causes hepatocyte necrosis; induction persists for weeks after abstinence. | ↑ NAPQI, ROS ↓ glutathione |
Acquired | acute liver failure in a chronic drinker on standard acetaminophen doses | ↑ LFTs | |
| Acute gout anti-inflammatory therapy (colchicine, NSAIDs, glucocorticoids) FMK 08.1 · slide 20, 28 Acute attack = treat inflammation; long-term = treat urate |
Colchicine (microtubule inhibitor), NSAIDs such as indomethacin (COX inhibitors), glucocorticoids such as prednisolone | Target the inflammatory response to MSU crystals during an acute attack, not uric acid levels themselves. | Acquired | Used for: the acute gouty attack (hot, swollen first MTP) — colchicine, NSAIDs (indomethacin) or glucocorticoids; they do not lower urate | |||
| Acute lymphoblastic leukemia (asparaginase therapy) FMK 07.1 · slide 23 |
Drug target: circulating asparagine hydrolyzed by therapeutic asparaginase | Leukemic cells cannot synthesize enough asparagine to support rapid growth and depend on circulating supply; asparaginase depletes plasma asparagine and starves them. | ↓ Circulating asparagine (therapeutically) |
Acquired | Leukemia treated with asparaginase chemotherapy | Asparaginase | |
| Allopurinol FMK 08.1 · slide 20, 28 Allopurinol treats the urate of Lesch-Nyhan, not the neurology |
Hypoxanthine analog that inhibits xanthine oxidase | Blocks oxidation of hypoxanthine to xanthine and xanthine to uric acid, so the more soluble hypoxanthine and xanthine accumulate and are excreted in urine instead of insoluble uric acid. | ↑ Hypoxanthine, xanthine (soluble, excreted) ↓ Uric acid |
Acquired | Long-term therapy for over-producers of uric acid (gout, Lesch-Nyhan urate manifestations) | Lowers serum uric acid | |
| Alpha-amanitin (death cap mushroom) poisoning FMK 03.2 · slide 2, 24, 27 Amanita = Amanitin = RNA Pol II (mRNA) |
Eukaryotic RNA polymerase II (non-competitive inhibition) | Alpha-amanitin from Amanita phalloides non-competitively inhibits RNA polymerase II, halting mRNA synthesis and killing hepatocytes and renal cells. | ↓ mRNA production |
Acquired | GI disturbances, electrolyte imbalance, fever, then liver and kidney dysfunction; 40-90% mortality within days | Elevated liver enzymes, renal failure | No antidote; supportive care, liver transplant |
| Antidepressants (monoamine reuptake inhibitors) FMK 04.3 · slide 21 |
Neuronal reuptake transporters for catecholamines/serotonin | Inhibiting high-affinity reuptake raises synaptic monoamine levels, enhancing postsynaptic signaling. | ↑ Synaptic monoamines (NE, serotonin) |
Acquired | therapeutic antidepressant effect | ||
| Antimycin A (Complex III inhibition) FMK 02.4 · slide 9, 11, 20 |
Complex III (cytochrome bc₁) | Antimycin A blocks electron transfer from CoQ to cytochrome c, backing up the ETC, lowering ATP and increasing ROS production. | ↑ reduced CoQ, ROS ↓ ATP |
Acquired | research tool, not a common clinical poisoning | ETC backed up, ↓ ATP, ↑ ROS | |
| Arsenic poisoning FMK 02.1 · slide 23, 24 |
Arsenite (As³⁺) binds SH groups of lipoic acid (PDH, α-KG DH, BCKA DH); arsenate (As⁵⁺) substitutes for Pi at G3P dehydrogenase | Arsenite inactivates the lipoic-acid-dependent dehydrogenases so pyruvate cannot enter the TCA cycle, while arsenate forms 1-arseno-3-PG that hydrolyzes spontaneously, bypassing 1,3-BPG and eliminating ATP production at the phosphoglycerate kinase step. | ↑ pyruvate, lactate ↓ ATP, acetyl-CoA |
Acquired | GI symptoms (vomiting, rice-water stools), peripheral neuropathy, Mees' lines on nails, hypotension, cardiovascular collapse, encephalopathy | Chelation (dimercaprol / DMSA) | |
| Aspirin (irreversible COX suicide inhibition / toxicity) FMK 01.5 · slide 2, 16 Suicide inhibitor kinetics resemble non-competitive when enzyme > inhibitor |
Cyclooxygenase COX-1 and COX-2 (irreversibly acetylated) | Aspirin covalently acetylates the COX active site, permanently blocking prostaglandin (and thromboxane) production. | ↓ Prostaglandins, thromboxane A2 |
Acquired | Analgesic/anti-inflammatory/antiplatelet effects; toxicity: tinnitus, hyperventilation, mixed respiratory alkalosis + metabolic acidosis, GI bleeding | Salicylate level; mixed acid-base disturbance in overdose | Alkalinize urine, dialysis in severe toxicity |
| Aspirin (salicylate) overdose FMK 02.4 · slide 13, 14, 25 |
Partial uncoupling of OXPHOS + inhibition of TCA enzymes | High-dose salicylates partially uncouple oxidative phosphorylation and inhibit TCA enzymes, causing fever and metabolic acidosis after an early respiratory alkalosis. | ↑ salicylate, lactate ↓ ATP |
Acquired | fever, tachypnea, tinnitus | respiratory alkalosis early → anion-gap metabolic acidosis | Urinary alkalinization, hemodialysis if severe |
| Azithromycin (50S ribosomal inhibitor) FMK 06.5 · slide Eukaryote vs Prokaryote Pharmacology targets 30S (doxycycline) and 50S (azithromycin) |
Binds the 50S subunit of the prokaryotic 70S ribosome | Blocks the bacterial large ribosomal subunit, halting translation selectively in prokaryotes whose ribosomes differ structurally from human 80S ribosomes. | ↓ Bacterial protein synthesis |
Acquired | Used for: atypical pneumonia, chlamydia, pertussis; side effects: GI upset, QT prolongation | ||
| Benzodiazepines / barbiturates (GABA-A agonists) FMK 04.3 · slide 15, 21 GABA = forebrain inhibitor; glycine = spinal cord/brainstem inhibitor |
GABA-A receptor (ligand-gated chloride channel) positive modulators | Enhancing GABA-A chloride influx hyperpolarizes neurons (IPSP), producing sedative, anxiolytic and anticonvulsant effects. | Acquired | sedation, anxiolysis, anticonvulsion, respiratory depression in overdose | |||
| Carbon monoxide (CO) poisoning FMK 06.1 · slide 06.1: 2, 23; 02.4: 9, 11, 17, 20, 25; 08.4: 6, 20 Cherry-red, pulse ox 98%, still suffocating — left-shifted, hyperbolic curve |
CO binds hemoglobin heme ~220× more tightly than O₂, forming carboxyhemoglobin (HbCO) | CO locks the tetramer toward the R state, raising the remaining subunits' O₂ affinity (left shift, more hyperbolic curve) so hemoglobin will not release the O₂ it carries — tissue delivery collapses despite adequate O₂ content. | ↑ Carboxyhemoglobin ↓ Tissue O₂ delivery |
