Background: Channelopathies are rare muscle disorders caused by mutations in genes that encode ion channels. The most common phenotypes are congenital myotonia, paramyotonia and periodic dyskalemic paralysis. The definitive diagnosis is based on genetic tests and patients can take years to have a defined diagnosis, often undergoing unnecessary and high-cost interventions. The relative low availability of clinical studies on this topic in Brazil brings the need for research in order to establish standards and make possible future efforts to find pharmacological treatments that help in symptomatic control. Objective: To describe clinical, genetic and electrophysiological characteristics in patients with muscle channelopathies diagnosed by next sequencing generation tests in a specialized outpatient clinic of a high-complexity hospital based on an observational, retrospective study and to describe the diagnostic journey of these patients. The study was approved by the local Ethics Committee. Methods: Data were collected from the medical records of 29 patients who presented with signs and symptoms of channelopathy. We excluded 5 patients with genetic mutation in the RYR1 gene without compatible clinical findings and also 9 patients who had a suggestive phenotype without genetic proof. We compared clinical features between patients according to genetic variations using non-parametric tests, given the sample size. The Mann-Whitney test for continuous variables and Fisher’s exact test for categorical ones. Results: Fifteen patients met inclusion criteria and had diagnostic confirmation through an NGS panel for pathogenic variants related to channelopathies. We identified 22 variants in 3 different genes: SCN4A (6 cases, 40%), CLCN1 (8 cases, 53.3%) and KCNJ2 (1 case, 6.66%). Of these patients, ten (66.6%) presented an AD inheritance pattern. Missense mutations in all positive panels accounted for 72.7% of mutations. It was noted greater difficulty in establishing a diagnosis in sodium channelopathies, with the highest percentage of misdiagnosis in these cases (83.3% versus 37.5%). We also observed the long journey until diagnostic definition (median 34.5 years). The presence of warm up phenomenon was present in all patients with chloride CLCN1 and paramyotonia was present in most patients with SCN4A, indicating the role of the active search for these phenomena in the differentiation between conditions (p=0.015). Weakness on physical examination, hypertrophy, presence of cramps, periodic paralysis, seizures, increased CK and diet have not shown statistical significance between the groups. We have found a new variant for the CLCN1 mutation (c.2284+1G> A) and for the KCNJ2 (c.788t> G - p.Leu263Arg) not previously described in literature. Conclusion: NGS panel has proven to be a relevant diagnostic tool in the assessment of channelopathies and the knowledge of clinical variables linked to these diagnoses enables better clinical practice.
Lima et al. (Mon,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: