δ-Sarcoglycan-deficient muscular dystrophy: from discovery to therapeutic approaches

In 1954, Walton and Nattrass described a group of patients who shared a similar pattern of proximal muscle weakness and whose symptoms could not be assigned to any of the known muscular dystrophies (MDs) of that time [1]. This highly heterogeneous group of patients was broadly characterised as having the limb-girdle muscular dystrophies (LGMDs). It was not until the discovery of dystrophin as the relevant protein missing in Duchenne muscular dystrophy (DMD) [2,3] and the isolation of the dystrophin glycoprotein complex (DGC) [4] that this group was further stratified according to the molecular defect. It is now known that a subgroup of patients who present with an LGMD phenotype harbour mutations in genes encoding four of a family of six transmembrane proteins called the sarcoglycans (SGs).LGMD2F was the fourth of the sarcoglycanopathies (LGMD2C to LGMD2F) to be characterised when the causative mutation in the δ-SG gene was identified in a group of Brazilian LGMD patients with a DMD-like presentation whose disease was linked to a region on chromosome 5 (q33-34) [5-7]. Since then, a large number of mutations causing both LGMD2F and δ-SG-associated cardiomyopathy have been described (Leiden Muscular Dystrophy database: http://www.dmd.nl/ webcite).The age of onset in LGMD2F can vary from early childhood to adulthood. Most patients present with progressive weakness and wasting of the proximal muscles and elevated serum creatine kinase in the first decade of life [8]. General survival depends on cardiac and respiratory involvement and patients can die, sometimes even at early stages of the disease, because of severe dilated cardiomyopathy or chest infections and respiratory failure [9,10]. The diagnosis is based initially on examination of a muscle biopsy (which exhibits dystrophic features with reduced SG expression) and is confirmed by genetics [11]. Sarcoglycanopathy has, as a whole, a relatively low prevalence in nonconsanguineous populations (2.27/100,000 is a recen