Muscle involvement in limb-girdle muscular dystrophy with GMPPB deficiency (LGMD2T)

摘要

Objective: In this study, muscle involvement assessed by MRI and levels of GMPPB and glycosylation of α-dystroglycan expression in muscle were examined in patients with limb-girdle muscular dystrophy (LGMD) type 2T. Methods: Six new patients with genetically verified mutations in GMPPB were studied. T1-weighted magnetic resonance images were obtained in 4 participants. Muscle strength and potential involvement of extramuscular organs were examined. Glycosylation of α-dystroglycan in muscle was studied, and GMPPB and α-dystroglycan expression was analyzed by Western blotting. Prevalence of LGMD2T was calculated from the total LGMD population in Denmark. GMPPB was sequenced in all unclassified cases. Results: Two patients carried 3 new mutations in GMPPB . The other 4 patients carried previously described pathogenic mutations in GMPPB . MRI showed that the paraspinal muscles were the most affected, followed by involvement of hamstrings. Our results showed a loss of glycosylation of α-dystroglycan as well as secondary loss of merosin expression on Western blotting. The prevalence of LGMD2T in the Danish cohort of patients with LGMD is 1.5%. Conclusions: The new findings of this study are (1) the consistent finding of a preferential affection of paraspinal and hamstring muscles in LGMD2T, (2) 3 new mutations in GMPPB, (3) variable loss of glycosylation tested with IIH6 and VIA4 antibodies, and (4) a prevalence of LGMD2T of 1.5% in a well-characterized Danish LGMD cohort. Limb-girdle muscular dystrophy (LGMD) designates a heterogeneous group of more than 31 muscle disorders characterized by weakness and atrophy of the proximal muscles of the shoulder and pelvic girdles. 1 Recently, a new gene ( GMPPB ), responsible for causing both LGMD type 2T and congenital muscular dystrophy (CMD), was identified. 2 GMPPB codes for the protein, guanosine diphosphate (GDP)-mannose pyrophosphorylase B (GMPPB), which catalyzes the formation of GDP-mannose, required for glycosylation of proteins and lipids, including α-dystroglycan. α-dystroglycan is part of the dystroglycan protein complex, which forms a critical link between the contractile elements and extracellular matrix in muscle cells. It is important for cell stability and membrane integrity. 3 Mutations in GMPPB lead to hypoglycosylation of α-dystroglycan. 2 Approximately 40 patients with GMPPB mutations and muscular dystrophy have been reported worldwide with phenotypes equally distributed between LGMD and CMD. 2 The majority of the patients with the LGMD phenotype are able to walk short distances. Patients with GMPPB deficiency and CMD have been described with hypotonia, epilepsy, intellectual disability, cataracts, cardiomyopathy, cerebellar/pontine hypoplasia, and neuromuscular junction dysfunction. 4 , – 6 However, phenotypic characterization in patients with the LGMD phenotype, especially knowledge about the pattern of muscle involvement, is lacking. We therefore studied 6 new cases of LGMD2T clinically, by MRI, with immunohistology and Western blotting, and estimated the prevalence of LGMD2T among LGMDs in Denmark.