However, regarding the LGMD subgroups with mental retardation and microcephaly (ie. LGMD2K and similar phenotypes), we found this specific phenotype only in patients with mutations either in POMT1 or

POMT2 (70). On the other hand, we identified a number of patients with considerably more severe muscle weakness than LGMD2K, clinically resembling MDC1C (i.e. non ambulant children), with absent brain involvement, due to mutations in fukutin. This suggests that while involvement of any of these genes can give rise to a very wide spectrum of clinical syndromes with Inhibitors,research,lifescience,medical overlapping features, there might be at the same time subtle differences in the Inhibitors,research,lifescience,medical involvement of brain and muscle secondary to specific gene mutations. POMT1 and POMT2 are apparently associated with more severe central nervous

system involvement even in patients with relatively mild weakness who remain ambulant (LGMD2K) whereas this phenotype has so far not been observed for POMGnT1, LARGE, fukutin or FKRP. These results may therefore allow the targeting Inhibitors,research,lifescience,medical of specific gene defects in individual subcategories of patients with dystroglycanopathies. The results also suggest that the original descriptions of several “core phenotypes” associated with each of these genes is related to the high prevalence of founder mutations within specific populations, such as the Inhibitors,research,lifescience,medical “Finnish” POMGnT1 mutation in MEB disease, and the “Japanese” fukutin mutation responsible for FCMD, and not to the fact that mutations in these genes are not capable of inducing GDC-941 different conditions. These observations therefore expand the clinical phenotypes associated with mutations in POMT1, POMT2, POMGnT1, fukutin and LARGE, and provide an indication of the relative frequency of their involvement in Caucasian patients with a dystroglycanopathy.

Adding together the patients recently studied for mutations in POMT1, POMT2, POMGnT1, fukutin and LARGE, and those in whom we have Inhibitors,research,lifescience,medical previously identified FKRP mutations (77 cases, Muntoni et al, personal observation) we have been able to identify causative mutations in approximately 65% of patients with a dystroglycanopathy. This means that a significant number of patients did not have mutations in any of the genes we know are associated with this phenotype, suggesting that more, as yet undefined gene(s) are likely to be implicated in the pathogenesis many of the dystroglycanopathies. The identification of these other genes may provide additional information on the pathway of glycosylation of α-dystroglycan. Conclusions All these forms of muscular dystrophies are characterized by the hypoglycosylation of ADG in both patients skeletal muscle biopsies and the skeletal muscle of equivalent animal models, suggesting the existence of a common pathogenetic pathway.