Genetic neurological channelopathies: molecular genetics and clinical phenotypes

Evidence accumulated over recent years has shown that genetic neurological channelopathies can cause many different neurological diseases. Presentations relating to the brain, spinal cord, peripheral nerve or muscle mean that channelopathies can impact on almost any area of neurological practice. Typically, neurological channelopathies are inherited in an autosomal dominant fashion and cause paroxysmal disturbances of neurological function, although the impairment of function can become fixed with time. These disorders are individually rare, but an accurate diagnosis is important as it has genetic counselling and often treatment implications. Furthermore, the study of less common ion channel mutation-related diseases has increased our understanding of pathomechanisms that is relevant to common neurological diseases such as migraine and epilepsy. Here, we review the molecular genetic and clinical features of inherited neurological channelopathies

Applying genomic and transcriptomic advances to mitochondrial medicine

Next-generation sequencing (NGS) has increased our understanding of the molecular basis of many primary mitochondrial diseases (PMDs). Despite this progress, many patients with suspected PMD remain without a genetic diagnosis, which restricts their access to in-depth genetic counselling, reproductive options and clinical trials, in addition to hampering efforts to understand the underlying disease mechanisms. Although they represent a considerable improvement over their predecessors, current methods for sequencing the mitochondrial and nuclear genomes have important limitations, and molecular diagnostic techniques are often manual and time consuming. However, recent advances in genomics and transcriptomics offer realistic solutions to these challenges. In this Review, we discuss the current genetic testing approach for PMDs and the opportunities that exist for increased use of whole-genome NGS of nuclear and mitochondrial DNA (mtDNA) in the clinical environment. We consider the possible role for long-read approaches in sequencing of mtDNA and in the identification of novel nuclear genomic causes of PMDs. We examine the expanding applications of RNA sequencing, including the detection of cryptic variants that affect splicing and gene expression and the interpretation of rare and novel mitochondrial transfer RNA variants

Mitochondrial DNA variants in genomic data: diagnostic uplifts and predictive implications

A broad spectrum of rare disease presentations can now be investigated by analysing mitochondrial DNA (mtDNA) variants from whole-genome sequencing (WGS) data. However, mtDNA mutations may cause unanticipated, extended phenotypes and have reproductive implications. We recommend that these be considered by patients and clinicians before embarking on WGS

Mexiletine (NaMuscla) for the treatment of myotonia in non-dystrophic myotonic disorders

Introduction: NaMuscla, (mexiletine), is the first licensed treatment for the Non-Dystrophic Myotonias (NDM). NDM are categorized by genetic ion channel dysfunction and cause significant morbidity. To date, off-license mexiletine, although less costly, has sometimes been subject to breaches in supply causing significant regional and national variation in availability. Areas covered: The evidence supporting mexiletine use in NDM, its mechanism of action, chemistry, and pharmacodynamics is reviewed. The evidence for other, unlicensed medications, used to treat myotonia as well as new antimyotonic compounds in development is also reviewed. Expert opinion: Mexiletine is an effective and safe treatment for NDM. However, while mexiletine is very effective in reducing muscle stiffness, it is less effective at treating the pain associated with NDM and some SCN4A genotypes may not respond to mexiletine treatment. In addition, gastrointestinal discomfort is frequent and may prevent adequate dose titration. Since the designation of mexiletine as an orphan drug for NDM, level 1 evidence for the antimyotonic effect of lamotrigine has emerged. However, no superiority trials have been completed. A head-to-head trial to compare the efficacy of mexiletine and lamotrigine in reducing both muscle stiffness and pain and to determine variation in genotype response would facilitate greater precision medicine in NDM

Designing clinical trials for rare diseases: unique challenges and opportunities

Orphan drug development is a rapidly expanding field. Nevertheless, clinical trials for rare diseases can present inherent challenges. Optimal study design and partnerships between academia and industry are therefore required for the successful development, delivery and clinical approval of effective therapies in this group of disorders

Muscle and brain sodium channelopathies: genetic causes, clinical phenotypes, and management approaches

Voltage-gated sodium channels are essential for excitability of skeletal muscle fibres and neurons. An increasing number of disabling or fatal paediatric neurological disorders linked to mutations of voltage-gated sodium channel genes are recognised. Muscle phenotypes include episodic paralysis, myotonia, neonatal hypotonia, respiratory compromise, laryngospasm or stridor, congenital myasthenia, and myopathy. Evidence suggests a possible link between sodium channel dysfunction and sudden infant death. Increasingly recognised phenotypes of brain sodium channelopathies include several epilepsy disorders and complex encephalopathies. Together, these early-onset muscle and brain phenotypes have a substantial morbidity and a considerable mortality. Important advances in understanding the pathophysiological mechanisms underlying these channelopathies have helped to identify effective targeted therapies. The availability of effective treatments underlines the importance of increasing clinical awareness and the need to achieve a precise genetic diagnosis. In this Review, we describe the expanded range of phenotypes of muscle and brain sodium channelopathies and the underlying knowledge regarding mechanisms of sodium channel dysfunction. We also outline a diagnostic approach and review the available treatment options

Improving genetic diagnostics of skeletal muscle channelopathies

Introduction: Skeletal muscle channelopathies are rare inherited conditions that cause significant morbidity and impact on quality of life. Some subsets have a mortality risk. Improved genetic methodology and understanding of phenotypes has improved diagnostic accuracy and yield. Areas covered: We discuss diagnostic advances since the advent of next generation sequencing and the role of whole exome and genome sequencing. Advances in genotype-phenotype-functional correlations have improved understanding of inheritance and phenotypes. We outline new phenotypes, particularly in the paediatric setting and consider co-existing mutations that may act as genetic modifiers. We also discuss four newly identified genes associated with skeletal muscle channelopathies. Expert Opinion/Commentary: Next generation sequencing using gene panels has improved diagnostic rates, identified new mutations and discovered patients with co-existing pathogenic mutations (“double trouble”). This field has previously focussed on single genes, but we are now beginning to understand interactions between co-existing mutations, genetic modifiers and their role in pathomechanisms. New genetic observations in paediatric presentations of channelopathies broadens our understanding of the conditions. Genetic and mechanistic advances have increased potential to develop treatments