Intrafamilial variability in GMPPB-associated dystroglycanopathy: Broadening of the phenotype.
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ABSTRACT:
SUBMITTER: Bharucha-Goebel DX
PROVIDER: S-EPMC4395885 | biostudies-literature | 2015 Apr
REPOSITORIES: biostudies-literature
Publications
Intrafamilial variability in GMPPB-associated dystroglycanopathy: Broadening of the phenotype.
Bharucha-Goebel Diana X DX Neil Erin E Donkervoort Sandra S Dastgir Jahannaz J Wiggs Edythe E Winder Thomas L TL Moore Steven A SA Iannaccone Susan T ST Bönnemann Carsten G CG
Neurology 20150313 14
Similar Datasets
Project description:Mutations in GDP-mannose pyrophosphorylase B (GMPPB), a catalyst for the formation of the sugar donor GDP-mannose, were recently identified as a cause of muscular dystrophy resulting from abnormal glycosylation of α-dystroglycan. In this series, we report nine unrelated individuals with GMPPB-associated dystroglycanopathy. The most mildly affected subject has normal strength at 25 years, whereas three severely affected children presented in infancy with intellectual disability and epilepsy. Muscle biopsies of all subjects are dystrophic with abnormal immunostaining for glycosylated α-dystroglycan. This cohort, together with previously published cases, allows preliminary genotype-phenotype correlations to be made for the emerging GMPPB common variants c.79G>C (p.D27H) and c.860G>A (p.R287Q). We observe that c.79G>C (p.D27H) is associated with a mild limb-girdle muscular dystrophy phenotype, whereas c.860G>A (p.R287Q) is associated with a relatively severe congenital muscular dystrophy typically involving brain development. Sixty-six percent of GMPPB families to date have one of these common variants.
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Project description:Recent studies have highlighted a significant association between mutations in GDP-mannose pyrophosphorylase B (GMPPB) gene with dystroglycanopathy (DGP), a rare disease characterized by neuromuscular phenotypes. To interrogate the molecular mechanisms driving the onset and progression and to identify potential therapeutic approaches for GMPPB-associated DGP, we here constructed genetically engineered mice models of Gmppb. We show that Gmppb knockout and P32L mutant mice are lethal in the homozygous form, whereas homologous R287Q mutants are viable. Heterozygous Gmppb-P32L mutant mice exhibit reduced muscle strength, decreased locomotor ability, elevated creatine kinase levels and increased centrally nucleated myofibers. Furthermore, loss of GMPPB results in defective differentiation of muscle stem cells, leading to failure to develop into mature myotubes and diminished muscle regeneration capability. Biochemical and transcriptomic analyses indicate that loss of GMPPB is associated with significant alterations in O-linked glycosylation level, intracellular Ca2+ storage and release and the Wnt/β-catenin signaling pathway. Pharmacological activation of the Wnt pathway alleviated disruption of muscle differentiation and regeneration post muscle injury in Gmppb-deficient models. Additionally, adeno-associated virus (AAV)-mediated gene replacement therapy successfully ameliorated the muscular phenotypes. Collectively, our findings provide direct evidence that impaired muscle stem cell differentiation contributes to GMPPB-associated dystroglycanopathy. Wnt pathway agonists and AAV gene therapy represent potential effective intervention strategies for treating DGP disease.
2025-05-17 | GSE268450 | GEO
Project description:Recent studies have highlighted a significant association between mutations in GDP-mannose pyrophosphorylase B (GMPPB) gene with dystroglycanopathy (DGP), a rare disease characterized by neuromuscular phenotypes. To interrogate the molecular mechanisms driving the onset and progression and to identify potential therapeutic approaches for GMPPB-associated DGP, we here constructed genetically engineered mice models of Gmppb. We show that Gmppb knockout and P32L mutant mice are lethal in the homozygous form, whereas homologous R287Q mutants are viable. Heterozygous Gmppb-P32L mutant mice exhibit reduced muscle strength, decreased locomotor ability, elevated creatine kinase levels and increased centrally nucleated myofibers. Furthermore, loss of GMPPB results in defective differentiation of muscle stem cells, leading to failure to develop into mature myotubes and diminished muscle regeneration capability. Biochemical and transcriptomic analyses indicate that loss of GMPPB is associated with significant alterations in O-linked glycosylation level, intracellular Ca2+ storage and release and the Wnt/β-catenin signaling pathway. Pharmacological activation of the Wnt pathway alleviated disruption of muscle differentiation and regeneration post muscle injury in Gmppb-deficient models. Additionally, adeno-associated virus (AAV)-mediated gene replacement therapy successfully ameliorated the muscular phenotypes. Collectively, our findings provide direct evidence that impaired muscle stem cell differentiation contributes to GMPPB-associated dystroglycanopathy. Wnt pathway agonists and AAV gene therapy represent potential effective intervention strategies for treating DGP disease.
2025-05-17 | GSE268448 | GEO
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Project description:LPIN1 molecular alterations were identified as a major cause of severe recurrent rhabdomyolysis. The prognosis is poor, with a third of patients dying from cardiac arrest during an acute episode. We describe herein a familial case of a young boy and his mother both affected by the same homozygous LPIN1 mutation. The index case experienced a first extremely severe episode of rhabdomyolysis at 14 months of age (creatine kinase 630,000 UI/L) and a second, lethal episode at 3 years of age. His mother had only 1 moderate episode of rhabdomyolysis (creatine kinase 3,050 UI/L) in adulthood. Several cases of sudden death were also reported in the family. To the best of our knowledge, the mother of the index case is, to date, the first patient described harbouring biallelic mutations in LPIN1 and only presenting with a mild phenotype. This report expands the phenotypic spectrum of LPIN1-related rhabdomyolysis, illustrating high intrafamilial variability.
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Project description:BackgroundPerrault syndrome is a genetically heterogenous, very rare disease, characterized clinically by sensorineural hearing loss, ovarian dysfunction and neurological symptoms. We present the case of a 33 years old female patient with TWNK-associated Perrault syndrome. The TWNK gene is coding the mitochondrial protein Twinkle and currently there are only two reports characterizing the phenotype of TWNK-associated Perrault syndrome. None of these publications reported about special brain MRI alterations and neuropathological changes in the muscle and peripheral nerves.Case presentationOur patients with TWNK-dependent Perrault syndrome had severe bilateral hypoacusis, severe ataxia, polyneuropathy, lower limb spastic paraparesis with pyramidal signs, and gonadal dysgenesis. Psychiatric symptoms such as depression and paranoia were present as well. Brain MRI observed progressive cerebellar hyperintensive signs associated with cerebellar, medulla oblongata and cervical spinal cord atrophy. Light microscopy of the muscle biopsy detected severe neurogenic lesions. COX staining was centrally reduced in many muscle fibers. Both muscle and sural nerve electron microscopy detected slightly enlarged mitochondria with abnormal cristae surrounded by lipid vacuoles. In the sural nerve, dystrophic axons had focally uncompacted myelin lamellae present. Genetic investigation revealed multiple mtDNA deletion and compound heterozygous mutations of the TWNK gene (c.1196 A > G, c.1358 G > A).ConclusionThis study demonstrates that TWNK associated Perrault syndrome has a much broader phenotype as originally published. The coexistence of severe hypoacusis, spastic limb weakness, ataxia, polyneuropathy, gonadal dysgensia, hyperintense signals in the cerebellum and the presence of the mtDNA multiple deletion could indicate the impairment of the TWNK gene. This is the first report about pyramidal tract involvement and cerebellar MRI alteration associated with TWNK-related Perrault syndrome.
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