P.361 - McArdle Disease: Clinical, biochemical and molecular genetic analysis of 58 patients

Abstract

McArdle disease is a common metabolic myopathy with autosomal recessive mode of inheritance. A frequent mutation p.Arg50Ter in the myophosphorylase gene is reported in patients with McArdle disease. We performed a systemic clinical, biochemical and molecular genetic analysis of 58 Caucasian patients (31 males and 27 females; mean age at diagnosis: 37 years) with McArdle disease. Clinically, all patients reported exercise induced myalgia and fatigue. However, permanent weakness was reported only in 45% patients. Twenty-one percentage patients had family history of McArdle disease. In 86% patients, the age of onset was in childhood (0–12 years). Myophosphorylase activity measured in all 18 available patients was highly reduced (mean: 0.17 U/g Tissue; Normal: 12–61). Molecular genetic analysis showed the common p. Arg50Ter mutation in 67% patients (25 homozygotes and 14 heterozygotes) with an allele frequency of 55%. The other frequent mutations identified were p.Arg270Ter (allele frequency: 6%) followed by c.2262delC and p.Met1Val (allele frequencies: 3%). Apart from these mutations, 25 other rare mutations were also identified. Three of these rare mutations were identified in two or more than two unrelated patients. A genotype-phenotype correlation could not be established as so many different genotypes were observed and all our patients did present with signs of exercise intolerance that is typical in McArdle disease. Moreover, despite different genotypes, the enzyme activity was highly reduced in all available patients. Present analysis shows an enormous genetic heterogeneity in McArdle disease with 28 rare or private mutations. However, high sensitivity of p.Arg50Ter mutation analysis emphasizes detection of this mutation as the first step of diagnosis in McArdle disease.