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Lysosomal storage diseases

The nine diseases from FMK-04.5, every direction at once: symptoms → gene, gene → disease, enzyme → substrate, histology → disease… Pick what you're given and what you have to name, or let it cycle through every combination. Each answer shows the whole card.

Sphingolipidosis 5

Disease	Gene	Enzyme	Accumulates	Inheritance	Findings	Histology / hallmark	Treatment
Tay-Sachs disease ~6 months; death by 3–5 years Cherry-red spot without organomegaly separates it from Niemann-Pick. Ashkenazi carrier screening. Condition card →	HEXA	Hexosaminidase A	GM2 ganglioside (in neurons of brain and spinal cord)	Autosomal recessive	Progressive weakness → paralysis Seizures Cherry-red spot on the macula NO hepatosplenomegaly No contractures Developmental regression	Neurons distended with lysosomal GM2 (no visceral storage cells)	Supportive only
Fabry disease Early childhood in males; heterozygous females can be affected The only X-linked sphingolipidosis. Lecture: cardiovascular disease is the top cause of death in both sexes. Condition card →	GLA	α-Galactosidase A	Ceramide trihexoside (globotriaosylceramide, Gb3)	X-linked	Acroparesthesias (burning pain in hands and feet) Angiokeratomas Anhidrosis with heat/cold intolerance Whorl keratopathy (vision unaffected) Renal failure Strokes Cardiovascular disease — LVH, mitral valve prolapse, arrhythmia; most common cause of death	Lamellar (zebra-body) inclusions in endothelium, podocytes and cardiomyocytes	Enzyme replacement (agalsidase); renal and cardiac care
Gaucher disease Any age; type 1 (non-neuronopathic) most common Most common lysosomal storage disease. GBA carriers have an increased risk of Parkinson-like tremor in their 50s–60s. Condition card →	GBA	Glucocerebrosidase (β-glucosidase)	Glucocerebroside (glucosylceramide)	Autosomal recessive	Hepatosplenomegaly Thrombocytopenia (easy bruising) and anemia Fatigue Osteopenia, bone crises, avascular necrosis Neurologic degeneration (types 2/3)	Gaucher cells — macrophages with 'crumpled/wrinkled tissue-paper' cytoplasm, nucleus pushed to the edge (bone marrow biopsy)	Enzyme replacement (imiglucerase); substrate reduction
Krabbe disease Infantile, first 6 months; death by ~2 years A leukodystrophy: myelin, not neurons, is the target. Condition card →	GALC	Galactocerebrosidase (galactocerebroside β-galactosidase)	Galactocerebroside (and psychosine) — in myelin	Autosomal recessive	Failure to thrive Irritability, restlessness Fevers without infection Optic atrophy → blindness; deafness Seizures Loss of milestones, decerebrate posturing Peripheral neuropathy	Globoid cells — large multinucleated macrophages in white matter (brain)	Hematopoietic stem-cell transplant if pre-symptomatic; otherwise supportive
Niemann-Pick disease type C Any age; adult onset most common for type C Cherry-red spot WITH hepatosplenomegaly (vs Tay-Sachs). Foam cells (vs Gaucher's tissue-paper cells). Note the lecture attributes sphingomyelinase to NPC; the acid-sphingomyelinase disease is Niemann-Pick A/B (SMPD1). Condition card →	NPC1 (95%) or NPC2 (5%)	Sphingomyelinase (per lecture) — NPC1/NPC2 are intracellular cholesterol-transport proteins	Sphingomyelin (and unesterified cholesterol) in lysosomes	Autosomal recessive	Vertical supranuclear gaze palsy Ataxia, dystonia, dysphagia Cognitive or motor developmental delay Cherry-red spot on the macula Hepatosplenomegaly	Foam cells — lipid-laden macrophages with small round nuclei and clear vacuoles (bone marrow)	Miglustat (substrate reduction); supportive

