New Challenges Resulting From the Loss of Function of Nav1.4 in Neuromuscular Diseases

The voltage-gated sodium channel Nav1.4 is a major actor in the excitability of skeletal myofibers, driving the muscle force in response to nerve stimulation. Supporting further this key role, mutations in SCN4A, the gene encoding the pore-forming α subunit of Nav1.4, are responsible for a clinical spectrum of human diseases ranging from muscle stiffness (sodium channel myotonia, SCM) to muscle weakness. For years, only dominantly-inherited diseases resulting from Nav1.4 gain of function (GoF) were known, i.e., non-dystrophic myotonia (delayed muscle relaxation due to myofiber hyperexcitability), paramyotonia congenita and hyperkalemic or hypokalemic periodic paralyses (episodic flaccid muscle weakness due to transient myofiber hypoexcitability). These last 5 years, SCN4A mutations inducing Nav1.4 loss of function (LoF) were identified as the cause of dominantly and recessively-inherited disorders with muscle weakness: periodic paralyses with hypokalemic attacks, congenital myasthenic syndromes and congenital myopathies. We propose to name this clinical spectrum sodium channel weakness (SCW) as the mirror of SCM. Nav1.4 LoF as a cause of permanent muscle weakness was quite unexpected as the Na+ current density in the sarcolemma is large, securing the ability to generate and propagate muscle action potentials. The properties of SCN4A LoF mutations are well documented at the channel level in cellular electrophysiological studies However, much less is known about the functional consequences of Nav1.4 LoF in skeletal myofibers with no available pertinent cell or animal models. Regarding the therapeutic issues for Nav1.4 channelopathies, former efforts were aimed at developing subtype-selective Nav channel antagonists to block myofiber hyperexcitability. Non-selective, Nav channel blockers are clinically efficient in SCM and paramyotonia congenita, whereas patient education and carbonic anhydrase inhibitors are helpful to prevent attacks in periodic paralyses. Developing therapeutic tools able to counteract Nav1.4 LoF in skeletal muscles is then a new challenge in the field of Nav channelopathies. Here, we review the current knowledge regarding Nav1.4 LoF and discuss the possible therapeutic strategies to be developed in order to improve muscle force in SCW.

Sodium Channelopathies of Skeletal Muscle and Brain

Voltage-gated sodium channels initiate action potentials in nerve, skeletal muscle, and other electrically excitable cells. Mutations in them cause a wide range of diseases. These channelopathy mutations affect every aspect of sodium channel function, including voltage sensing, voltage-dependent activation, ion conductance, fast and slow inactivation, and both biosynthesis and assembly. Mutations that cause different forms of periodic paralysis in skeletal muscle were discovered first and have provided a template for understanding structure, function, and pathophysiology at the molecular level. More recent work has revealed multiple sodium channelopathies in the brain. Here we review the well-characterized genetics and pathophysiology of the periodic paralyses of skeletal muscle, and then use this information as a foundation for advancing our understanding of mutations in the structurally homologous a subunits of brain sodium channels that cause epilepsy, migraine, autism, and related co-morbidities. We include studies based on molecular and structural biology, cell biology and physiology, pharmacology, and mouse genetics. Our review reveals unexpected connections among these different types of sodium channelopathies.

Skeletal muscle channelopathies: a guide to diagnosis and management

Skeletal muscle channelopathies are a group of rare episodic genetic disorders comprising the periodic paralyses and the non-dystrophic myotonias. They may cause significant morbidity, limit vocational opportunities, be socially embarrassing, and sometimes are associated with sudden cardiac death. The diagnosis is often hampered by symptoms that patients may find difficult to describe, a normal examination in the absence of symptoms, and the need to interpret numerous tests that may be normal or abnormal. However, the symptoms respond very well to holistic management and pharmacological treatment, with great benefit to quality of life. Here, we review when to suspect a muscle channelopathy, how to investigate a possible case and the options for therapy once a diagnosis is made.