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PA11.1-3 | Genetic & Pediatric Diseases — SDL Guide (Part 4)

Mucopolysaccharidoses & Glycogen Storage Diseases

Diagram showing lysosomal glycosaminoglycan accumulation in mucopolysaccharidoses, key MPS disorder comparisons, and glycogen accumulation in liver and muscle cells. — **Panel A:** Normal lysosome, lysosomal enzyme deficiency, pathological lysosome, accumulated glycosaminoglycans, heparan sulphate, dermatan sulphate, keratan sulphate, connective tissue cell, fibroblast, neuron. **Panel B:** Hurler syndrome, alpha-L-iduronidase deficiency, autosomal recessive inheritance, coarse facies, corneal clouding, Hunter syndrome, iduronate sulphatase deficiency, X-linked recessive inheritance, no corneal clouding, Sanfilippo syndrome, severe CNS involvement, Morquio syndrome, skeletal dysplasia, normal intelligence. **Panel C:** Hepatocyte, skeletal muscle fiber, excess glycogen granules, glucose to glycogen pathway, blocked enzyme step, hepatomegaly, hypoglycemia, muscle cramps, exercise intolerance, cardiomyopathy.

Mucopolysaccharidoses (MPS)

Deficient lysosomal enzymes for degrading glycosaminoglycans (GAGs — heparan, dermatan, keratan sulphates). Undegraded GAGs accumulate in connective tissue cells, fibroblasts, and neurons.

Disorder	Enzyme deficiency	Inheritance	Key features
Hurler syndrome (MPS I-H)	α-L-iduronidase	AR	Coarse facies (gargoylism), corneal clouding, intellectual disability, hepatosplenomegaly, kyphosis (gibbus), death in childhood
Hunter syndrome (MPS II)	Iduronate sulfatase	X-linked recessive	Milder; no corneal clouding; intellectual disability; pebble-skin nodules; survival into adulthood

Pathology: vacuolated fibroblasts, Kupffer cell swelling; gargoyle cells in spleen. Excess urinary GAGs on screening.

Glycogen Storage Diseases (GSD)

Defects in glycogen synthesis or degradation → glycogen accumulates in specific tissues depending on enzyme:

Disease	Enzyme	Affected organ	Key feature
von Gierke (GSD type I)	Glucose-6-phosphatase	Liver + kidney	Severe fasting hypoglycaemia, hepatomegaly, doll face, lactic acidosis
Pompe disease (GSD type II)	Acid maltase (α-glucosidase)	Heart + skeletal muscle	Massive cardiomegaly, hypotonia, death from cardiorespiratory failure in infancy
McArdle (GSD type V)	Myophosphorylase	Skeletal muscle	Exercise-induced muscle cramps; elevated CK; normal lactate with exercise

SELF-CHECK

An 8-month-old infant has massive cardiomegaly, generalised hypotonia, and dies from cardiorespiratory failure. Biopsy of myocardial cells shows PAS-positive vacuoles. Which enzyme deficiency is responsible?

A. Glucose-6-phosphatase

B. Acid maltase (lysosomal α-glucosidase)

C. Glucocerebrosidase

D. Debranching enzyme

Reveal Answer

Answer: B. Acid maltase (lysosomal α-glucosidase)

Pompe disease (GSD type II) is caused by acid maltase (lysosomal α-glucosidase) deficiency. Glycogen accumulates in lysosomes of cardiac and skeletal muscle → massive cardiomegaly + hypotonia. Glucose-6-phosphatase deficiency = von Gierke (liver/kidney, hypoglycaemia); glucocerebrosidase = Gaucher disease.

CLINICAL PEARL

High-yield LSD memory aid — "GNT MHP":
- Gaucher → Glucocerebrosidase → Gaucher cells (wrinkled macrophages)
- Niemann-Pick → NsphingomyeliNase → foam cells + neurodegeneration
- Tay-Sachs → Texosaminidase A → cherry-red spot (neurons)
- Mucopolysaccharidoses → Multiple GAG-enzyme defects → MPS I (Hurler, AR) / MPS II (Hunter, X-linked)
- Hex from Hurler = Heparan + dermatan; Hunter = no corneal clouding
- Pompe → Pump failure (heart); von Gierke → Glucose-6-P = Gluconeogenesis failure → hypoglycaemia

Note: Pompe is unique — the only GSD that is also a lysosomal storage disorder (acid maltase is a lysosomal enzyme).