G.P.314: Alpha-dystroglycanopathy: Two new patients with GMPPB mutations and a mild limb-girdle phenotype

Abstract

Recessive mutations in the guanosine diphosphate mannose pyrophosphorylase B (GMPPB) gene have recently been reported to cause muscular dystrophies with hypoglycosylation of alpha-dystroglycan. Associated phenotypes range from severe congenital muscular dystrophies with structural brain involvement to limb girdle muscular dystrophy (LGMD). Here we describe two new patients with mild LGMD phenotype and GMPPB gene mutations. The first patient, a girl, was referred to our attention with a clinical history of acute-onset weakness at 10 years of age and increased CK level (4807 UI). A diagnosis of polymyositis was first suggested in view of changes on muscle biopsy suggestive of myositis, but steroid and immunosuppressive treatment showed no benefits and symptoms gradually worsened. Clinical examination at the age of 16 years showed waddling gait with prevalent proximal lower limb muscle wasting and weakness. She had cataract diagnosed at the age of 11 years. There was no cardiac and respiratory involvement, nor learning difficulties. Review of the muscle biopsy demonstrated decreased alpha-dystroglycan immunostaining and GMPPB gene sequencing identified two pathogenic changes (c.559C>T and c.578T>C). The second patient is a 43 years old woman, referred to our NSCT service for genetic testing. She was born with congenital hip dislocation and she was delayed in walking. Onset was in the third decade with predominant proximal weakness, scapular winging, mild axial and facial weakness. CK level was increased up to 2668 UI. Muscle biopsy immunoanalysis showed reduction in alpha-dystroglycan labelling and secondary reduction of Lamininα2 chain labelling on western blot. GMPPB gene analysis showed compound heterozygosity for two mutations (c.79G>C and c.907C>T). In summary these two patients with GMPPB gene mutations further expand the clinical spectrum associated with this type of secondary dystroglycanopathy, in particular with regard to age at onset and prevalent skeletal involvement.