BACKGROUND AND METHODS: Myophosphorylase deficiency (McArdle's disease) is one of the most common causes of exercise intolerance, muscle cramps, and recurrent myoglobinuria. The myophosphorylase gene has been sequenced and assigned to chromosome 11, but the molecular basis of McArdle's disease is not known. We sequenced complementary DNA in 4 patients and studied genomic DNA by restriction-endonuclease analysis in 40 patients with McArdle's disease. RESULTS: Sequence analysis revealed three distinct point mutations: the substitution of thymine for cytosine at codon 49 in exon 1, changing an encoded arginine to a stop codon; the substitution of adenine for guanine at codon 204 in exon 5, changing glycine to serine; and the substitution of cytosine for adenine at codon 542 in exon 14, changing lysine to threonine. Analysis of restriction-fragment-length polymorphisms of appropriate fragments of genomic DNA after amplification with the polymerase chain reaction showed that 18 patients were homozygous for the stop-codon mutation, 6 had different mutations in the two alleles (compound heterozygotes), and 11 were presumed to be compound heterozygotes for a known mutation and an unknown one; only 5 patients had none of the three mutations. All three mutations were present in various combinations in five members of a family in which transmission appeared to be autosomal dominant. CONCLUSIONS: McArdle's disease is genetically heterogeneous, but the most common mutation is the substitution of thymine for cytosine at codon 49. These results suggest that in about 90 percent of patients the diagnosis of McArdle's disease can be made from a patient's leukocytes, thus avoiding the need for muscle biopsy.
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