66. Lysosomal diseases: sphingolipidoses, Gaucher, Fabry, Niemann-Pick, mucopolysaccharidoses, Hurler/Scheie.

I. Introduction

• Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders caused by deficiency of specific lysosomal enzymes or transport proteins.
• Result: incomplete degradation of macromolecules (glycosaminoglycans, sphingolipids, glycoproteins) → accumulation inside lysosomes → cell dysfunction, organ damage.
• Inheritance: mostly autosomal recessive, except some X-linked (e.g., Hunter syndrome, Fabry disease).
• Major groups:

1. Mucopolysaccharidoses (MPS) – defective degradation of glycosaminoglycans (GAGs).
2. Sphingolipidoses – defective degradation of sphingolipids.
3. Mucolipidoses – defective degradation/transport of glycoproteins.

II. Mucopolysaccharidoses (MPS)

Pathogenesis

• Defective lysosomal enzymes → impaired breakdown of GAGs (heparan sulfate, dermatan sulfate, keratan sulfate, chondroitin sulfate).
• Accumulation → coarse facial features, organomegaly, skeletal deformities, developmental delay.

Major Types

1. Hurler Syndrome (MPS I-H)

• Defect: α-L-iduronidase deficiency.
• Inheritance: AR.
• Features:
• Coarse facies, hepatosplenomegaly, corneal clouding.
• Developmental delay, dwarfism, skeletal dysplasia (dysostosis multiplex).
• Death often by age 10 due to cardiopulmonary complications.

2. Hunter Syndrome (MPS II)

• Defect: iduronate sulfatase deficiency.
• Inheritance: X-linked recessive.
• Features: similar to Hurler but no corneal clouding.
• Onset later, milder course.

3. Sanfilippo Syndrome (MPS III)

• Defects: several enzymes (heparan sulfate degradation).
• Features: severe CNS degeneration, mild somatic features.

Diagnosis

• Urine: ↑ GAGs.
• Enzyme assays, genetic testing.

Management

• Enzyme replacement therapy (ERT) for MPS I, II, VI.
• HSCT for severe cases.
• Supportive care for organ complications.