Morales Fernando, Pusch Michael
Instituto de Investigaciones en Salud, Universidad de Costa, San José, Costa Rica.
Istituto di Biofisica, CNR, Genova, Italy.
Front Neurol. 2020 Jan 17;10:1404. doi: 10.3389/fneur.2019.01404. eCollection 2019.
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, and ) 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 and 65 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) trans-acting 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.
强直性肌营养不良症是遗传性神经肌肉疾病，分为营养不良性肌强直和非营养不良性肌强直（NDM）。后者是由参与骨骼肌动作电位产生和控制的离子通道基因突变引起的一组显性或隐性疾病。它们功能的改变导致肌膜兴奋性过高，从而引发肌强直，这是NDM的主要体征。编码电压门控性氯离子通道和钠离子通道（分别为 和 ）的基因突变产生了广泛的表型，这些表型在发病年龄、受累肌肉、肌强直严重程度、肥大程度、肌肉无力、疾病进展等方面存在差异。已经鉴定并描述了200多个 和65个 突变，但其中只有大约一半进行了功能表征，这种方法可能对改善目前NDM中相当差的临床相关性非常有帮助。观察到的相关性较差可能是由于：（1）两组（氯离子和钠离子肌强直通道病）中存在的广泛症状和重叠表型；（2）两个基因都存在高度的基因型变异性。一方面，一些突变在大多数患者中会导致独特且可重复的表型。另一方面，一些突变在不同家族中可能具有不同的遗传模式和临床表型。相反，不同的突变可能转化为非常相似的表型。由于这些原因，肌强直通道病中的基因型-表型关系被认为很复杂。尽管肌强直通道病中临床变异性的分子基础仍然不清楚，但已经提出了几种假说来解释这种变异性，包括：（a）等位基因差异表达；（b）反式作用遗传修饰因子；（c）表观遗传、激素或环境因素；（d）低外显率的显性。临床试验的改进、对特定突变导致的不同表型的认识以及对突变如何影响离子通道结构和功能的理解，再加上基因筛查，有望改善NDM的临床相关性。
