This finding also explains the muscle inexcitability after repeated nerve stimulation observed many years ago in McArdle patients. Over 40 mutations have been identified all along the gene (PYGM) encoding myophosphorylase. While by far the most common mutation in Caucasian patients is the R49X (Arg49Stop) mutation, it is important to keep in mind that the frequency of different mutations varies in different ethnic groups. For example, the R49X mutation Inhibitors,research,lifescience,medical has never been described in Japan, where a single codon deletion 708/709 seems to

prevail (18). To complicate things further, it was documented that an apparently innocent polymorphism in the PYGM gene impaired cDNA splicing and was, Inhibitors,research,lifescience,medical in fact, pathogenic (19). This phenomenon, aptly dubbed “echo of silence” by

Mankodi and Ashizawa (20), has to be taken into account in McArdle patients without clearly pathogenic mutations. Genotype:phenotype correlations are not easily discernible, as patients with the same genotype (e.g. homozygous for the commonest mutation, R49X) may have very different clinical manifestations, varying from relatively mild exercise-related discomfort to almost crippling myalgia and recurrent myoglobinuria. Although these differences can be due in part to different lifestyles or dietary regimens, genetic must play a role. Inhibitors,research,lifescience,medical For example, rare cases of genetic “double trouble”, such as the coexistence in the same individual of homozygous mutations in PYGM and in the gene for adenylate deaminase, may explain more severe phenotypes (21, 22). Perhaps more importantly, screening for insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) in 47 patients showed a good Inhibitors,research,lifescience,medical correlation between clinical

severity and number of ACE genes harboring deletion (22). I will briefly Inhibitors,research,lifescience,medical consider only one other glycogenosis causing exercise intolerance and myoglobinuria, phosphoglycerate mutase (PGAM) deficiency (GSD X), in part for sentimental reasons, as my group discovered this enzyme defect in 1981 (23). Nine of the 13 patients identified thus far have been African American, and they all harbor one common nonsense mutation (W78X) either in homozygosity or in heterozygosity (Table ​(Table3).3). However, the disease is not confined to this ethnic group, and different mutations have been identified in Italian (24), Japanese (25), and most recently, Pakistani isothipendyl and Ashkenazi Jewish patients (Naini et al, unpublished observations). Table 3 Main features of 14 patients with GSD X (PGAM deficiency). There are two curious LY2835219 purchase aspects of PGAM deficiency. The first is the frequency of manifesting heterozygotes, which is counterintuitive considering that PGAM is the glycolytic enzyme with the highest activity (26). The second peculiarity is that this enzyme defect is frequently associated with tubular aggregates (27).