MOLECULAR-GENETIC HETEROGENEITY OF MYOPHOSPHORYLASE DEFICIENCY (MCARDLES-DISEASE)

Background and Methods. Myophosphorylase deficiency (McArdle's disease ) is one of the most common causes of exercise intolerance, muscle cra mps, and recurrent myoglobinuria. The myophosphorylase gene has been s equenced and assigned to chromosome 11, but the molecular basis of McA rdle's disease is not known. We sequenced complementary DNA in 4 patie nts 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 cytosi ne 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, chan ging glycine to serine; and the substitution of cytosine for adenine a t codon 542 in exon 14, changing lysine to threonine. Analysis of rest riction-fragment-length polymorphisms of appropriate fragments of geno mic DNA after amplification with the polymerase chain reaction showed that 18 patients were homozygous for the stop-codon mutation, 6 had di fferent 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 thr ee mutations were present in various combinations in five members of a family in which transmission appeared to be autosomal dominant. Concl usions. McArdle's disease is genetically heterogeneous, but the most c ommon mutation is the substitution of thymine for cytosine at codon 49 . These results suggest that in about 90 percent of patients the diagn osis of McArdle's disease can be made from a patient's leukocytes, thu s avoiding the need for muscle biopsy.