SCN4A mutation as modifying factor of Myotonic Dystrophy Type 2 phenotype

Bugiardini, Enrico; Rivolta, Ilaria; Binda, Anna; Caminero, A. Soriano; Cirillo, Federica; Cinti, Alessandro; Giovannoni, Roberto; Botta, Annalisa; Cardani, Rosanna; Wicklund, Matthew; Meola, G.

doi:10.1016/j.nmd.2015.01.006

Cited by 40 publications

(31 citation statements)

References 21 publications

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“…Co-existence of CLCN1 or SNC4A mutations with DM2 mutations has been reported in certain families. Patients with such dual mutations can have early-onset and more severe clinical and electrical myotonia [17][18][19]. Thus, DM2 patients with atypical presentation or severe myotonia should be screened for CLCN1 or SCN4A mutations.…”

Section: Non-dystrophic Myotoniamentioning

confidence: 99%

Skeletal Muscle Channelopathies

Phillips

Trivedi

2018

Neurotherapeutics

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Skeletal muscle channelopathies are rare heterogeneous diseases with marked genotypic and phenotypic variability. These disorders cause lifetime disability and impact quality of life. Despite advances in understanding of the molecular pathology of these disorders, the diverse phenotypic manifestations remain a challenge in diagnosis, therapeutic, genetic counseling, and research planning. Electrodiagnostic testing is useful in directing the diagnosis, but has several limitations: patient discomfort, time consuming, and significant overlap of findings in muscle channelopathies. Although genetic testing is the gold standard in making a definitive diagnosis, a mutation might not be identified in many patients with a well-supported clinical diagnosis of periodic paralysis. In the recent past, there have been landmark clinical trials in non-dystrophic myotonia and periodic paralysis which are encouraging as they demonstrate the ability of robust clinical research consortia to conduct well-controlled trials of rare diseases.

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Section: Non-dystrophic Myotoniamentioning

confidence: 99%

Skeletal Muscle Channelopathies

Phillips

Trivedi

2018

Neurotherapeutics

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“…Nevertheless, recently it has been observed that CLCN1 is not the only gene that alters the myotonic phenotype in DM2 patients. Bugiardini et al [54] have described a DM2 patient with severe and early onset myotonia without mutation in CLCN1 gene. However the screening of SCN4A gene revealed a novel mutation c.215C>T (p.Pro72Leu) localized in the cytoplasmic N-terminus.…”

Section: Myotonic Dystrophy Typementioning

confidence: 99%

“…However the screening of SCN4A gene revealed a novel mutation c.215C>T (p.Pro72Leu) localized in the cytoplasmic N-terminus. This novel missense mutation P72L is remarkable because it represents the first mutation described in the cytoplasmic N terminus of Nav1.4 [54]. SCN4A codes for Nav1.4 a voltage gate sodium channel expressed in skeletal muscle and is another gene implicated in myotonic disorders (Myotonia, Potassium-aggravated OMIM 608390) [55].…”

Section: Myotonic Dystrophy Typementioning

confidence: 99%

“…SCN4A codes for Nav1.4 a voltage gate sodium channel expressed in skeletal muscle and is another gene implicated in myotonic disorders (Myotonia, Potassium-aggravated OMIM 608390) [55]. The study of the biophysical alteration of P72L by whole-cell voltage clamping in a heterologous expression system showed the Nav1.4 mutant gain of function effect suggesting that the mutation described may act as a modulating factor increasing the severity of myotonia [54]. Investigation of other DM2 patients presenting atypical phenotype with no mutation on CLCN1 gene, leaded Meola and collaborators to identify a DM2 patient who presented an early severe myotonia since he was 12 years old and mexiletine treatment resulted ineffective in reducing myotonia.…”

Section: Myotonic Dystrophy Typementioning

confidence: 99%

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Myotonic Dystrophy Type 2: An Update on Clinical Aspects, Genetic and Pathomolecular Mechanism

Meola

Cardani

2015

JND

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Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert’s disease) is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) is caused by a (CCTG)n expansion in CNBP. Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders. The pathogenesis of DM is explained by a common RNA gain-of-function mechanism in which the CUG and CCUG repeats alter cellular function, including alternative splicing of various genes. However additional pathogenic mechanism like changes in gene expression, modifier genes, protein translation and micro-RNA metabolism may also contribute to disease pathology and to clarify the phenotypic differences between these two types of myotonic dystrophies.This review is an update on the latest findings specific to DM2, including explanations for the differences in clinical manifestations and pathophysiology between the two forms of myotonic dystrophies.

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“…For example, Dr. Meola described 2 patients with DM2 that had additional heterozygous mutations in CLCN1, which caused an unusually young juvenile-onset myotonia [45]. In an adult patient with DM2, an additional mutation in SCN4A increased the severity of myotonia [46]. Dr. Mani Mahadevan (University of Virginia School of Medicine, USA) gave a Short Talk entitled “A new inducible/reversible mouse model of RNA toxicity and RAN translation in DM1”.…”

Section: Session 5: Recent Advances In Myotonic Disordersmentioning

confidence: 99%