In some cases, the severe phenotype may be explained by the association with mutation in the AMPD1 gene (1). In addition, an angiotensin converter enzyme (ACE) insertion/deletion polymorphism might play a significant role as a phenotype modulator in individuals with GSD-V (44). Conclusion Molecular genetics studying by DNA testing should be the first choice in the diagnostic of McArdle disease, starting to analyse the common p.R50X mutation. However, since most of the PYGM mutations are private, the possibility of finding
new mutations has to be taken into account. Any a priori silent variant has Inhibitors,research,lifescience,medical to be evaluated as possible putative pathogenic mutation. Finally, we underline the importance Inhibitors,research,lifescience,medical of the cDNA analysis that may allow the genetic diagnosis, providing novel information on the mechanisms of the PYGM gene splicing machinery. Acknowledgements Supported by grants from the Fondo de Investigación Sanitaria (FIS PI040487, FIS PI040362), the Spanish Network for Rare Diseases (CB06/07/0015), Ricerca Corrente-Istituto Gaslini, and the Italian Ministry of Health.
McArdle disease (MCA) is the muscle glycogenosis
due to defect of myophosphorylase. The pathological hallmark of the disease is the Inhibitors,research,lifescience,medical accumulation in the skeletal muscle of normal glycogen, and the absence of histochemical staining for glycogen phosphorylase in muscle. The pathology Sotrastaurin research buy reflects the biochemical functional block in access to muscle glycogen, which while causing the local storage,
is the physiopathological basis Inhibitors,research,lifescience,medical of the clinical signs associated with the disease. Patients with MCA show exercise intolerance which is maximal for the efforts which depend upon the rapid mobilization of muscle glycogen. Acute anaerobic efforts, when sustained after the first minute, depend heavily upon glycolytic Inhibitors,research,lifescience,medical metabolism, which in skeletal muscle utilises blood born glucose and glucose-1-P obtained from glycogen breakdown, which is blocked in MCA patients (1). Indeed, one of the most typical sign of MCA is the second-wind phenomenon, by which the patient, who experienced exhaustion after few minutes of acute effort slightly above the anaerobic threshold, is able to resume the effort with a much improved capacity and resistance (2). There are two rational Calpain approaches to circumvent this metabolic limitation, either the provision of a sufficient and continuous blood glucose flux, or a more efficient utilization of the available fuels. The first approach is efficiently achieved by timely oral administration of sugar (2), which was shown to significantly improve perceived exhaustion and sustainable workload. This approach however cannot cover for all the unforecasted efforts, and has obvious limitation in terms of sustainable amount of sugar ingested.