Acquired | Found unconscious in a running car in a closed garage, cherry-red skin, barely breathing/unresponsive, pulse oximeter falsely reads 98% | Normal-appearing pulse oximetry despite tissue hypoxia; HbCO level | 100% O₂ or hyperbaric O₂ — mass action competes CO off hemoglobin and shortens HbCO half-life |
| CETP inhibitors (anacetrapib class) FMK 04.4 · slide 19; FMK 05.1 slide 12 Raising a lab value ≠ improving a clinical outcome |
Cholesteryl ester transfer protein | Blocking CETP exchange of VLDL-TAG for HDL-CE raises HDL and lowers LDL, but clinical outcome benefit has been inconsistent. | ↑ HDL cholesteryl esters |
Acquired | raised HDL in trials without improving outcomes | ↑ HDL, ↓ LDL | |
| Chloramphenicol (50S - inhibits peptidyltransferase) FMK 03.5 · slide 9 50S: Chloramphenicol (peptidyltransferase), Erythromycin (translocation) |
Bacterial 50S ribosomal subunit peptidyltransferase | Chloramphenicol binds the 50S subunit and inhibits peptidyltransferase, blocking peptide bond formation. | ↓ Bacterial protein synthesis |
Acquired | Antibiotic; can affect human mitochondria; adverse: aplastic anemia, gray baby syndrome | ||
| Cholera toxin FMK 05.5 · slide 19, 21 Cholera = Gs ON permanently; Pertussis = Gi OFF — both raise cAMP |
Gαs subunit ADP-ribosylated by Vibrio cholerae toxin | Constitutive Gαs activation sustains cAMP, PKA phosphorylates and opens CFTR so Cl- and Na+ pour into the gut lumen and water follows osmotically. | ↑ cAMP; Cl-, Na+ and water in the intestinal lumen |
Acquired | massive 'rice-water' diarrhea, life-threatening dehydration | Oral/IV rehydration | |
| Cigarette smoke / benzo[a]pyrene DNA adducts (NER substrate) FMK 02.5 · slide 14, 15, 22 Bulky lesions -> NER |
Benzo[a]pyrene oxidized by cytochrome P450 to a reactive epoxide that binds guanine | The P450-generated epoxide binds covalently to guanine, its bulk disrupts G-C hydrogen bonding and distorts the helix, interfering with replication; repaired by nucleotide excision repair. | ↑ Bulky guanine DNA adducts |
Acquired | Smoking-related carcinogenesis (lung cancer) | ||
| Ciprofloxacin (DNA gyrase inhibitor) FMK 06.5 · slide Prokaryotic DNA is Supercoiled; Eukaryote vs Prokaryote DNA gyrase in prokaryotes ~ topoisomerase II in eukaryotes (Turn and Talk) |
Inhibits prokaryotic DNA gyrase | Bacteria rely on DNA gyrase to cut, twist, and reseal DNA to maintain negative supercoiling of their circular chromosome; inhibiting gyrase blocks bacterial replication and transcription while eukaryotes use histone-bound linear DNA. | ↓ Bacterial DNA supercoiling / replication |
Acquired | Used for: UTIs, gram-negative infections; side effects: tendinopathy/tendon rupture, QT prolongation, avoided in children and pregnancy | ||
| Cisplatin (DNA cross-linker) FMK 02.2 · slide 15 |
DNA (tight covalent binding causing structural distortion) | Cisplatin binds tightly to DNA, distorting its structure so replication and transcription malfunction. | Acquired | Used for bladder, lung and other cancers; adverse: nephrotoxicity, ototoxicity | |||
| Cocaine (catecholamine reuptake inhibitor) FMK 04.3 · slide 11, 21 Catecholamines are inactivated by reuptake first, then MAO and/or COMT |
High-affinity sodium-cotransport reuptake of catecholamines into the nerve terminal | Blocking reuptake leaves norepinephrine/dopamine in the synaptic cleft longer, prolonging and amplifying adrenergic and dopaminergic signaling. | ↑ Catecholamines in the synaptic cleft |
Acquired | sympathomimetic state: tachycardia, hypertension, mydriasis, euphoria | ||
| Complex I inhibition (rotenone, amobarbital) FMK 02.4 · slide 9, 11, 20 |
Complex I (NADH dehydrogenase) | Rotenone (pesticide) and amobarbital (barbiturate sedative) block NADH electron entry at Complex I, raising NADH/NAD⁺ and lowering ATP. | ↑ NADH, lactate ↓ ATP |
Acquired | pesticide/barbiturate exposure, energy failure, lactic acidosis | ↑ NADH/NAD⁺, ↓ ATP, ↑ lactate | |
| Corticosteroids (phospholipase A2 inhibition) FMK 04.1 · slide 22 Steroids act upstream of the COX/LOX branch point; NSAIDs only hit COX |
Phospholipase A2 inhibited | Blocking PLA2 prevents arachidonic acid release from membrane phosphatidylinositol, shutting off both COX and LOX eicosanoid branches. | ↓ Free arachidonic acid, prostaglandins, thromboxanes, leukotrienes |
Acquired | broad anti-inflammatory effect | ||
| Curare (non-depolarizing NMJ blocker) FMK 04.3 · slide 19, 21 NMJ blockade sites: presynaptic release, vesicle fusion, receptor binding |
Competitive antagonist at the nicotinic ACh receptor of the neuromuscular junction | Curare occupies nAChRs without opening them, so ACh cannot generate an end-plate potential and skeletal muscle is paralyzed. | Acquired | flaccid skeletal muscle paralysis, respiratory paralysis | Reversed by anticholinesterases | ||
| Cyanide poisoning FMK 02.4 · slide 9, 11, 13, 17, 20, 25 Cyanide binds Fe³⁺, CO binds Fe²⁺ |
Complex IV (cytochrome c oxidase) — CN⁻ binds Fe³⁺ in heme a₃ | Cyanide blocks O₂ reduction at Complex IV so electron flow stops, ATP synthesis fails and cells shift to anaerobic glycolysis with lactic acidosis despite adequate O₂ delivery. | ↑ NADH, lactate ↓ ATP |
Acquired | confusion, coma, house-fire (polyurethane smoke) exposure, bitter-almond odor, industrial exposure | ↑ lactate (anion-gap acidosis), ↑ mixed venous O₂ (cells cannot use O₂), normal PaO₂ | Hydroxocobalamin + 100% O₂ |
| Dactinomycin (actinomycin D) - DNA intercalator FMK 02.2 · slide 02.2: 15; 03.2: 2, 23, 27 Actinomycin D intercalates -> prevents transcription elongation |
DNA double helix (intercalates into the narrow groove), blocking RNA polymerase movement | Dactinomycin intercalates into DNA and interferes with DNA and RNA synthesis by blocking RNA polymerase elongation along the template. | ↓ RNA (and DNA) synthesis |
Acquired | Cytotoxic antitumor antibiotic; first antibiotic used in tumor chemotherapy (eukaryotes) | ||
| Daunorubicin / doxorubicin (anthracycline intercalators) FMK 02.2 · slide 15 |
DNA (intercalation between bases) and topoisomerase II | Anthracyclines intercalate between DNA bases and interfere with topoisomerase II, preventing replication. | ↓ DNA replication |
Acquired | Used to treat leukemias; adverse: dose-dependent cardiotoxicity | ||
| Diphtheria toxin (eEF2 inactivation) FMK 03.5 · slide 17 Diphtheria toxin & Pseudomonas exotoxin A both ADP-ribosylate EF-2 |
