G.P.313: Intrafamilial heterogeneity in an alpha-dystroglycanopathy due to GDP-Mannose Pyrophosphorylase B (GMPPB) mutations

Abstract

We describe two brothers who presented with different phenotypes and progression, sharing compound heterozygous mutations in the GMPPB gene. The index case, 34 years old, was referred to the muscle clinic for increased CK (>2.000), proximal weakness and calf hypertrophy. He is on therapy for myoclonic epilepsy following encephalitis in infancy and has mild cognitive and motor delay. Because of his symptoms, a muscle biopsy was performed: the immune-histochemistry showed a reduction in alpha dystroglycan labelling, with a secondary reduction of laminin alpha2 chain on western blot. Genes known to be associated to alpha-dystroglycanopathy have been excluded by direct sequencing (FKRP,POMT1, POMT2, POMGnT1,LARGE, FKTN). Two heterozygous variants in the GMPPB gene, a previously described mutation[c.860G>A (p.Arg287Gln)] and a novel variant [c.656T>C (p.Ile219Thr)]. The older brother, 36 years old, shares the same mutations having been shown to also have increased CK (2.832). He has global developmental delay presenting with speech and language difficulties, motor delay, impaired fine motor coordination and autistic spectrum disorder. He is not affected by weakness or fatigue, nor has weakness at physical examination. GMPPB catalyses the formation of GDP-mannose, required for O-mannosylation of alpha-dystroglycan. Mutations in this gene have been recently described in association to a spectrum of muscular dystrophy variants (Carss et al. AJHG, 2013), ranging from congenital to limb girdle muscular dystrophy, with additional symptoms as intellectual disability, epilepsy or brain structural anomalies. The family we describe highlights the clinical variability of these patients, with different presentation despite sharing the same mutations. Furthermore, it underlines the importance of testing CK in children presenting with global developmental delay: if the younger brother had not presented with a LGMD phenotype, the diagnosis in the older brother would have continued to be missed.