Non-dystrophic myotonia Chilean cohort with predominance of the SCN4A Gly1306Glu variant
Introduction
Non-dystrophic myotonias are muscle channelopathies caused by pathogenic variants in CLCN1 or SCN4A. The specific phenotype or subtype, treatment, and inheritance pattern of non-dystrophic myotonias depend on the involved gene and pathogenic variant of the same gene [1], [2], [3].
Patients with non-dystrophic myotonias typically experience a reduced quality of life, including disability and difficulty finding a job, although the severity tends to be lower in patients with CLCN1 variants compared to in those whose disease is caused by SCN4A variants [3]. In addition, some younger patients exhibit severe neonatal episodic laryngospasm (SNEL), which is linked to specific SCN4A variants [4]. Differential diagnosis is based on clinical and genetic evaluation. An electrophysiology test, the Repeated Short Exercise Test (RSET), allows the identification of Fournier patterns I–III, which can help to distinguish between SCN4A or CLCN1 variants and even among different variants of the same gene. Fournier patterns are defined by variations in the compound muscle action potential amplitude of the abductor digiti minimi muscle after a set of three isometric exercises in this muscle at room temperature and after cooling. Pattern I is characterized by a progressive decrease in the compound muscle action potential amplitude after each exercise that does not recover after a period of rest; pattern II by a decrease immediately after exercise that recovers after a period of rest; and pattern III by no significant decrement. Cold temperatures may aggravate or unmask patterns I–II. Fournier patterns I and III are typically associated with SCN4A, whereas Fournier pattern II is more commonly associated with variants in CLCN1 [5].
Myotonia permanens is among the most severe phenotypes of non-dystrophic myotonia, which is associated with the Gly1306Glu variant of SCN4A, accounting for 0.6% of all cases [6]. Myotonia permanens is a rare entity with only sporadic case reports and a recent report of a 10-patient cohort published to date, demonstrating features of severe disease, high mortality, and frequent SNEL in European patients [7].
To further understand this disease entity on a global scale, we characterized the clinical, electrophysiological, and genetic findings from a Chilean cohort of adult and paediatric patients with non-dystrophic myotonias and evaluated the predictive value of the RSET in these patients. We aimed to determine the mutational spectrum of our population and their associated phenotypes to provide diagnosis, treatment, and prognosis that is more specific, in clinical practice in our patients and other populations. We observed a striking predominance of the Gly1306Glu variant in SCN4A and describe the natural history and specific phenotypic findings of the largest cohort of patients carrying this variant published to date to contribute to clinical management of affected patients.
Section snippets
Patient selection and inclusion/exclusion criteria
Patients with non-dystrophic myotonia diagnosed by an experienced neuromuscular diseases child neurologist, with available electromyography (EMG) results showing myotonic discharges and RSET performed in at least one family member were recruited for this study from three paediatric neuromuscular disorders reference centres in Chile between January 2013 and June 2019, including Complejo Asistencial Dr. Sótero del Río, Hospital de Niños Roberto del Río, and Red de Salud UC-Christus. The pedigree
General clinical and genetic evaluation
We recruited 30 patients from 13 different families, including 17 females and 13 males with a median age of 20 years (IQR = 13–36 years). There was a high variability in these characteristics according to the involved gene and according to variants within each affected gene (Table 1).
Most patients (n = 28, 93%) had pathogenic variants in SCN4A, with only two patients (7%) harbouring a variant in CLCN1. We found two different pathogenic variants in SCN4A, both of which showed an autosomal
Discussion
We present the clinical and genetic characteristics of a cohort of patients with non-dystrophic myotonia in a South American (Chilean) population, with a high predominance of SCN4A-related cases, mostly comprising cases of myotonia permanens linked to the SCN4A Gly1306Glu variant. This is the largest myotonia permanens cohort linked to Gly1306Glu reported to date, and its high frequency suggest a founder effect in this population.
In our cohort, disease onset in patients with the SCN4A
Acknowledgements
The authors wish to thank the patients who participated in this research and the clinicians who referred them.
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