CLCN1 Molecular Characterization in 19 South-Italian Patients With Dominant and Recessive Type of Myotonia Congenita.

Chiara Orsini,Paola D'Ambrosio,Manuela Ergoli,Esther Picillo,Alessandro De Luca,Luigia Passamano,Marianna Scutifero,Roberta Petillo,Luisa Politano

doi:10.3389/fneur.2020.00063

Chiara Orsini, Paola D'Ambrosio + Show 7 more

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https://doi.org/10.3389/fneur.2020.00063

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Abstract

Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction (myotonia). It is caused by mutations in the CLCN1 gene, encoding the voltage-gated chloride channel of skeletal muscle, ClC-1. According to the pattern of inheritance, two distinct clinical forms have been described, Thomsen disease, inherited as an autosomal dominant trait and Becker disease inherited as an autosomal recessive trait. We report genetic and clinical data concerning 19 patients−13 familial and six isolated cases—all but one originating from the Campania Region, in southern Italy. Twelve patients (63.2%) present Becker type myotonia and 7 (36.8%) Thomsen type. Sex ratio M:F in Becker type is 6:6, while in Thomsen myotonia 4:3. The age of onset of the disease ranged from 2 to 15 years in Becker patients, and from 4 to 20 years in Thomsen. Overall 18 mutations were identified, 10 located in the coding part of the gene (exons 1, 3, 4, 5, 7, 8, 13, 15, 21, 22), and four in the intron part (introns 1, 2, 10, 18). All the exon mutations but two were missense mutations. Some of them, such as c.2551 G > A, c.817G > A and c.86A > C recurred more frequently. About 70% of mutations was inherited with an autosomal recessive pattern, two (c.86A and c.817G>A) with both mechanisms. Three novel mutations were identified, never described in the literature: p.Gly276Ser, p.Phe486Ser, and p.Gln812*, associated with Becker phenotype. Furthermore, we identified three CLCN1 mutations—c.86A>C + c.2551G > A, c.313C > T + c.501C > G and 899G > A + c.2284+5C > T, two of them inherited in cis on the same allele, in three unrelated families. The concomitant occurrence of both clinical pictures—Thomsen and Becker—was observed in one family. Intra-familial phenotypic variability was observed in two families, one with Becker phenotype, and one with Thomsen disease. In the latter an incomplete penetrance was hypothesized.

Highlights

Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction
Depending on whether the mutation is present on both alleles or only on one of them, the clinical pictures of Becker’s myotonia (BM, AR), or Thomsen myotonia (TM, AD), are observed
One with Thomsen type (N11) and the other with Becker type (N9) are asymptomatic, while their relatives present the typical symptoms of the disease

Summary

Introduction

Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction (myotonia). The diseases characterized by the presence of CLCN1 Mutations in Southern Italy the “myotonia” can be subdivided into two large groups [3]: Myotonic Dystrophies (DM), characterized by the presence of progressive muscular atrophy and weakness, and multisystemic involvement and Non-dystrophic myotonias (NDM), characterized by the absence of progressive muscle atrophy and weakness, and multi-systemic involvement. The latter include the so-called Muscular Channelopathies, due to mutations in genes that code for proteins in the channels of sodium, chlorine, calcium, and potassium, some of which may be responsible for both myotonic and periodic paralysis. Patients with Becker’s myotonia present a more severe clinical picture [1]

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