Eukaryotic elongation factor 2 (eEF2), ADP-ribosylated by the toxin | Diphtheria toxin, encoded by a phage carried in Corynebacterium diphtheriae, modifies (ADP-ribosylates) eEF2 and blocks translocation, halting eukaryotic protein synthesis. | ↓ Functional eEF2, host protein synthesis |
Acquired | Pharyngitis with gray pseudomembrane, bull neck, myocarditis, neuropathy | Antitoxin, antibiotics; prevented by toxoid vaccine | |
| Disulfiram (Antabuse) - acetaldehyde reaction FMK 01.5 · slide 01.5: 2, 14; 03.4: 21 Non-competitive: lowers Vmax, Km unchanged |
Aldehyde dehydrogenase (non-competitive, allosteric-site inhibition) | Disulfiram binds aldehyde dehydrogenase at a site other than the active site, lowering Vmax so acetaldehyde from ethanol builds up. | ↑ Acetaldehyde |
Acquired | facial flushing, headache, nausea, vomiting, hypotension, tachycardia, palpitations after alcohol | used therapeutically as aversive therapy for alcohol use disorder | |
| Doxycycline (30S ribosomal inhibitor) FMK 06.5 · slide Eukaryote vs Prokaryote 70S prokaryote = 50S + 30S; 80S eukaryote = 60S + 40S |
Binds the 30S subunit of the prokaryotic 70S ribosome | Selective toxicity: prokaryotic ribosomes (70S = 50S + 30S) differ from eukaryotic 80S (60S + 40S) ribosomes, so blocking the 30S subunit stops bacterial translation without harming human ribosomes. | ↓ Bacterial protein synthesis |
Acquired | Used for: atypical pneumonia, Lyme, acne, rickettsia; side effects: photosensitivity, tooth discoloration in children, GI upset | ||
| Drug displacement of bilirubin from albumin (salicylates, sulfonamides) FMK 08.4 · slide handout |
Drug target: albumin binding sites for unconjugated bilirubin | Salicylates and sulfonamides compete with unconjugated bilirubin for albumin, raising free bilirubin that can cross the immature neonatal blood-brain barrier. | ↑ Free (unbound) unconjugated bilirubin ↓ Albumin-bound bilirubin |
Acquired | Increased kernicterus risk in neonates given or exposed to these drugs | Avoid salicylates/sulfonamides in neonates | |
| Erythromycin (50S - prevents translocation) FMK 03.5 · slide 9 |
Bacterial 50S ribosomal subunit | Erythromycin (macrolide) binds the 50S subunit and prevents ribosome translocation along mRNA. | ↓ Bacterial protein synthesis |
Acquired | Macrolide antibiotic; adverse: GI upset, QT prolongation | ||
| Ethylene glycol (antifreeze) poisoning FMK 01.5 · slide 2, 13 Ethanol out-competes ethylene glycol for the ADH active site: competitive inhibition raises Km, Vmax unchanged |
Alcohol dehydrogenase converts ethylene glycol to toxic metabolites (glycolate, oxalate) | Ethylene glycol is a substrate of alcohol dehydrogenase and is oxidized to toxic acids that cause metabolic acidosis and calcium oxalate renal injury. | ↑ Glycolic acid, oxalate (calcium oxalate crystals) |
Acquired | Inebriation, anion-gap metabolic acidosis, acute kidney injury | Anion-gap acidosis, osmolar gap, calcium oxalate crystals in urine | Ethanol (100-fold higher ADH affinity, competitive inhibitor) or fomepizole |
| Etoposide (VP-16) - topoisomerase inhibitor FMK 02.5 · slide 9 |
Eukaryotic topoisomerase (II) | Etoposide inhibits topoisomerase, leaving DNA strand breaks unresealed and blocking replication in dividing tumor cells. | ↑ DNA double-strand breaks |
Acquired | Widely used for lung, ovarian, testicular and prostate cancer | ||
| Ezetimibe (NPC1L1 inhibitor) FMK 04.4 · slide 9, 29, 30 |
NPC1L1 cholesterol transporter at enterocyte brush border | Blocking NPC1L1 lowers intestinal cholesterol absorption, giving additive LDL lowering when paired with a statin. | Acquired | used for LDL lowering, often with a statin; part of FH therapy | ↓ LDL (additive) | ||
| Fibrates (PPAR-α agonists) FMK 04.4 · slide 30; FMK 05.1 slide 14 |
PPAR-α activation → ↑ lipoprotein lipase | Increased LPL expression accelerates TAG clearance (first-line for severe hypertriglyceridemia); paradoxically raise gallstone risk by increasing biliary cholesterol secretion. | ↑ biliary cholesterol (gallstone risk) |
Acquired | first-line for severe ↑TAG; side effect gallstones | ↓↓ TAG | |
| Fluconazole (antifungal) and the challenge of fungal infections FMK 06.5 · slide Eukaryote vs Prokaryote; Think-Pair-Share Think-Pair-Share: why fungal infections are harder to treat than bacterial — fungi are eukaryotes |
Targets fungal cell wall/membrane (ergosterol synthesis; widely known) | Fungi are eukaryotes like humans, so selective toxicity relies on the fungal cell wall (chitin) and ergosterol-based membrane; this shared eukaryotic biology makes fungal infections harder to treat than bacterial ones. | ↓ Fungal ergosterol |
Acquired | Used for: candidiasis, cryptococcal meningitis prophylaxis; side effects: hepatotoxicity, drug interactions (CYP inhibition) | ||
| Gentamicin (30S - prevents ribosome assembly) FMK 03.5 · slide 9 |
Bacterial 30S ribosomal subunit | Gentamicin binds the 30S subunit and prevents ribosome assembly. | ↓ Bacterial protein synthesis |
Acquired | Aminoglycoside antibiotic; can affect human mitochondria; adverse: nephrotoxicity, ototoxicity | ||
| Givosiran FMK 08.4 · slide 18 |
Drug target: ALAS1 mRNA (siRNA) | A small interfering RNA that degrades hepatic ALAS1 mRNA, lowering ALAS1 protein and thereby ALA/PBG production to prevent recurrent acute porphyria attacks. | Acquired | Newer option for recurrent acute hepatic porphyria attacks | |||
| Hydrogen sulfide (H₂S) poisoning FMK 02.4 · slide 9, 11 |
Complex IV (cytochrome c oxidase) | H₂S, like cyanide and CO, inhibits cytochrome c oxidase so O₂ is not reduced and the ETC stops. | ↑ NADH, lactate ↓ ATP |
Acquired | listed as a Complex IV inhibitor alongside cyanide and CO (ETC stops, ATP failure) | ↑ lactate | |
| Hydroxyurea FMK 08.1 · slide 15, 29 RNR is the ONLY enzyme making deoxyribonucleotides — inhibited by hydroxyurea pharmacologically, by dATP pathologically (ADA deficiency) |
Directly inhibits ribonucleotide reductase (RNR) | Blocks conversion of all ribonucleoside diphosphates to deoxyribonucleoside diphosphates, halting dNTP production and therefore DNA synthesis in rapidly dividing cells. | ↑ Ribonucleotides (NDPs) ↓ All four dNTPs |
Acquired | Used as an antineoplastic (melanoma, myeloproliferative disorders) and at lower doses in sickle cell disease to raise fetal hemoglobin; toxicity is myelosuppression | ||
