Pompe's Disease

1. DEFINITION AND CLASSIFICATION

Definition: Autosomal recessive Lysosomal Storage Disorder (LSD) characterized by the accumulation of glycogen within lysosomes due to enzyme deficiency.
[cite_start]Unique Feature: It is the only Glycogen Storage Disorder (GSD) that is also a Lysosomal Storage Disorder.
Classification:
- Infantile-Onset Pompe Disease (IOPD): Classic, severe, cardiac involvement.
- Late-Onset Pompe Disease (LOPD): Childhood, juvenile, or adult-onset; primarily skeletal muscle involvement.

Enzyme Deficiency: Acid $α$ -glucosidase (also known as acid maltase).
Gene: GAA gene on chromosome 17q25.
Inheritance: Autosomal Recessive.
Pathophysiology:
- Deficiency leads to inability to degrade lysosomal glycogen.
- Intralysosomal accumulation of glycogen causes lysosomal swelling and rupture.
- Target Tissues: Cardiac muscle, skeletal muscle, and smooth muscle are most severely affected.

Onset: Typically presents in first months of life (median 4 months).
General: Failure to thrive, feeding difficulties, profound generalized weakness.
Neuromuscular:
- Severe hypotonia ("Floppy Infant").
- Areflexia.
- Macroglossia: Large, protruding tongue (Classic sign).
Cardiac:
- Hypertrophic Cardiomyopathy: Massive cardiomegaly, often biventricular.
- Cardiac failure and arrhythmias.
Respiratory: Recurrent infections, respiratory failure due to muscle weakness.
Hepatic: Hepatomegaly (moderate, due to congestion or storage).

Onset: Infancy (without cardiomyopathy) to adulthood.
Skeletal Muscle: Progressive proximal muscle weakness (limb-girdle distribution). Gower's sign may be positive.
Respiratory: Diaphragmatic weakness (major cause of morbidity/mortality), sleep apnea.
Cardiac: Typically absent or mild.
CNS: Vascular aneurysms (dilative arteriopathy) noted in long-term survivors.

Biochemical Screening:
- Creatine Kinase (CK): Markedly elevated (often >2000 U/L) in IOPD; variably elevated in LOPD.
- Urine Oligosaccharides: Elevated glucose tetrasaccharide (Hex4 or Glc4) – useful biomarker.
Enzyme Assay (Gold Standard): Reduced Acid $α$ -glucosidase activity in Dried Blood Spots (DBS), leukocytes, or fibroblasts.
Molecular Genetics: GAA gene sequencing (confirms diagnosis/carrier status).
Imaging:
- CXR: Massive cardiomegaly ("Globular heart").
- ECHO: Severe concentric biventricular hypertrophy.
Muscle Biopsy:
- Histopathology: Vacuolated myopathy.
- Staining: PAS-positive, diastase-sensitive glycogen accumulation within lysosomes.

IOPD: Spinal Muscular Atrophy (SMA) type 1, hypothyroidism, endocardial fibroelastosis, other causes of floppy infant.
LOPD: Duchenne/Becker muscular dystrophy, Limb-girdle muscular dystrophy, Polymyositis.

Goal: Prevent irreversible muscle damage and manage complications.

Enzyme Replacement Therapy (ERT):
- Drug: Recombinant human acid $α$ -glucosidase (e.g., Alglucosidase alfa).
- Mechanism: Replaces deficient enzyme; improves survival and cardiac function.
- Efficacy: Significantly reverses cardiomyopathy; variable effect on skeletal muscle.
- CRIM Status: Cross-Reactive Immunologic Material status determines risk of antibody formation against ERT (CRIM-negative patients need immunomodulation).

Cardiac: Management of heart failure (diuretics, ACE inhibitors); avoid digoxin (risk of toxicity in hypertrophied muscle).
Respiratory: Aggressive infection management, CPAP/BiPAP, vaccination (RSV, Flu, Pneumococcal).
Nutritional: High-protein diet, physiotherapy to prevent contractures.

Untreated IOPD: Rapidly fatal; death usually <1 year of age due to cardiorespiratory failure.
Treated (ERT): Significantly prolonged survival; ventilator-free survival improved.
LOPD: Slowly progressive; morbidity primarily from respiratory insufficiency.