Dataset Information

Mutations in GMPPB Presenting with Pseudometabolic Myopathy.

ABSTRACT: Mutations in the guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) gene encoding a key enzyme of the glycosylation pathway have been described in families with congenital (CMD) and limb girdle (LGMD) muscular dystrophy with reduced alpha-dystroglycan (?-DG) at muscle biopsy.Patients typically display a combined phenotype of muscular dystrophy, brain malformations, and generalized epilepsy. However, a wide spectrum of clinical severity has been described ranging from classical CMD presentation to children with mild, yet progressive LGMD with or without intellectual disability. Cardiac involvement, including a long QT interval and left ventricular dilatation, has also been described in four cases.Two missense mutations in GMPPB gene, one novel and one already reported, have been identified in a 21-year-old man presenting with elevated CK (38,650 UI/L; normal values <150 UI/L) without overt muscle weakness. Major complaints included limb myalgia, exercise intolerance, and several episodes of myoglobinuria consistent with a form of metabolic myopathy. Muscle biopsy showed only minimal alterations, whereas a marked reduction of glycosylated ?-DG was evident.This case further expands the phenotypic spectrum of GMPPB mutations and highlights the importance of exhaustive molecular characterization of patients with reduced glycosylation of ?-DG at muscle biopsy.

SUBMITTER: Panicucci C

PROVIDER: S-EPMC5874214 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Mutations in GMPPB Presenting with Pseudometabolic Myopathy.

Panicucci Chiara C Fiorillo Chiara C Moro Francesca F Astrea Guja G Brisca Giacomo G Trucco Federica F Pedemonte Marina M Lanteri Paola P Sciarretta Lucia L Minetti Carlo C Santorelli Filippo M FM Bruno Claudio C

JIMD reports 20170430

Mutations in the guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) gene encoding a key enzyme of the glycosylation pathway have been described in families with congenital (CMD) and limb girdle (LGMD) muscular dystrophy with reduced alpha-dystroglycan (α-DG) at muscle biopsy.Patients typically display a combined phenotype of muscular dystrophy, brain malformations, and generalized epilepsy. However, a wide spectrum of clinical severity has been described ranging from classic ...[more]

PMID: 28456886

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Project description:Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.

Dataset Information

Mutations in GMPPB Presenting with Pseudometabolic Myopathy.

Publications

Mutations in GMPPB Presenting with Pseudometabolic Myopathy.

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