| Isoniazid-induced vitamin B6 (pyridoxine) deficiency FMK 08.4 · slide 9 ALA synthase needs PLP, like transaminases and decarboxylases |
Isoniazid antagonizes/depletes pyridoxal phosphate, the cofactor of ALA synthase | Isoniazid binds and inactivates pyridoxal phosphate, impairing PLP-dependent ALA synthase (and other PLP enzymes), which can unmask sideroblastic changes or worsen porphyria-like presentations. | ↑ Iron in erythroid mitochondria (sideroblastic changes) ↓ Pyridoxal phosphate (vitamin B6); ALA / heme synthesis |
Acquired | Sideroblastic anemia, peripheral neuropathy on isoniazid therapy | Ring sideroblasts, microcytic anemia | Co-administer pyridoxine (vitamin B6) with isoniazid |
| IV hemin (hematin) for acute porphyria FMK 08.4 · slide 18; handout 'Give glucose and hemin, avoid inducers' |
Drug target: hepatic ALAS1 (heme feedback repression) | Exogenous heme repletes the hepatic free heme pool, restoring repression of ALAS1 transcription and mitochondrial import, which shuts off ALA/PBG overproduction at its source. | Acquired | Mainstay treatment for acute neurovisceral porphyria attacks (AIP, HCP, VP) | Falling urinary ALA/PBG with treatment | ||
| Jamaican vomiting sickness (hypoglycin toxicity) FMK 05.6 · slide 18 Mimics to know for FAO disorders: Jamaican vomiting sickness (hypoglycin) and Reye syndrome (aspirin + viral illness) |
Hypoglycin A (unripe ackee fruit) inhibits acyl-CoA dehydrogenases | The toxin blocks β-oxidation, mimicking an inherited FAO disorder with fasting hypoketotic hypoglycemia and vomiting. | ↑ acylcarnitines ↓ ketones, glucose |
Acquired | vomiting, hypoketotic hypoglycemia — a mimic of mitochondrial FAO disorders | hypoketotic hypoglycemia | |
| Lead poisoning FMK 08.4 · slide 10, 11, 30; handout Two lead enzymes: ALA dehydratase and ferrochelatase. ALA up + PBG normal = lead; ALA and PBG both up = AIP |
Lead inhibits ALA dehydratase (step 2, zinc-dependent) and ferrochelatase (step 8) | Lead displaces zinc from ALA dehydratase and inhibits ferrochelatase, so ALA accumulates upstream and protoporphyrin accumulates at the end of the pathway (zinc substitutes for the iron that cannot be inserted), producing a microcytic anemia. | ↑ delta-Aminolevulinic acid (ALA), zinc protoporphyrin / free erythrocyte protoporphyrin, coproporphyrinogen III in urine, lead ↓ Heme / hemoglobin |
Acquired | Pediatric patient with microcytic anemia, abdominal pain, neurotoxicity; can mimic AIP | Elevated blood lead, microcytic anemia with basophilic stippling, elevated zinc protoporphyrin, elevated urinary ALA with normal-to-mildly elevated PBG (vs AIP where both ALA and PBG are markedly elevated), elevated urinary coproporphyrin III | Remove exposure; chelation |
| Lomitapide (MTP inhibitor) FMK 04.4 · slide 12, 30 |
Microsomal triglyceride transfer protein | Inhibiting MTP lowers LDL and TAG by blocking VLDL/chylomicron assembly, at the cost of hepatic steatosis (pharmacologic abetalipoproteinemia). | ↑ hepatic lipid (steatosis) ↓ VLDL/chylomicron secretion |
Acquired | lipid-lowering drug; risk of hepatic steatosis | ↓ LDL, ↓ TAG | |
| Malonate (Complex II inhibition) FMK 02.4 · slide 9, 11 |
Complex II (succinate dehydrogenase) — competitive inhibitor | Malonate competitively inhibits succinate dehydrogenase, reducing FADH₂ electron entry into CoQ (minimal effect since Complex II pumps no protons). | ↑ succinate |
Acquired | ↓ electron flow (minimal clinical effect); research tool | ||
| MAO inhibitors (MAOIs) FMK 04.3 · slide 11, 21 MAO (deamination) and COMT (methylation) can act in sequence |
Monoamine oxidase (oxidative deamination of catecholamines in the nerve terminal) | Blocking MAO prevents intraneuronal catecholamine breakdown so more transmitter is available for release. | ↑ Catecholamines in the nerve terminal |
Acquired | antidepressant effect; hypertensive crisis with tyramine-rich foods | ||
| MAOI–tyramine hypertensive crisis ('cheese reaction') FMK 07.2 · slide 19, 27 Cheese reaction — classic drug–food interaction |
Monoamine oxidase inhibited by MAOI antidepressants; dietary tyramine (from decarboxylation of tyrosine in aged cheese, fermented meat, beer, wine) | Gut/liver MAO normally destroys dietary tyramine on first pass; with MAO blocked, tyramine reaches the circulation and triggers massive norepinephrine release. | ↑ Tyramine, norepinephrine (also serotonin escapes breakdown on MAOIs) |
Acquired | Hypertensive crisis after tyramine-rich foods in a patient on an MAOI | Avoid tyramine-rich foods on MAOIs | |
| Metformin-associated lactic acidosis FMK 02.4 · slide 17, 23; FMK 03.1 slide 10; FMK 02.1 slide 21 |
Mild Complex I inhibition; AMPK activation; ↓ hepatic glucose output/lactate clearance | Metformin accumulates in renal failure, inhibits Complex I and impairs hepatic lactate clearance (Cori cycle), producing Type B lactic acidosis. | ↑ lactate |
Acquired | rare lactic acidosis, mainly with renal failure or overdose; T2DM first-line agent | ↑ lactate | Hold for contrast procedures; contraindicated eGFR <30 |
| Methanol poisoning FMK 01.5 · slide 13 |
Alcohol dehydrogenase converts methanol to formaldehyde/formic acid | Methanol is also an alcohol dehydrogenase substrate; its oxidation yields formic acid that damages the retina and causes acidosis. | ↑ Formaldehyde, formic acid |
Acquired | Visual disturbance/blindness, anion-gap metabolic acidosis | Anion-gap acidosis, osmolar gap | Ethanol (competitive substrate) or fomepizole |
| Methotrexate (folate analog) FMK 08.1 · slide 9, 24, 29 5-FU + methotrexate are combined because they hit the same reaction (thymidylate synthase) from two angles — the enzyme and its cofactor supply |
Inhibits dihydrofolate reductase (DHFR) | Blocks regeneration of tetrahydrofolate, starving cells of N10-formyl-THF needed for two ring-closure steps of purine synthesis and of the reduced folate cofactor thymidylate synthase needs to make dTMP, so rapidly dividing cells (tumor, marrow, gut epithelium) cannot synthesize DNA. | ↑ Dihydrofolate ↓ Tetrahydrofolate, purine nucleotides, dTMP |
Acquired | Toxicity in rapidly dividing tissues: myelosuppression, mucositis/GI epithelial injury | Leucovorin (folinic acid) rescue | |
| MPTP-induced Parkinsonism FMK 02.4 · slide 20 |
Complex I inhibition (MPTP street-drug contaminant) | MPTP (a street-drug contaminant) inhibits Complex I in dopaminergic neurons, causing Parkinsonism. | ↓ ATP in substantia nigra neurons |
