Chapter 48: Neuromuscular Ionic Channelopathies

INTRODUCTION

Ion channelopathies are a group of genetic disorders affecting functions of the ionic channels. The ionic channels are complex glycoprotein structures crossing the lipid cellular membrane, allowing the passage of electronically charged ions through the membrane. Neuromuscular ionic channelopathies include nondystrophic myotonias and primary periodic paralysis.

NONDYSTROPHIC MYOTONIAS

The nondystrophic myotonias are a rare, heterogeneous group of hereditary genetic skeletal muscle ionic channelopathies including myotonia congenita, paramyotonia congenita, and sodium channel myotonia, defined by distinct clinical phenotypes ranging from severe neonatal myotonia to milder late-onset myotonia. Besides the clinical features, electromyogram (EMG) and genetic analyses are essential in the diagnosis. Causative genes include the skeletal muscle voltage-gated chloride channel gene (CLCN1) and the voltage-gated sodium channel gene (SCN4A). Management is provided by a multidisciplinary neuromuscular team. In addition to supportive treatment, medical treatments primarily target reducing persistent muscle sodium currents or enhancing the conductance of mutant chloride channels.

Clinical Findings

Symptoms and Signs

Patients present with muscle stiffness as a consequence of myotonia. The most severe type is a neonatal life-threatening presentation, with onset of myotonia symptoms at birth with respiratory deficiency. Others present with muscle stiffness or myotonia later in life, some may or may not have slow progression of disease, and some may have muscle weakness. Severe infantile presentations are associated with marked muscle stiffness and may lead to death from respiratory failure in early life. Other affected children may mostly have a relatively static course with muscle stiffness and myotonia, and some children may have slow disease progression with development of muscle weakness. Cardiac complications with primarily conductive abnormalities can be seen. Painful myotonia is commonly recognized in patients with nondystrophic myotonia, and some patients had severe and prolonged attacks.

Myotonia congenita is the most common form, with muscle stiffness and myotonia most pronounced during rapid voluntary movements following a period of rest and improvement with repeated activity, called the “warm-up” phenomenon. The causative genetic mutation is related to CLCN1. Compared to the autosomal dominant form, the recessive form tends to be more severe and more associated with transient muscle weakness, muscle hypertrophy, and depressed tendon reflexes.

Paramyotonia congenita is related to SCN4A mutations. The inheritance is autosomal dominant, and symptoms usually present in the first decade of life. Facial, tongue, and hand muscles are predominantly involved, and lower extremities are generally mildly affected. Myotonia typically lasts from seconds to minutes, but the weakness can persist up to hours and sometimes days. Episodic muscle cramps and paralysis are profoundly exacerbated by cold and exercise.