A 5-year-old girl from Mumbai is brought to the pediatric clinic with a 2-year history of progressive muscle weakness, particularly in the proximal lower limbs and trunk. Her parents report she has difficulty climbing stairs and rising from the floor. On examination, she has generalized muscle weakness (grade 3–4/5), hepatomegaly, and mild cardiomegaly on chest X-ray. Serum creatine kinase is markedly elevated at 2500 IU/L. Muscle biopsy shows vacuolar myopathy with glycogen accumulation. Which enzyme deficiency is responsible for this disorder?

Explanation

## Diagnosis: Glycogen Storage Disease Type II (Pompe Disease) ### Clinical Presentation & Enzyme Deficiency **Key Point:** Pompe disease (GSD Type II) is caused by deficiency of **acid maltase (also called lysosomal α-1,4-glucosidase)**. This is the ONLY glycogen storage disorder with a lysosomal enzyme defect, making it unique in its pathophysiology and clinical presentation. ### Why Acid Maltase Deficiency Causes This Picture 1. **Lysosomal dysfunction:** Acid maltase normally degrades glycogen within lysosomes 2. **Glycogen accumulation:** Without acid maltase, glycogen accumulates in lysosomes, forming vacuoles 3. **Muscle involvement:** Skeletal and cardiac muscle are most severely affected because they have high metabolic demands and depend on lysosomal autophagy for energy 4. **Progressive weakness:** Glycogen-filled vacuoles disrupt muscle fiber structure and function ### Clinical Features Matching This Case | Feature | Pompe Disease (GSD II) | This Patient | |---------|----------------------|---------------| | **Age of onset** | Infantile form: <1 year; Late-onset: 2–5 years | ✓ 5 years (late-onset form) | | **Muscle weakness** | Proximal > distal; progressive | ✓ Proximal lower limbs, trunk | | **Cardiomegaly** | Present in infantile form; mild in late-onset | ✓ Mild cardiomegaly | | **Hepatomegaly** | Present | ✓ Present | | **Elevated CK** | Marked elevation (often >1000) | ✓ CK 2500 IU/L | | **Muscle biopsy** | Vacuolar myopathy with glycogen | ✓ Vacuolar myopathy with glycogen | | **Respiratory involvement** | Diaphragmatic weakness in infantile form | Late-onset: variable | ### Mnemonic: "POMPE = Lysosomal Protease Enzyme" - **P**rotease = Acid maltase (lysosomal enzyme) - **O**rgans = Muscle (skeletal & cardiac) most affected - **M**uscle = Vacuolar myopathy (glycogen in lysosomes) - **P**rogressive = Weakness worsens over time - **E**nzyme = Acid maltase deficiency ### Pathophysiology Flowchart ```mermaid flowchart TD A[Acid maltase deficiency]:::outcome --> B[Lysosomal glycogen accumulation]:::outcome B --> C[Glycogen-filled vacuoles in muscle]:::outcome C --> D[Disruption of muscle fiber structure]:::outcome D --> E[Progressive proximal muscle weakness]:::action D --> F[Cardiac dysfunction]:::action E --> G[Difficulty climbing stairs, rising from floor]:::outcome F --> H[Cardiomegaly]:::outcome ``` ### High-Yield: Distinguishing Pompe from Other Muscle-Affecting GSDs | Disorder | Enzyme | Muscle Involvement | Vacuolar Myopathy | Cardiomegaly | |----------|--------|-------------------|-------------------|---------------| | **Type II (Pompe)** | Acid maltase | Severe, progressive | **Yes** | **Yes** | | **Type III (Cori)** | Debranching enzyme | Mild myopathy | No | No | | **Type V (McArdle)** | Phosphorylase | Exercise-induced cramps, myoglobinuria | No | No | | **Type VII** | Phosphofructokinase | Exercise-induced symptoms | No | No | ### Clinical Pearl Pompe disease is the only glycogen storage disorder that responds to enzyme replacement therapy (ERT) with recombinant acid maltase (alglucosidase alfa). Early diagnosis and treatment can slow disease progression and improve outcomes. [cite:Robbins 10e Ch 7]