DOI: 10.31832/smj.1777129 ISSN: 2146-409X

A Rare Metabolic Disorder: Two Siblings with a Pathogenic Variant in the PYGM Gene

Kübra Ateş, Dilcan Kotan, Levent Avcı
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McArdle disease (glycogen storage disease type V) is a rare autosomal recessive metabolic myopathy caused by pathogenic variants in the PYGM gene, leading to myophosphorylase deficiency. It typically presents with exercise intolerance, muscle pain, cramps, and, in some cases, rhabdomyolysis. Due to marked clinical heterogeneity, diagnosis is often delayed. We report two adult siblings with McArdle disease carrying the same homozygous PYGM variant and highlight the importance of family screening. Both siblings underwent detailed clinical, biochemical, and genetic evaluation. Laboratory investigations included creatine kinase levels, alanine aminotransferase, aspartate aminotransferase levels, and genetic analysis was performed using a next-generation sequencing panel targeting myopathy-related genes. The first case was a 38-year-old male with long-standing exercise-induced muscle pain, cramps, weakness, and a history of rhabdomyolysis. His creatine kinase level was 2,490 U/L, and physical examination revealed limb asymmetry, a high-arched palate, and kyphoscoliosis. The second case was his 26-year-old sister, who developed exercise-induced muscle pain at 20 years of age and had a markedly elevated creatine kinase level of 12,380 U/L. She showed a high-arched palate and atrophy of the left gastrocnemius muscle. Molecular analysis identified a homozygous PYGM c.1A>G (p.Met1Val) variant affecting the translation initiation codon in both siblings. Despite sharing the same pathogenic variant, the siblings exhibited notable intrafamilial phenotypic variability. This report underscores the clinical diversity of McArdle disease and emphasizes the value of family screening and molecular testing for early diagnosis and appropriate management.

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