GeneticsTier 1Medical Sciences concept

Lysosomal storage diseases - enzyme deficiencies (Fabry, Gaucher, Tay-Sachs, Krabbe)

Core concept

All caused by deficiency of a specific lysosomal enzyme, leading to accumulation of its substrate within lysosomes -- accumulating substrate identity determines which organs are affected
Fabry disease: alpha-galactosidase A deficiency -> accumulation of globotriaosylceramide (Gb3) -- X-linked (unlike most other lysosomal storage diseases, which are autosomal recessive)
Gaucher, Tay-Sachs, Krabbe: all autosomal recessive, each accumulating a different sphingolipid substrate in a different predominant tissue

Disease	Enzyme deficient	Substrate accumulated	Key feature
Fabry	Alpha-galactosidase A	Globotriaosylceramide (Gb3)	X-linked; angiokeratomas, acroparaesthesia, renal failure, cardiomyopathy, stroke
Gaucher	Glucocerebrosidase	Glucocerebroside	Hepatosplenomegaly, bone pain/avascular necrosis, cytopenias; "crumpled tissue paper" macrophages
Tay-Sachs	Hexosaminidase A	GM2 ganglioside	Cherry-red macular spot, progressive neurodegeneration, no organomegaly (distinguishes from Sandhoff, which has hepatosplenomegaly)
Krabbe	Galactocerebrosidase	Galactosylceramide (via psychosine toxicity)	Severe infantile neurodegeneration, globoid cells on histology

Fabry's X-linked inheritance means affected males are typically more severely affected; female carriers can still manifest disease (X-inactivation skewing) unlike classic X-linked recessive conditions where carriers are usually asymptomatic

Trap: assuming all lysosomal storage diseases are autosomal recessive -- Fabry is the significant X-linked exception, relevant to inheritance-pattern and family-risk questions
Enzyme replacement therapy exists for several (Gaucher -- imiglucerase, Fabry -- agalsidase) -- diagnosis via enzyme assay (leukocyte enzyme activity) confirmed by genetic testing, distinct from a purely clinical diagnosis
Tay-Sachs carrier screening is offered in Ashkenazi Jewish populations given elevated carrier frequency (same founder-effect logic as the Hardy-Weinberg note) -- relevant to reproductive counselling

Pompe disease (glycogen storage disease II) is also technically lysosomal (acid alpha-glucosidase) -- bridges this note and the glycogen storage disease note via shared organelle biology
Cherry-red spot differential: Tay-Sachs, Sandhoff, Niemann-Pick -- distinguished by presence/absence of organomegaly and specific enzyme assay
Same founder-population carrier-frequency principle (Hardy-Weinberg) applies across Tay-Sachs, Gaucher and other conditions enriched in specific ancestral populations

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