Acquired | Parkinsonism after street-drug use | ||
| Multidrug resistance (P-glycoprotein / MDR pumps) FMK 02.3 · slide 18 ABC = ATP-Binding-Cassette; CFTR, SUR, MDR |
P-glycoprotein and other ABC MDR pumps (overexpressed) | ABC-family MDR pumps such as P-glycoprotein export organic molecules (e.g., chemotherapy drugs) out of cells, conferring drug resistance. | ↓ Intracellular drug concentration |
Acquired | Tumor resistance to multiple chemotherapeutic agents | ||
| Mycophenolic acid (mycophenolate) FMK 08.1 · slide 10, 29 IMP -> GMP branch requires ATP; IMP -> AMP branch requires GTP (cross-regulation) |
Inhibits IMP dehydrogenase (first step of the GMP branch from IMP) | Blocks GMP synthesis, preferentially affecting rapidly proliferating T and B lymphocytes, which depend on de novo purine synthesis; used as an immunosuppressant to prevent transplant graft rejection. | ↑ IMP ↓ GMP/GTP in lymphocytes |
Acquired | Used for: transplant immunosuppression; side effects: GI upset, leukopenia, infections | ||
| Nerve agent (anticholinesterase) poisoning FMK 04.3 · slide 21 Same enzyme target as myasthenia therapy — dose makes the poison |
Acetylcholinesterase inhibited | Blocking ACh degradation causes ACh to accumulate at nicotinic and muscarinic synapses, producing sustained receptor activation and cholinergic crisis. | ↑ Acetylcholine in the synaptic cleft |
Acquired | cholinergic crisis: salivation, lacrimation, urination, diarrhea, bronchospasm, muscle fasciculations then paralysis | Atropine, pralidoxime | |
| NRTI mitochondrial toxicity (zidovudine, stavudine) FMK 02.4 · slide 23, 25 |
Mitochondrial DNA polymerase γ inhibition | NRTIs inhibit pol-γ, depleting mtDNA and ETC subunits, causing OXPHOS failure in muscle, liver and nerves. | ↑ lactate ↓ mtDNA, ETC subunits |
Acquired | myopathy, lactic acidosis, hepatic steatosis (fatty liver), peripheral neuropathy; stavudine highest risk | ↑ lactate, ↑ CK, ↑ LFTs | Switch drug; monitor lactate |
| NSAID-induced GI bleeding FMK 04.1 · slide 22, 23 COX pathway = prostaglandins/thromboxanes (NSAID-sensitive); LOX pathway = leukotrienes/lipoxins (unaffected) |
Cyclooxygenase (COX-1/COX-2) inhibited by NSAIDs (e.g., ibuprofen) | NSAIDs block COX-derived prostaglandins and thromboxanes, including the protective gastric-mucosal prostaglandins, so the stomach lining erodes and bleeds. | ↓ Protective gastric prostaglandins (PGE2), thromboxane A2 |
Acquired | GI bleeding, gastric ulceration (the 71-year-old on ibuprofen case) | ||
| Oligomycin (ATP synthase inhibition) FMK 02.4 · slide 10, 11, 20 |
Complex V (ATP synthase) F₀ proton channel | Oligomycin blocks the F₀ proton channel so the gradient cannot dissipate; the ETC slows secondarily and ATP falls despite an intact ETC. | ↑ proton gradient ↓ ATP |
Acquired | research tool; concept: blocking ATP synthase secondarily slows ETC | ETC slows, ↓ ATP | |
| Opioid analgesics FMK 04.3 · slide 13, 21 Endorphin = 'endogenous morphine' |
Opiate (endorphin) G-protein-coupled receptors | Exogenous opioids mimic endorphins ('endogenous morphine') at GPCR opiate receptors, inhibiting pain transmission. | Acquired | analgesia, sedation, respiratory depression | |||
| Orlistat (lipase inhibitor) — iatrogenic steatorrhea FMK 04.4 · slide 7, 28, 30 |
Covalent inhibition of gastric and pancreatic lipase | Blocking lipases reduces TAG hydrolysis and absorption, mimicking mild pancreatic lipase deficiency. | ↑ undigested TAG in stool ↓ fat-soluble vitamin absorption |
Acquired | anti-obesity drug; expected side effect steatorrhea, reduced fat-soluble vitamin absorption | ||
| PCSK9 inhibitors (evolocumab, alirocumab) FMK 04.4 · slide 21, 29, 30; FMK 05.1 slide 12 |
PCSK9 (normally binds LDL receptor and targets it for lysosomal degradation) | Blocking PCSK9 lets more LDL receptors recycle to the surface, further lowering LDL; additive to statins in FH. | Acquired | add-on therapy for familial hypercholesterolemia | ↓↓ LDL (additive) | ||
| Penicillins (cell wall synthesis inhibitors) FMK 06.5 · slide Eukaryote vs Prokaryote Selective toxicity targets structures unique to prokaryotes |
Inhibit peptidoglycan cell wall synthesis | Prokaryotes possess a rigid peptidoglycan cell wall that humans lack (human cells have only a cholesterol-containing plasma membrane), so blocking its synthesis is selectively toxic to bacteria. | ↓ Bacterial peptidoglycan cross-links |
Acquired | Used for: streptococcal and many gram-positive infections; side effects: hypersensitivity/anaphylaxis, rash | ||
| Pertussis toxin FMK 05.5 · slide 19, 21 Cholera = Gs ON permanently; Pertussis = Gi OFF — both raise cAMP |
Gαi subunit blocked (ADP-ribosylated) by Bordetella pertussis toxin | Inhibiting Gαi removes the brake on adenylyl cyclase, producing sustained elevated cAMP. | ↑ cAMP |
Acquired | whooping cough, paroxysmal cough, lymphocytosis | ||
| Puromycin (aminoacyl-tRNA analog - premature termination) FMK 03.5 · slide 9 Puromycin = Premature termination in Pro- and eukaryotes |
Ribosomal A-site (both eukaryotic and prokaryotic) | Puromycin mimics aminoacyl-tRNA, is incorporated into the growing chain and causes premature release, mimicking termination in both eukaryotes and prokaryotes. | ↑ Truncated peptidyl-puromycin chains ↓ Complete protein synthesis |
Acquired | Not clinically used (toxic to human cells); research tool | ||
| Quinolones / fluoroquinolones (DNA gyrase inhibition) FMK 02.5 · slide 7 Gyrase = topoisomerase II; -floxacins |
Bacterial DNA gyrase (topoisomerase II) | Fluoroquinolones inhibit DNA gyrase, preventing relief of supercoils and blocking bacterial DNA replication and transcription. | ↓ Bacterial DNA replication |
Acquired | Active against gram-negative bacteria; treatment of gonorrhea and urinary tract infections (levofloxacin, ciprofloxacin, moxifloxacin) | ||
| Rasburicase (recombinant urate oxidase) FMK 08.1 · slide 16, 20 Humans lack urate oxidase — that is why uric acid, not allantoin, is our end product and why gout exists |
Supplies urate oxidase, the enzyme humans and other primates lack | Rapidly degrades uric acid to the far more soluble allantoin, lowering uric acid in high-risk patients. | ↑ Allantoin (soluble, excreted) ↓ Uric acid |
Acquired | First-line in tumor lysis syndrome | Rapid fall in serum uric acid | |
