P.36 - Limb girdle muscular dystrophy type 2I: Lack of correlation between clinical severity, histopathological alterations and levels of glycosylated α-dystroglycan in patients homozygous for the common FKRP mutation

Abstract

Limb girdle musclular dystrophy type 2I (LGMD2I) is a progressive disorder caused by mutations in the FuKutin-Related Protein gene (FKRP). LGMD2I displays clinical heterogeneity with onset of severe symptoms in early childhood to mild calf and thigh hypertrophy in the second or third decade. Patients homozygous for the common FKRP mutation c.826C > A (p.Leu276Ile) show phenotypes within the milder end of the clinical spectrum. However, this group also manifests substantial clinical variability. FKRP deficiency causes hypoglycosylation of α-dystroglycan; a component of the dystrophin associated glycoprotein complex. α-Dystroglycan hypoglycosylation is in turn associated with loss of interaction with -, and hence, depletion of laminin α2. Here, we have attempted to clarify if the clinical variability seen in patients homozygous for c.826C > A, is related to alterations in muscle fiber pathology, α-DG glycosylation levels, levels of laminin α2 as well as the capacity of α-DG to bind to laminin. We have assessed vastus lateralis muscle biopsies from 25 LGMD2I patients harboring the c.826C > A/c.826C > A genotype by histological examination, immunohistochemistry and immunoblotting. No clear correlation was found between clinical severity, as determined by self-reported walking function, and the above features, suggesting that more complex molecular processes are contributing to the progression of disease.