An Up-to-Date Overview of the Complexity of Genotype-Phenotype Relationships in Myotonic Channelopathies

Abstract

Myotonic disorders are inherited neuromuscular diseases divided into dystrophic myotonias and non-dystrophic myotonias (NDM). The latter is a group of dominant or recessive diseases caused by mutations in genes encoding ion channels that participate in the generation and control of the skeletal muscle action potential. Their altered function causes hyperexcitability of the muscle membrane, thereby triggering myotonia, the main sign in NDM. Mutations in the genes encoding voltage-gated Cl − and Na + channels (respectively, CLCN1 and SCN4A) produce a wide spectrum of phenotypes, which differ in age of onset, affected muscles, severity of myotonia, degree of hypertrophy, and muscle weakness, disease progression, among others. More than 200 CLCN1 and 65 SCN4A mutations have been identified and described, but just about half of them have been functionally characterized, an approach that is likely extremely helpful to contribute to improving the so-far rather poor clinical correlations present in NDM. The observed poor correlations may be due to: (1) the wide spectrum of symptoms and overlapping phenotypes present in both groups (Cl − and Na + myotonic channelopathies) and (2) both genes present high genotypic variability. On the one hand, several mutations cause a unique and reproducible phenotype in most patients. On the other hand, some mutations can have different inheritance pattern and clinical phenotypes in different families. Conversely, different mutations can be translated into very similar phenotypes. For these reasons, the genotype-phenotype relationships in myotonic channelopathies are considered complex. Although the molecular bases for the clinical variability present in myotonic channelopathies remain obscure, several hypotheses have been put forward to explain the variability, which include: (a) differential allelic expression; (b) transacting genetic modifiers; (c) epigenetic, hormonal, or environmental factors; and (d) dominance with low penetrance. Improvements in clinical tests, the recognition of the different phenotypes that result from particular mutations and the understanding of how a mutation affects the structure and function of the ion channel, together with genetic screening, is expected to improve clinical correlation in NDMs.

Myotonia congenita and periodic hypokalemia paralysis in a consanguineous marriage pedigree: Coexistence of a novel CLCN1 mutation and an SCN4A mutation

“…Other researchers have also reported a few patients with the same genes mutated (Table 3) [15][16][17][18]. These patients showed an atypical phenotype, suggesting that concomitant mutations may act synergistically to influence the phenotype [19]. However, the symptoms of the two diseases so far seemed independent of each other in VI: 3.…”

Functional and Structural Characterization of ClC-1 and Nav1.4 Channels Resulting from CLCN1 and SCN4A Mutations Identified Alone and Coexisting in Myotonic Patients

“…It has been widely recognized that NDMs are not easy to distinguish, clinically or genetically, mainly due to the phenotypic overlap among these diseases and the great number of mutations with different effects, inheritance patterns and associated phenotypes [ 3 ]. In this study, we identified four genetic mutations in the CLCN1 and SCN4A genes in three Costa Rican families and described their clinical and electrophysiological findings.…”

“…In this study, proband NDM16, who is compound heterozygous carrying these two mutations, was, in fact, diagnosed with RMC, indicating that neither allele can give rise to a functional ClC-1 channel. Similarly, proband NDM15, who resulted homozygous for the W322* mutation, should have been diagnosed with Becker’s type myotonia, but instead, he was diagnosed with severe DMC [ 17 ], indicating that the W322* mutation might be another example of CLCN1 mutations associated with both phenotypes and inheritance patterns [ 3 ].…”

“…Non-dystrophic myotonias (NDM) are a group of hereditary muscle diseases characterized by myotonia, muscle stiffness and a non-dystrophic phenotype [ 1 ]. Myotonia, detected by electromyography (EMG), is primarily due to enhanced muscle excitability, leading to sustained bursts of discharges that correlate with the magnitude and duration of involuntary after-contractions [ 2 , 3 ]. Myotonia congenita (MC), either dominantly (Thomsen’s disease, dominant myotonia congenita (DMC)) or recessively (Becker generalized myotonia, recessive myotonia congenita (RMC)) inherited, paramyotonia congenita (PC, dominantly inherited) and the sodium channel myotonias (SCM, dominantly inherited) are NDM [ 4 , 5 ].…”

The roles of mitochondrial tRNA mutations in non-dystrophic myotonias

“…Myotonia was a genetically and heterogeneous disease due to the electrical hyper-excitability of muscle fibers (Morales and Pusch 2019). Non-dystrophic myotonia (NDM), a common type of myotonia, had been estimated to be approximately 1 in 100,000 according to a recent report (Snyder et al 2015).…”