| Reye syndrome FMK 05.6 · slide 18; FMK 02.4 slide 23 |
Aspirin given during viral illness in children → mitochondrial injury/impaired β-oxidation | Salicylate plus viral illness causes mitochondrial dysfunction with impaired fatty acid oxidation and urea cycle, producing hepatic microvesicular steatosis, hyperammonemia and encephalopathy. | ↑ fat in liver (microvesicular), ammonia ↓ ketones, glucose |
Acquired | encephalopathy and hepatic dysfunction after aspirin + viral illness; mimic of FAO disorders (Reye-like picture also with valproate) | hypoketotic hypoglycemia, ↑ NH₃, ↑ LFTs | |
| Rifampin (bacterial RNA polymerase inhibitor for TB) FMK 03.2 · slide 2, 23, 27 Rifampin = Red/orange body fluids |
Bacterial (prokaryotic) RNA polymerase | Rifampin binds selectively to bacterial RNA polymerase and prevents RNA chain growth; eukaryotic RNA polymerase is unaffected. | ↓ Bacterial transcription |
Acquired | Antibiotic for tuberculosis; benign orange-red discoloration of tears, saliva, urine, feces from drug metabolites | ||
| SGLT-2 inhibitors (gliflozins: empagliflozin, dapagliflozin) FMK 02.1 · slide 6, 25 |
SGLT-2 Na⁺-coupled glucose transporter in the proximal kidney tubule (normally reabsorbs ~90% of filtered glucose) | Blocking renal glucose reabsorption causes glucosuria, lowering blood glucose and weight with cardioprotection. | ↑ urinary glucose |
Acquired | T2DM therapy: glucosuria, ↓ blood glucose, ↓ weight, cardioprotection | glucosuria | |
| Shiga toxin / verotoxin (EHEC) - 28S rRNA inactivation FMK 03.5 · slide 17 Shiga/verotoxin = removes Adenine from 28S = 60S subunit |
28S rRNA of the eukaryotic 60S ribosomal subunit (RNA glycosylase removes a single adenine) | Shiga toxin's RNA glycosylase depurinates one adenine of 28S rRNA, preventing aminoacyl-tRNA binding and halting protein synthesis. | ↓ Host protein synthesis |
Acquired | Enterohemorrhagic E. coli infection: bloody diarrhea, hemolytic uremic syndrome | HUS: hemolytic anemia, thrombocytopenia, acute kidney injury | Supportive; avoid antibiotics (may increase toxin release) |
| Statins (HMG-CoA reductase inhibition) FMK 01.2 · slide 01.2: 12; 05.1: 2, 6, 8, 12; FMK 04.4 slide 21, 30 HMG-CoA reductase = the PFK-1 of cholesterol synthesis |
HMG-CoA reductase (rate-limiting enzyme of cholesterol synthesis) | Lower intracellular cholesterol activates SREBP-2, which upregulates LDL receptors — the actual mechanism of plasma LDL lowering; liver-targeted because it dominates circulating supply. | ↓ Hepatic cholesterol synthesis |
Acquired | Used for FH/hypercholesterolemia; adverse: myopathy, hepatotoxicity | Lower LDL-C | |
| Streptomycin (30S - prevents initiation) FMK 03.5 · slide 9 30S: Streptomycin (initiation), Tetracycline (A-site), Gentamicin (assembly) |
Bacterial 30S ribosomal subunit | Streptomycin binds the 30S subunit and prevents translation initiation. | ↓ Bacterial protein synthesis |
Acquired | Aminoglycoside antibiotic; may affect human mitochondria (bacteria-like translation); adverse: ototoxicity, nephrotoxicity | ||
| Succinylcholine (depolarizing NMJ blocker) FMK 04.3 · slide 19, 21 NMJ blockade sites: presynaptic release, vesicle fusion, receptor binding |
Agonist at the nicotinic ACh receptor of the neuromuscular junction | Persistent receptor activation depolarizes the end plate and keeps it depolarized so Na+ channels inactivate and the muscle cannot fire again. | Acquired | initial fasciculations followed by flaccid paralysis (used for intubation) | |||
| Sulfonamides (PABA analogs) FMK 08.1 · slide 08.1 slides 9, 29; 06.5 'Eukaryote vs Prokaryote' Selective toxicity: humans get folate from the diet; bacteria must make their own |
Competitive inhibition of bacterial folate synthesis (dihydropteroate synthase) as structural analogs of para-aminobenzoic acid (PABA) | Bacteria must synthesize folate de novo because they cannot absorb preformed folate, whereas humans obtain folate from the diet, so blocking sequential steps in bacterial folate synthesis is selectively antibacterial. | ↓ Bacterial folate (and therefore bacterial purine/thymidylate synthesis) |
Acquired | Used for: UTIs, PCP (with trimethoprim); side effects: rash/hypersensitivity, kernicterus in neonates, crystalluria | ||
| Tetracycline (30S - blocks aminoacyl-tRNA at A-site) FMK 03.5 · slide 9 Tetracycline = Tied up tRNA at the A-site |
Bacterial 30S ribosomal subunit | Tetracycline binds the 30S subunit and prevents aminoacyl-tRNA binding to the A-site. | ↓ Bacterial protein synthesis |
Acquired | Broad-spectrum antibiotic; adverse: tooth discoloration, photosensitivity | ||
| Thalidomide disaster (enantiomer toxicity) FMK 01.6 · slide ~8 Chirality is central to medicine; R/S vs D/L systems |
Racemic thalidomide - one enantiomer teratogenic | Enantiomers of a drug behave as entirely different drugs in the body; the teratogenic thalidomide enantiomer caused limb defects (phocomelia). | Acquired | Limb reduction defects (phocomelia) in infants exposed in utero | |||
| Uricosuric agents (probenecid, sulfinpyrazone) FMK 08.1 · slide 20 |
Block renal tubular urate reabsorption (URAT1; widely known) | Increase renal uric acid excretion, lowering serum urate below its saturation point (~6.5 mg/dL) to prevent crystal formation in under-excretors. | ↑ Urinary uric acid ↓ Serum uric acid |
Acquired | Long-term therapy for under-excretors of uric acid | ||
| Valproate (VPA) hepatotoxicity / mitochondrial toxicity FMK 02.4 · slide 23 |
Impairs mitochondrial β-oxidation; inhibits urea cycle enzymes | Valproate impairs β-oxidation and urea cycle function, causing Reye-like hepatotoxicity and hyperammonemia, especially in children under 2. | ↑ NH₃ ↓ carnitine |
Acquired | hepatotoxicity (Reye-like), hyperammonemia, encephalopathy, weight gain | ↑ NH₃, ↑ LFTs, low carnitine | caution in children <2 years |
| β-blocker therapy (GPCR antagonism) FMK 05.5 · slide 2, 21 β1/β2/β3 → Gs → ↑cAMP; blockers turn the cAMP faucet down |
Antagonist at β-adrenergic receptors (Gαs-coupled GPCR) | Blocking β-receptors prevents Gs activation of adenylyl cyclase, lowering cAMP/PKA and reducing heart rate and contractility. | ↓ cAMP in cardiac myocytes |
Acquired | bradycardia, reduced contractility, bronchospasm in asthmatics (non-selective agents) |
Other 25
