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