A 6-year-old girl from Mumbai is brought to the pediatric clinic with a 2-year history of progressive muscle weakness and calf hypertrophy. Her mother reports that she has difficulty climbing stairs and running. On examination, she has generalized muscle weakness, pseudohypertrophy of the calves, and hepatomegaly. Serum creatine kinase (CK) is markedly elevated at 3500 U/L. Muscle biopsy shows glycogen accumulation within muscle fibers with normal glycogen structure. Which glycogen storage disorder is most consistent with these findings?

Explanation

## Diagnosis: Glycogen Storage Disease Type II (Pompe Disease) **Key Point:** GSD Type II (acid α-glucosidase deficiency) is the only glycogen storage disorder with **primary cardiac and skeletal muscle involvement** and **lysosomal glycogen accumulation**. The late-onset form presents with progressive muscle weakness and pseudohypertrophy in childhood. ### Clinical Features and Pathophysiology | Feature | GSD Type II (Pompe) | GSD Type III (Cori) | GSD Type V (McArdle) | GSD Type VII (Tarui) | |---------|-------------------|-------------------|-------------------|---------------------| | **Primary tissue affected** | Heart + skeletal muscle | Liver + muscle | Skeletal muscle only | Skeletal muscle + RBC | | **Enzyme deficiency** | Lysosomal acid α-glucosidase | Debranching enzyme | Glycogen phosphorylase | Phosphofructokinase | | **Glycogen location** | Lysosomal (abnormal) | Cytoplasmic (normal structure) | Cytoplasmic | Cytoplasmic | | **Age of onset** | Infantile (<1 yr) or late (5–20 yr) | Early childhood (1–3 yr) | Adolescence/adulthood | Adolescence/adulthood | | **Muscle weakness** | Progressive, severe | Mild to moderate | Exercise-induced cramps | Exercise-induced cramps | | **CK elevation** | Marked (>1000) | Mild–moderate | Normal or mildly elevated | Marked (>1000) | | **Cardiomegaly** | Infantile form: YES; Late form: NO | No | No | No | | **Hepatomegaly** | Infantile form: YES; Late form: mild | YES | No | No | | **Hypoglycemia** | Infantile form: YES; Late form: NO | Mild | No | No | ### Pathophysiology of Late-Onset Pompe Disease ```mermaid flowchart TD A[Acid α-glucosidase deficiency]:::urgent --> B[Lysosomal glycogen cannot be degraded] B --> C[Glycogen accumulates in lysosomes] C --> D[Lysosomal rupture & autophagy dysfunction] D --> E[Muscle fiber necrosis]:::outcome E --> F[Progressive muscle weakness]:::outcome E --> G[Elevated serum CK]:::outcome C --> H[Pseudohypertrophy of calves] H --> I[Compensatory fat & connective tissue proliferation]:::outcome ``` **High-Yield:** GSD Type II is the **only glycogen storage disorder with lysosomal pathology**. All others involve cytoplasmic glycogen. This explains why Pompe is the only one with primary muscle involvement and why enzyme replacement therapy (imiglucerase) is effective. **Clinical Pearl:** Late-onset Pompe disease (presenting at 5–20 years) mimics muscular dystrophy clinically but is **treatable with enzyme replacement therapy (ERT)** — making early diagnosis critical. Infantile Pompe (presenting <1 year) is rapidly fatal without ERT due to cardiomegaly and respiratory failure. **Mnemonic: Pompe = "Pump" the lysosomes** - **P**ompe = lysosomal pathology - **O**nly GSD with **O**rgan (heart) involvement in infants - **M**uscle weakness (progressive) - **P**seudohypertrophy (calf enlargement) - **E**nzyme replacement therapy available ### Why This Case Is Type II, Not Others **Infantile vs. Late-Onset Pompe:** This 6-year-old girl has the **late-onset form** (juvenile Pompe), which: - Presents after age 2–3 years - Has progressive muscle weakness (not acute cardiomegaly) - Mild hepatomegaly (not massive) - Normal fasting glucose (no hypoglycemia) - Markedly elevated CK (muscle necrosis from lysosomal rupture) [cite:Robbins 10e Ch 5; Harrison 21e Ch 439]