| Condition | Defect / target | Mechanism | Accumulates ↑ / deficient ↓ | Inh. | Presentation | Labs | Treatment |
|---|---|---|---|---|---|---|---|
| Abdominal wall defects (gastroschisis, omphalocele) FMK 08.5 · slide Second Trimester Screen Omphalocele = covered (sac), midline; gastroschisis = uncovered, right-sided |
Failure of abdominal wall closure allowing organs outside the body | An open abdominal wall exposes fetal tissue/organs to amniotic fluid, raising maternal serum AFP; gastroschisis is right of the umbilicus without a covering sac, omphalocele is through the umbilicus with a membranous sac. | ↑ Alpha-fetoprotein in maternal serum |
Acquired | Gastroschisis: organs herniate to the right of the belly button with no sac; omphalocele: organs herniate through the center of the belly button covered by a sac | Elevated maternal serum AFP; ultrasound | Surgical repair after birth |
| Antiphospholipid syndrome FMK 01.2 · slide 12 |
Autoantibodies against phospholipid-binding proteins (anticardiolipin, lupus anticoagulant, anti-beta2-glycoprotein I) | Antiphospholipid antibodies activate endothelium and platelets and promote a hypercoagulable state. | Acquired | Venous/arterial thrombosis, recurrent pregnancy loss | Positive antiphospholipid antibodies, paradoxically prolonged PTT | Anticoagulation | |
| Bacterial overgrowth (detected by hydrogen breath test) FMK 01.6 · slide ~20 |
Excess bacteria in small intestine fermenting carbohydrates | Overgrown small-bowel bacteria ferment sugars early, producing H2 that appears in exhaled breath. | ↑ H2, CH4 gas |
Acquired | Bloating, diarrhea, malabsorption | Early rise on hydrogen breath test | |
| Biliary atresia FMK 08.4 · slide 25, 27, 29 |
Congenital obliteration of the extrahepatic bile ducts | Absent bile duct patency in the infant blocks excretion of conjugated bilirubin, producing pathologic obstructive neonatal jaundice. | ↑ Conjugated bilirubin ↓ Bile flow to gut, stercobilin |
Acquired | Pathologic neonatal jaundice (must be distinguished from physiologic jaundice), pale stool, dark urine | Conjugated hyperbilirubinemia in a newborn | Surgery (Kasai portoenterostomy), liver transplant |
| Celiac disease (gut damage causing malabsorption) FMK 01.6 · slide ~19 |
Autoimmune small-intestinal mucosal damage (gluten-triggered) impairing brush-border enzymes and transporters | Gluten-driven immune injury flattens villi, so lactase/sucrase and SGLT-1/GLUT-5/GLUT-2 are lost and carbohydrates are malabsorbed. | ↓ Brush-border disaccharidases and transporters |
Acquired | Chronic diarrhea, bloating, weight loss, secondary lactose intolerance | Anti-tissue transglutaminase IgA, villous atrophy on biopsy | Gluten-free diet |
| Cholangiocarcinoma / primary sclerosing & biliary cholangitis FMK 08.4 · slide 27 |
Malignant or inflammatory narrowing of bile ducts | Bile duct tumor or fibrosing inflammation obstructs bile outflow, producing a post-hepatic cholestatic jaundice pattern. | ↑ Conjugated bilirubin, bile salts ↓ Stercobilin, urine urobilinogen |
Acquired | Jaundice, pruritus, dark urine, pale stool | Conjugated hyperbilirubinemia, ALP/GGT markedly elevated | |
| Chronic granulomatous disease (CGD) FMK 03.1 · slide 18, 24 |
NADPH oxidase (phagocytes) | Neutrophils cannot generate superoxide during the respiratory burst, so catalase-positive organisms are not killed and granulomas form. | ↓ superoxide / H₂O₂ / HOCl in phagocytes |
XR | recurrent Staphylococcus aureus and Aspergillus infections, granuloma formation | Negative NBT test (no blue color — NBT reduction requires superoxide) | |
| Chronic hypoxia / anemia (COPD, high altitude) — ↑2,3-BPG FMK 06.1 · slide 22 |
Increased RBC 2,3-BPG production in chronic hypoxia (COPD, high altitude) and anemia | Elevated 2,3-BPG binds the central pocket of deoxyhemoglobin, stabilizing the T state and right-shifting the curve so more O₂ is unloaded into hypoxic tissue — a compensatory adaptation. | ↑ 2,3-BPG |
Acquired | Compensatory right shift of the O₂ dissociation curve | ||
| Crohn's disease (gut damage causing malabsorption) FMK 01.6 · slide ~19 |
Inflammatory damage to small-intestinal mucosa | Transmural inflammation damages mucosal cells, impairing digestive enzymes and transporters and causing carbohydrate malabsorption. | ↓ Brush-border enzymes and transporters |
Acquired | Chronic diarrhea, abdominal pain, weight loss | ||
| Duodenal atresia FMK 08.5 · slide Level II Ultrasound; Autosomal Aneuploidies |
Complete blockage of the duodenum from failed recanalization | The duodenal lumen is completely blocked, causing proximal dilation (double bubble) and polyhydramnios; strongly associated with Down syndrome. | ↑ Amniotic fluid (polyhydramnios); gastric/duodenal contents |
Acquired | Bilious vomiting in the newborn, double-bubble sign; a Level II ultrasound marker of Down syndrome | Ultrasound double bubble and polyhydramnios | Surgical repair |
| Gallstone obstruction of the common bile duct (choledocholithiasis) FMK 08.4 · slide 22, 25, 26, 27; handout Pigment gallstones follow chronic hemolysis |
Stone lodged in the common bile duct | A gallstone blocks bile flow so conjugated bilirubin backs up into blood and urine and no pigment reaches the gut; chronic hemolysis predisposes to pigment stones from excess unconjugated bilirubin. | ↑ Conjugated bilirubin ↓ Stercobilin, urine urobilinogen |
Acquired | Painful jaundice, dark urine, acholic stool, fibrotic non-distensible gallbladder | Conjugated hyperbilirubinemia, elevated ALP/GGT | ERCP stone extraction, cholecystectomy |
| Hepatocellular injury (ALT/AST pattern) FMK 01.2 · slide 01.2: 8; 07.1: 8 Enzymes as clinical labs: ALT/AST = liver, troponin = heart |
Leakage of hepatocyte enzymes ALT/AST into serum | Damaged hepatocytes release intracellular transaminases into the blood, so elevated serum ALT/AST signals liver cell injury. | ↑ Serum ALT, AST |
Acquired | Hepatitis, jaundice, RUQ pain depending on cause | ALT > AST = hepatocellular injury | |
| Hirschsprung disease FMK 08.5 · slide Autosomal Aneuploidies |
Loss of enteric (ganglionic) innervation of the distal colon | Failure of neural crest cell migration leaves an aganglionic segment of colon that cannot relax, causing functional obstruction; associated with Down syndrome. | ↑ Stool proximal to the aganglionic segment (megacolon) ↓ Enteric ganglion cells in distal colon |