Mucopolysaccharidosis 2

Disease	Gene	Enzyme	Accumulates	Inheritance	Findings	Histology / hallmark	Treatment
Hurler syndrome (MPS I) Normal at birth; features emerge over the first 1–3 years Severity spectrum: Hurler (0% enzyme) → Hurler-Scheie (~5%) → Scheie (~10%, no cognitive delay). Condition card →	IDUA (written 'IUDA' in the lecture)	α-L-Iduronidase	Dermatan sulfate and heparan sulfate (GAGs)	Autosomal recessive	Coarse facial features that worsen with age (flat face, wide upturned nostrils, thick lips, large tongue, large head) Corneal clouding (ground-glass), glaucoma Claw hand, finger contractures, joint stiffness Gibbus deformity, hip dysplasia, abnormal clavicles Hydrocephalus Chronic rhinitis / otitis media Progressive developmental delay Cardiomyopathy — most common cause of death Growth retardation	Urine positive for dermatan and heparan sulfate; vacuolated ('gargoyle') cells	Enzyme replacement (laronidase / Aldurazyme — does not cross the BBB); HSCT
Hunter syndrome (MPS II) Presents at 2–4 years; males (female carriers usually asymptomatic) X-linked and no corneal clouding are the two discriminators from Hurler. Only ~20% enzyme activity is needed to be symptom-free. Condition card →	IDS	Iduronate-2-sulfatase	Dermatan sulfate and heparan sulfate (GAGs)	X-linked	Milder Hurler-like features NO corneal clouding Aggressive behaviour Hearing impairment Nodular skin lesions ('pebbling') Thickened heart wall Vision loss from optic-nerve pressure Progressive developmental delay	Urine positive for dermatan and heparan sulfate	Enzyme replacement (idursulfase / Elaprase — does not cross the BBB)

Glycogen storage (lysosomal) 1

Disease	Gene	Enzyme	Accumulates	Inheritance	Findings	Histology / hallmark	Treatment
Pompe disease (GSD II) Infantile-onset: death by ~10 months untreated. Late-onset: slower, spares the heart, limb-girdle/respiratory weakness The only glycogen storage disease that is lysosomal. Diagnose by GAA activity on a dried blood spot or biallelic GAA variants. Condition card →	GAA	Acid α-glucosidase (acid maltase)	Glycogen inside lysosomes of cardiac, skeletal and smooth muscle	Autosomal recessive	Hypotonia, head lag, 'floppy infant' Cardiomegaly (92% by 4 months) and cardiomyopathy Macroglossia Feeding and swallowing difficulty, failure to thrive Moderate hepatomegaly Respiratory infections, sleep apnoea Elevated CK	PAS-positive glycogen-filled lysosomes that rupture and replace myofibrils; normal cytosolic glycogen metabolism	Enzyme replacement (alglucosidase alfa / Myozyme) slows progression; supportive cardiac/respiratory care

Mucolipidosis (trafficking defect) 1

Disease	Gene	Enzyme	Accumulates	Inheritance	Findings	Histology / hallmark	Treatment
I-cell disease (mucolipidosis II) Infancy Not an enzyme deficiency but a targeting failure: no M6P tag → no delivery to the lysosome. Condition card →	GNPTAB	N-acetylglucosamine-1-phosphotransferase (adds the mannose-6-phosphate tag in the Golgi)	Everything — lysosomal enzymes are secreted into plasma instead of reaching the lysosome, so many substrates accumulate	Autosomal recessive	Coarse facial features Skeletal deformities and restricted joints Corneal clouding Organomegaly Developmental delay Very high plasma lysosomal enzyme levels Often fatal in childhood	Inclusion bodies in fibroblasts; lysosomal enzymes high in plasma, low in cells	Supportive only

Source: FMK-04.5 Protein targeting & lysosomal disorders. Gene spelling and the NPC enzyme follow the lecture, with the textbook version noted.