Clinical, electrophysiologic, and genetic study of non-dystrophic myotonia in French-Canadians

https://doi.org/10.1016/j.nmd.2008.01.007Get rights and content

Abstract

Thirty-three French-Canadian families with non-dystrophic myotonia were identified. Fifty subjects were recruited and submitted to a complete clinical, electrophysiologic and genetic evaluation. Thirteen mutations were identified in CLCN1 and five mutations were identified in SCN4A. Onset in the lower extremities, presence of tongue myotonia and transient weakness suggested recessive CLCN1 mutations. Lid myotonia, absence of hypertrophy and exacerbation with cold temperature suggested SCN4A mutations. Pain was not a feature of dominant CLCN1 mutations while it could be seen in the others, more frequently in SCN4A mutations. Warm up phenomenon, hand grip myotonia, percussion myotonia, lid lag and hormonal effects were not distinguishing features. Repetitive nerve stimulation and short exercise test showed either a large (>50%) or mild-moderate (10–50%) decrement with recessive CLCN1 mutations while they showed only mild or no decrement with dominant CLCN1 and SCN4A mutations. The French-Canadian population shows wide phenotypic and genotypic heterogeneity in non-dystrophic myotonias.

Introduction

Myotonia is defined as an impairment of muscle relaxation often caused by mutations in voltage gated chloride (CLCN1) or sodium (SCN4A) channels of striated muscles. Julius Thomsen, a Danish physician, first described this entity. He assessed individuals with significant muscle stiffness and hypertrophy without overt weakness within families showing an autosomal dominant inheritance. Later, Becker described a more severe phenotype with muscle hypertrophy and weakness that showed autosomal recessive inheritance. Further on, Eulenberg described an autosomal dominant phenotype showing “paradoxical myotonia” that he called paramyotonia congenita. Following the development of genetic testing, Thomsen’s and Becker’s myotonia congenita were generally found to be caused by chloride channel mutations and paramyotonia by sodium channel mutations [1]. Additionally, some autosomal dominant families with “atypical” clinical manifestations were also found to be caused by sodium channel mutations; these phenotypes were referred to as potassium-aggravated myotonia, myotonia permanens, myotonia fluctuans and acetazolamide-responsive myotonia congenita [2], [3].

Other than clinical history, mode of inheritance, and neurological examination, electrophysiological studies are an important part of the initial evaluation of patients with muscle stiffness. They are essential in confirming the presence of myotonia by showing myotonic bursts (waxing and waning muscle potentials in frequency and amplitude) with needle electromyography (EMG). Other more specific tests may also be used to help discriminate between the different myotonia phenotypes, such as repetitive nerve stimulation (RNS), short exercise test (SET), long latency test or muscle cooling,. These studies, however, show variable sensitivity and specificity depending on mutation and channel type [4], [5], [6], [7], [8].

In the following paper, we are reporting a number of new mutations in sodium and chloride channels causing non-dystrophic myotonia in the French-Canadian population, which is known to be relatively homogeneous genetically. We have sought additionally to address which clinical and electrophysiologic characteristics were present in this large cohort, as well as to define which of these characteristics could enable targeted genetic testing.

Section snippets

Clinical and electrophysiologic evaluation

The study was conducted at the CHAUQ (Enfant-Jésus) and all patients were evaluated after they had signed a consent form approved by the Local Ethics Committee. A standardized clinical questionnaire (derived from the protocol developed by the French Resocanaux group) was used to collect relevant information on targeted symptoms and various features of the neuromuscular evaluation Thereafter, subjects were assessed by a standardized electrophysiologic protocol [9] that lasted on average 30 min.

Results

Altogether, 50 patients with non-dystrophic myotonia were evaluated clinically: 36 with CLCN1 mutations and 14 with SCN4A mutations (Tables Table 1, Table 2a, Table 2b).

Discussion

In the era of genetic diagnosis, non-dystrophic myotonias can be classified in three broad categories: dominant CLCN1, recessive CLCN1, and SCN4A. In the present study, we have assessed one of the biggest cohorts of non-dystrophic myotonia in a population with a relatively homogeneous genetic background and shown considerable phenotypic and genotypic heterogeneity. Despite this heterogeneity, we have found clinical features that are more likely to be associated with particular categories: onset

Acknowledgements

Nicolas Dupré is supported by a salary grant from the Canadian Institute of Health Research; Nicolas Chrestian is supported by a bursary from the Faculty of Medicine of Laval University; the project was supported financially by the Réseau de Médecine Génétique du Québec (section neurogénétique). We are thankful to the participants of this study that gave their time generously. A research assistant, Pierre Provencher, was involved in data collection.

References (19)

There are more references available in the full text version of this article.

Cited by (52)

  • Identification of recurrent pathogenic alleles using exome sequencing data: Proof-of-concept study of Russian subjects

    2022, European Journal of Medical Genetics
    Citation Excerpt :

    Five of the studied variants demonstrated increased prevalence as compared to European populations (Table 2). NM_000083.3 CLCN1 c.2680C>T (p.Arg894Ter) substitution (MAF = 0.011) is associated with autosomal recessive myotonia congenita (Dupré et al., 2009; Meyer-Kleine et al., 1995). In addition to Russia, this allele is also widespread in Finland and Germany (Suominen et al., 2008).

  • Mutation spectrum and health status in skeletal muscle channelopathies in Japan

    2020, Neuromuscular Disorders
    Citation Excerpt :

    When severity in the same family is highly variable, the probands may have two mutations. Although MC is more common than PMC/SCM, as confirmed by a study on the prevalence of skeletal muscle channelopathies in the UK, the Netherlands, Italy, and Canada [29–32], the frequency of NDM with SCN4A mutations was higher than that with CLCN1 mutations in Japan (Table 6). As mentioned above, we found a higher percentage of dominant MC pedigrees in Japan.

  • NMR investigation of the isolated second voltage-sensing domain of human Nav1.4 channel

    2017, Biochimica et Biophysica Acta - Biomembranes
    Citation Excerpt :

    This domain represents important pharmacological target. It hosts the mutations linked to different onsets of periodic paralysis (R669H, R672H/G/S/C, R675G/Q/W) [27,28], paramyotonia congenita (I693T) [2] and myotonia (F671S) [29], and accommodates binding sites for spider ‘voltage sensor’ and β-scorpion toxins which modulate voltage-gating [15,30]. Three variants of isolated VSD-II with different N- and C-termini were produced by cell-free (CF) expression.

  • Structural basis of pH-dependent activation in a CLC transporter

    2024, Nature Structural and Molecular Biology
View all citing articles on Scopus
View full text