• Anna Sarkozy, Silvia Torelli, Rachael Mein, Matt Henderson, Rahul Phadke, Lucy Feng, Caroline Sewry, Pierpaolo Ala, Michael Yau, Marta Bertoli, Tracey Willis, Simon Hammans, Adnan Manzur, Maria Sframeli, Fiona Norwood, Wojtek Rakowicz, Aleksandar Radunovic, Sujit S Vaidya, Matt Parton, Mark Walker, Silvia Marino, Curtis Offiah, Maria Elena Farrugia, Godwin Mamutse, Chiara Marini-Bettolo, Elizabeth Wraige, David Beeson, Hanns Lochmüller, Volker Straub, Kate Bushby, Rita Barresi, and Francesco Muntoni.
• Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, UK.
• J. Neurol. Neurosurg. Psychiatr. 2018 Jul 1; 89 (7): 762-768.

BackgroundDefects in glycosylation of alpha-dystroglycan (α-DG) cause autosomal-recessive disorders with wide clinical and genetic heterogeneity, with phenotypes ranging from congenital muscular dystrophies to milder limb girdle muscular dystrophies. Patients show variable reduction of immunoreactivity to antibodies specific for glycoepitopes of α-DG on a muscle biopsy. Recessive mutations in 18 genes, including guanosine diphosphate mannose pyrophosphorylase B (GMPPB), have been reported to date. With no specific clinical and pathological handles, diagnosis requires parallel or sequential analysis of all known genes.MethodsWe describe clinical, genetic and biochemical findings of 21 patients with GMPPB-associated dystroglycanopathy.ResultsWe report eight novel mutations and further expand current knowledge on clinical and muscle MRI features of this condition. In addition, we report a consistent shift in the mobility of beta-dystroglycan (β-DG) on Western blot analysis of all patients analysed by this mean. This was only observed in patients with GMPPB in our large dystroglycanopathy cohort. We further demonstrate that this mobility shift in patients with GMPPB was due to abnormal N-linked glycosylation of β-DG.ConclusionsOur data demonstrate that a change in β-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect in GMPPB.© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

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