McArdle Disease: Update of Reported Mutations and Polymorphisms in the PYGM Gene.

McArdle disease is an autosomal-recessive disorder caused by inherited deficiency of the muscle isoform of glycogen phosphorylase (or "myophosphorylase"), which catalyzes the first step of glycogen catabolism, releasing glucose-1-phosphate from glycogen deposits. As a result, muscle metabolism is impaired, leading to different degrees of exercise intolerance. Patients range from asymptomatic to severely affected, including in some cases, limitations in activities of daily living. The PYGM gene codifies myophosphoylase and to date 147 pathogenic mutations and 39 polymorphisms have been reported. Exon 1 and 17 are mutational hot-spots in PYGM and 50% of the described mutations are missense. However, c.148C>T (commonly known as p.R50X) is the most frequent mutation in the majority of the studied populations. No genotype-phenotype correlation has been reported and no mutations have been described in the myophosphorylase domains affecting the phosphorylated Ser-15, the 280's loop, the pyridoxal 5'-phosphate, and the nucleoside inhibitor binding sites. A newly generated knock-in mouse model is now available, which renders the main clinical and molecular features of the disease. Well-established methods for diagnosing patients in laboratories around the world will shorten the frequent ∼20-year period stretching from first symptoms appearance to the genetic diagnosis.