Acquired | Failure to pass meconium, abdominal distension, constipation in a newborn; feature of Down syndrome | Rectal biopsy showing absent ganglion cells | Surgical resection of aganglionic segment |
| Hypoalbuminemia FMK 01.2 · slide 8 |
Low plasma albumin (transport protein) | Low albumin reduces plasma oncotic pressure and drug binding, causing fluid to leak into tissues. | ↑ Interstitial fluid (edema) ↓ Albumin, oncotic pressure, drug-binding capacity |
Acquired | Edema, ascites, altered free-drug levels | Low serum albumin | |
| Hypoparathyroidism FMK 05.1 · slide 24 PTH level separates it from renal osteodystrophy |
Absent PTH | Without PTH there is no bone resorption and no stimulation of renal 1α-hydroxylase, so calcium falls and phosphate rises. | ↑ phosphate ↓ PTH, calcitriol, Ca²⁺ |
Acquired | hypocalcemia | ↓ Ca²⁺, ↑ PO₄³⁻, ↓ PTH | Calcitriol + calcium |
| Kidney dysfunction (rising creatinine) FMK 07.2 · slide 23 |
Reduced renal clearance of creatinine | Creatine spontaneously cyclizes to creatinine at a rate proportional to muscle mass; with falling glomerular filtration its blood level rises. | ↑ Blood creatinine |
Acquired | Renal insufficiency | Rising blood creatinine; reduced creatinine clearance | |
| Mixed connective tissue disease (anti-U1 snRNP) FMK 03.2 · slide 24 Anti-U1 snRNP = MCTD; anti-Smith = SLE |
Autoantibodies against U1 snRNP (spliceosome component) | Autoantibodies target the U1 small nuclear ribonucleoprotein of the spliceosome, associated with overlapping features of SLE, scleroderma and polymyositis. | Acquired | Overlap of lupus, scleroderma and myositis features; Raynaud phenomenon | Anti-U1 snRNP (anti-U1 RNP) antibodies | ||
| Pancreatic exocrine insufficiency FMK 01.6 · slide ~19 |
Insufficient pancreatic amylase, protease, and lipase secretion | The pancreas fails to produce enough digestive enzymes, so starch, protein and fat are maldigested and malabsorbed. | ↑ Undigested starch, protein, fat in stool ↓ Pancreatic amylase, proteases, lipase |
Acquired | Steatorrhea, weight loss, bloating, osmotic diarrhea, fat-soluble vitamin deficiency | Low fecal elastase, fecal fat | Pancreatic enzyme replacement |
| Pancreatic head cancer (malignant biliary obstruction) FMK 08.4 · slide 25, 27; handout Courvoisier sign = palpable non-tender gallbladder + painless jaundice = think malignancy, not stones |
Tumor compressing/obstructing the distal common bile duct | A mass in the pancreatic head obstructs bile outflow, producing post-hepatic conjugated hyperbilirubinemia with a distended, non-fibrotic gallbladder. | ↑ Conjugated bilirubin ↓ Stercobilin, urine urobilinogen |
Acquired | Painless jaundice in an older adult, palpable non-tender gallbladder (Courvoisier sign), pale stool, dark urine, pruritus | Conjugated hyperbilirubinemia, elevated ALP/GGT | Surgical resection/biliary decompression |
| Pseudogout (CPPD deposition) FMK 08.1 · slide 18 Synovial fluid crystal analysis under polarized light is the gold standard to distinguish gout from pseudogout and septic arthritis |
Calcium pyrophosphate dihydrate crystal deposition (not purine-related) | Deposition of calcium pyrophosphate crystals in joints provokes an inflammatory arthritis that mimics gout. | ↑ Calcium pyrophosphate dihydrate crystals |
Acquired | Acute inflammatory monoarthritis (classically knee) mimicking gout | Rhomboid, positively birefringent crystals in synovial fluid — contrast with needle-shaped negatively birefringent MSU crystals of gout | |
| Renal osteodystrophy (secondary hyperparathyroidism of CKD) FMK 05.1 · slide 15, 24 Discriminator vs hypoparathyroidism: identical Ca/PO₄, PTH high vs low separates them |
Failed renal 1α-hydroxylase + phosphate retention in CKD | CKD cannot make calcitriol and retains phosphate, so calcium falls and PTH rises markedly (secondary hyperparathyroidism) with bone disease. | ↑ phosphate, PTH ↓ calcitriol, Ca²⁺ |
Acquired | bone disease in chronic kidney disease; kidney-failure patient can have normal 25-OH-D3 but be functionally deficient | ↓ Ca²⁺, ↑ PO₄³⁻, ↑↑ PTH | Calcitriol AND phosphate reduction |
| Septic arthritis FMK 08.1 · slide 18 Mentioned as a differential that synovial fluid crystal analysis rules out |
Bacterial infection of the joint space | Infection of the joint produces an acute inflammatory monoarthritis that must be distinguished from crystal arthritis. | Acquired | Hot, swollen, painful joint with fever — clinical mimic of acute gout | Synovial fluid aspiration: no MSU crystals, positive Gram stain/culture | ||
| Stored-blood 2,3-BPG depletion FMK 06.1 · slide 22 |
Progressive loss of 2,3-BPG (and ATP) in banked RBCs | Without 2,3-BPG to stabilize the T state, transfused hemoglobin has abnormally high O₂ affinity (left shift) and under-delivers O₂ to tissue. | ↓ 2,3-BPG, ATP in stored RBCs |
Acquired | Transfused blood holds O₂ too tightly, poor tissue oxygen unloading | 'Rejuvenation solution' to restore 2,3-BPG and ATP before use | |
| Systemic lupus erythematosus (anti-H1 histone, anti-Smith antibodies) FMK 02.2 · slide 02.2: 18; 03.2: 2, 24 Anti-Smith = SLE; anti-U1 snRNP = MCTD |
Autoantibodies against histone H1 (~60% of SLE) and against snRNPs (anti-Smith) | Autoantibodies to nuclear components (histone H1, spliceosomal snRNPs) form immune complexes that deposit in tissues and drive systemic inflammation. | ↑ Immune complexes |
Acquired | Women of childbearing age, butterfly (malar) rash on the face, arthritis, nephritis, serositis | Anti-H1 histone antibodies (~60% of cases), anti-Smith antibodies (specific), ANA, anti-dsDNA | |
| Warburg effect (cancer aerobic glycolysis) FMK 02.1 · slide 21 |
Tumor metabolic reprogramming favoring glycolysis + lactate even with O₂ | Fast glucose uptake supplies biosynthetic precursors (ribose-5-P, NADPH) for rapid growth and the acidic microenvironment may suppress immune cells. | ↑ lactate, glucose uptake |
Acquired | tumors; exploited clinically by FDG-PET imaging (¹⁸F-deoxyglucose trapped in cells) | ↑ FDG uptake on PET |
Harvested from the slide text of every FMK lecture (01.2 through 08.2, plus the metabolism and lysosomal decks). Where a slide was terse the mechanism line is filled from standard textbook wording; the lecture and slide are listed so you can check the original.