Molecular and clinical study of McArdle’s disease in a cohort of 123 European patients. Identification of 20 novel mutations

Abstract

McArdle’s disease is the most common muscle glycogenosis. It is caused by the deficiency of myophosphorylase, encoded by the PYGM gene. We studied 123 patients previously diagnosed with McArdle’s disease and we identified 20 novel mutations (10 missense and 3 nonsense mutations, 3 small deletions, 2 gross deletions and 2 small insertions). Most patients of this cohort belong to Spanish and French populations. This allowed us to determine the differences between the allelic frequencies of the common mutations R50X and G205S of these populations. The R50X has an allelic frequency in this cohort of about 61.7%, being 68.5% in French and 53.7% in Spanish patients. The G205S had a higher allelic frequency in the Spanish (10.2%) than in the French population (3.2%). Moreover, a clinical study of 91 patients was performed to establish both genotype–phenotype correlation and gender influence in the severity of the disease. We conclude that no genotype–phenotype correlation is evident and that no gender effect is related to the phenotype.

Introduction

Glycogen storage disease type V or McArdle’s disease (MIM# 232600), the most common muscle glycogenosis, is caused by the deficiency of muscle glycogen phosphorylase (myophosphorylase, EC 2.4.1.1) [1], [2]. This enzyme exists as a homodimer formed of two identical subunits of 97 kDa each, and plays an important role in muscle glycogen metabolism breaking up glycogen into glucose subunits.

Most McArdle’s disease patients are clinically characterized by onset in childhood or adolescence with exercise intolerance and premature fatigue, myalgia, muscle cramps, moderate to high increased serum levels of creatine kinase (CK) at rest, and episodes of recurrent myoglobinuria and rabdomyolysis, which could result in acute renal failure. Exercise forearm test displays no increase in lactate values [3]. Most patients experience the so-called “second wind” phenomenon, characterized by the ability to resume exercise after a short period of rest at the first appearance of fatigue [4]. However, atypical presentations have been described in some patients as fatal infantile form [5] and permanent muscle weakness form [6], [7]. Recently, a classification of McArdle’s disease has been reported based on the severity of the clinical phenotype [8]. Diagnosis is based on the clinical and neurophysiological phenotype, and the histochemical or biochemical demonstration of myophosphorylase deficiency in muscle biopsy [9].

McArdle’s disease is caused by genetic defects in the PYGM gene (MIM# 608455) which has been cloned, sequenced, and assigned to chromosome 11q13 [10] and is transmitted in an autosomal recessive pattern. Molecular genetic studies have demonstrated the high allelic heterogeneity of the PYGM gene by the identification of over 100 different mutations in the coding region and splice sites of the gene (see Human Gene Mutation Database http://www.hgmd.cf.ac.uk/). The most common mutation in Caucasian population is the nonsense R50X in exon 1, initially reported as R49X [11].

This mutation shows its highest frequency in North American and British patients. In European countries there seems to be a decreasing North–South gradient with the lowest frequency in Italy [11], [12], [13], [14], [15], [16], [17], [18], [19]. The second most common mutation in Caucasian population identified is the missense mutation G205S in exon 5, and the missense mutation W798R which has only been reported so far in patients of Spanish origin [17], [20].

In this paper, we present the molecular results in a cohort of 123 European patients with glycogenosis V, the largest series reported so far, and the genetic comparison between French and Spanish populations. Moreover, clinical studies permitted the analysis of a possible genotype–phenotype correlation and the effect of gender on the severity of this pathology.