U01.01.118 Lysosomal storage diseases

Lysosomal storage diseases are a group of disorders caused by deficiencies in specific lysosomal enzymes, leading to the accumulation of abnormal metabolic products. These diseases often present with neurological, developmental, or systemic manifestations and are usually inherited in either an autosomal recessive or X-linked recessive manner.

Sphingolipidoses

These diseases are characterized by the accumulation of sphingolipids, which are normally broken down by lysosomal enzymes.

Disease	Clinical Findings	Deficient Enzyme	Accumulated Substrate	Inheritance
Tay-Sachs Disease	Progressive neurodegeneration, developmental delay, hyperreflexia, hyperacusis, “cherry-red” spot on macula, lysosomes with onion skin (no hepatosplenomegaly).	Hexosaminidase A	GM2 ganglioside	Autosomal Recessive (AR)
Fabry Disease	Early: episodic peripheral neuropathy, angiokeratomas, hypohidrosis. Late: renal failure, cardiovascular disease.	α-galactosidase A	Ceramide trihexoside (globotriaosylceramide)	X-linked Recessive (XR)
Metachromatic Leukodystrophy	Central and peripheral demyelination with ataxia and dementia.	Arylsulfatase A	Cerebroside sulfate	Autosomal Recessive (AR)
Krabbe Disease	Peripheral neuropathy, destruction of oligodendrocytes, developmental delay, optic atrophy, globoid cells.	Galactocerebrosidase	Galactocerebroside, psychosine	Autosomal Recessive (AR)
Gaucher Disease	Hepatosplenomegaly, pancytopenia, osteoporosis, avascular necrosis of femur, bone crises, Gaucher cells (lipid-laden macrophages).	Glucocerebrosidase (β-glucosidase)	Glucocerebroside	Autosomal Recessive (AR)
Niemann-Pick Disease	Progressive neurodegeneration, hepatosplenomegaly, foam cells (lipid-laden macrophages), “cherry-red” spot on macula.	Sphingomyelinase	Sphingomyelin	Autosomal Recessive (AR)

Mnemonic:

No man picks (Niemann-Pick) his nose with his sphinger (sphingomyelinase).
Hunters see clearly (no corneal clouding) and aggressively aim for the X (X-linked recessive).

Mucopolysaccharidoses

These disorders result from deficiencies in enzymes that degrade glycosaminoglycans (GAGs), leading to the accumulation of heparan sulfate, dermatan sulfate, and other related compounds.

Disease	Clinical Findings	Deficient Enzyme	Accumulated Substrate	Inheritance
Hurler Syndrome	Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly.	α-l-iduronidase	Heparan sulfate, dermatan sulfate	Autosomal Recessive (AR)
Hunter Syndrome	Similar to Hurler but with milder symptoms and aggressive behavior. No corneal clouding.	Iduronate-2-sulfatase	Heparan sulfate, dermatan sulfate	X-linked Recessive (XR)

Points to Remember

Sphingolipidoses involve the accumulation of sphingolipids due to enzyme deficiencies like hexosaminidase A in Tay-Sachs or sphingomyelinase in Niemann-Pick disease.
Mucopolysaccharidoses are due to defects in enzymes involved in the breakdown of GAGs like heparan sulfate and dermatan sulfate.
Inheritance patterns vary: Most sphingolipidoses are autosomal recessive, but Fabry disease and Hunter syndrome are X-linked recessive.
The cherry-red spot on macula is a common finding in Tay-Sachs and Niemann-Pick diseases.

Key Learning Objective

Students should understand the clinical presentation, enzyme deficiencies, and accumulated substrates for each lysosomal storage disease, as well as the inheritance patterns to help differentiate among these conditions. Recognizing key signs, such as the cherry-red spot on the macula, is essential for identifying specific diseases in clinical practice.

Your voice matters – comment below!Cancel reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.

USMLE Step 1 Review Series

Curriculum