Glycogen Storage Disease, Type V (McArdle Disease) via the PYGM Gene

Glycogen storage disease type V (GSDV; OMIM 232600), also known as McArdle disease, is characterized by exercise-induced muscle fatigue, pain, and cramps. Onset is usually in the second to third decade. Intense exercise can lead to rhabdomyolysis with concomitant myoglobinuria and renal failure. Patients have elevated serum creatine kinase activity. Severity is highly variable.

GSDV is an autosomal recessive disorder. Defects in the PYGM gene encoding the muscle phosphorylase enzyme are the only known cause of GSDV. Roughly 65 different causative variants have been reported in PYGM (www.hgmd.org; Martin et al. Ann Neurol 50:574-581, 2001; Bruno et al. Hum Mut 27:718, 2006). The variants are missense, nonsense, splicing and frameshift and are located throughout the length of this compact gene. Two variants, p.Arg50* in exon 1 and p.Gly205Ser, in exon 5 are common among European patients. No genotype-phenotype connections have yet been made. Amino acid numbering differs among research groups; for example p.Arg50* is sometimes referred to as p.Arg49*. A few authors have reported muscle symptoms in carriers of PYGM variants (see for example Manfredi et al. J Neurol Sci 115:91-94, 1993, but see also Andersen et al. Neurol 67:716-718, 2006). Recently, Vladutiu et al. (Muscle Nerve 34:153-162, 2006) reported a much higher frequency of PYGM variant carriers among patients with adverse muscle side effects to statins than among control groups.

Two causative variants will apparently be identified in nearly all patients with absence of muscle phosphorylase activity (Martin et al. 2001). The sensitivity in patients who have not had a test for enzyme activity is unknown.

This test provides full coverage of all coding exons of the PYGM gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.