In 2002 we described how mutations of the newly-identified selenoprotein N (SEPN) are at the origin of a novel recessive entity called SEPN-related myopathy (SEPN-RM) or "selenopathy". SEPN-RM groups together two early-onset myopathies previously considered as different: the form of congenital muscular dystrophy with rigid spine (Rigid Spine Muscular Dystrophy, RSMD1) and the most severe cases of the classical form of multi-minicore myopathy (Multi-minicore Disease, MmD). Recently, in collaboration with P. Richard (Federation of Genetics, Pitié-Salpêtrière Hospital) we have shown that mutations of the SEPN1 gene are also responsible for a third entity, an early and autosomal recessive form of desmin-related myopathy with Mallory body-type inclusions (Ferreiro et al., 2004).

 
On the other hand, a clinical, morphological and molecular re-evaluation of the 80 patients carrying SEPN1 mutations identified up to now allowed us to establish that all these patients presented an identical picture, clinically very homogenous (characterised by muscle weakness affecting mainly the neck and trunk muscles) but whose morphological presentation is very variable (Gonzales et al, in preparation).

Also, we have characterised the phenotype and identified the genetic defect associated with a novel form of core myopathy affecting the skeletal and cardiac muscles in young children; a very severe dilated cardiomyopathy results in the death of 80% of patients before the age of 18 years. This novel early-onset myopathy is caused by homozygous deletions of the titin gene (Carmignac et al., 2007).

 

Several forms of Core Myopathies are associated with defects in two genes encoding sarcoplasmic reticulum proteins: the skeletal muscle ryanodine receptor (RyR1), a Ca2+-release-channel which plays a key role in excitation-contraction coupling; and the selenoprotein N (SelN), a ubiquitously-expressed glycoprotein. Despite these recent advances, the pathophysiological mechanisms involved in Core Myopathies are far from fully known. SelN is the only selenoprotein implicated in a human genetic disorder. Its function remains unknown, although SelN has significant structural similarities with other selenoproteins which are involved in redox processes and implicated in defence against reactive oxygen species (ROS) and nitric oxide (NO) derivatives. On the other hand, RyR1 is emerging as a paradigm of redox-sensor ion channel, modulated by NO. These and other data suggest that oxidative/nitrosative stress (OxNS) could play a key role in the pathogenesis of CM. Our objective is to examine the pathophysiological role of oxidative/nitrosative stress in CM, and its potential applications as a target for therapeutic approaches. Those ex vivo and in vitro pathophysiological studies are at present under development in our team.

 Also, we studied the expression of the proteins involved in calcium homeostasis on the muscular biopsies of patients presenting different forms of core myopathies. This approach has allowed us to identify a pattern of protein distribution associated with RYR1 mutations which is different to that associated with SEPN1 mutations. This immunohistochemical pattern will be useful in orienting the genetic studies of the different forms of core myopathies, and suggests that the mechanisms involved in the formation of these morphological lesions are heterogeneous (Parain et al., 2004, Herasse et al. 2007).

 

All this work has brought about immediate advances in the diagnosis, management and genetic counselling of patients and families at risk. We have also shown the existence of unsuspected phenotypic and molecular links between different entities, thus leading to a fundamental revision of classic diagnostic criteria and the nosological classification of early onset myopathies. This has been possible thanks to national and international collaboration, particularly that established in the framework of the MmD Consortium of the European Neuromuscular Centre (Jungbluth et al., 2004).