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Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset neuromuscular degenerative disease characterised by proximal muscle weakness, ptosis and swallowing difficulty. The causative genetic abnormality is an expansion consisting of 2-7 additional base triplets in a repeat sequence in exon 1 of thePABPN1(PABP2) gene and results in an increase in length of the polyalanine tract in the PABPN1 protein from 10 to 12-17 residues. The expansions are stable through meiosis and mitosis suggesting a different mechanism of mutation from that of most other triplet repeat mutations. Most reports describe OPMD expansions as consisting of multiples of a GCG sequence. However, some studies have detected GCA interspersions. We have analysed 86 OPMD patients with aPABPN1gene expansion, including three compound heterozygotes, and have identified 13 different types of expansion mutation, six of which contain GCA and GCG and almost all of which are consistent with a mutational mechanism of unequal recombination. [ABSTRACT FROM AUTHOR]

Background: Defects 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., Methods: We describe clinical, genetic and biochemical findings of 21 patients with GMPPB -associated dystroglycanopathy., Results: We 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., Conclusions: Our data demonstrate that a change in β-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect in GMPPB., Competing Interests: Competing interests: None declared., (© 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.)

Background: Charcot Marie Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies. CMT4H is an early onset autosomal recessive demyelinating neuropathy. The locus responsible for CMT4H was assigned to chromosome 12p11.21-q13.11 by homozygosity mapping and mutations in the Frabin gene (FGD4 Rho GDP/GTP exchange factor) were subsequently identified in six families., Methods: We sequenced the Frabin gene in a cohort of 12 UK CMT families with clinically defined autosomal recessive demyelinating neuropathy., Results: We identified a novel homozygous Frabin p.R275X mutation in a family from Northern Ireland. The two affected cases in this family had a very slowly progressive neuropathy with both cases remaining ambulant into middle age. Examination of mRNA from lymphoblasts showed that this stop mutation caused very little nonsense mediated mRNA decay and the predominant mRNA species was the mutant form that is likely to be translated into a truncated protein., Conclusions: This work extends the understanding of the pathogenesis of Frabin mutation-associated Charcot Marie Tooth (CMT) 4H and suggests that mutations in Frabin should also be considered in ambulant adults with CMT1.