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Neurogenetics
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Sonia Gandhi, Sarah Tabrizi, Nicholas Wood
Myotonia is a disorder in which muscle stiffness occurs as a result of failure of muscle relaxation. Myotonia congenita may be dominant (Thomsen’s disease) or recessive (Becker’s disease). Myotonia may be detected clinically or on electromyography (EMG). Both types are caused by mutations in the muscle chloride channel gene (CLCN1). Paramyotonia congenita is a myotonic autosomal dominant disorder that occurs during exercise and, in contrast to myotonia congenita, worsens with activity. This disorder is caused by mutations in the muscle sodium channel SCN4A, which also causes hyperkalaemic periodic paralysis.
Sodium Channel Myotonia and a Novel Gly701Asp Mutation in the SCN4A Gene: From an Ophthalmological Symptom to a Familial Disease
Published in Neuro-Ophthalmology, 2021
Filipa Sampaio, Sérgia Soares, Sara Pereira, José Alberto Lemos, Ágata Mota
The non-dystrophic myotonias are caused by dysfunction of key skeletal muscle ion channels. The worldwide prevalence of non-dystrophic myotonia has been estimated to be 1 in 100 000.1 The major clinical manifestation of the non-dystrophic myotonias is muscle stiffness and additional common symptoms include pain, weakness and fatigue.2,3 Myotonia can be demonstrated on examination as delayed muscle relaxation following muscle contraction. Non-dystrophic myotonias are classified as myotonia congenita, caused by mutations in the skeletal muscle chloride channel gene (CLCN1) and inherited in a dominant or in a recessive fashion; paramyotonia congenita and the sodium channel myotonias, characterised by allelic, autosomal dominant disorders caused by mutations in the skeletal muscle sodium channel gene (SCN4A); and hyperkalaemic periodic paralysis, also caused by mutations in SCN4A gene in which episodic paralysis is usually the dominant feature (Table 1).4
Improving genetic diagnostics of skeletal muscle channelopathies
Published in Expert Review of Molecular Diagnostics, 2020
Vinojini Vivekanandam, Roope Männikkö, Emma Matthews, Michael G. Hanna
Myotonia Congenita (MC) is the most common skeletal muscle channelopathy. It is caused by mutations in the CLCN1 gene, which encodes the voltage-gated chloride channel ClC-1. The functional channel protein is comprised of two gene products [5]. The symptoms of myotonia generally present in the first or second decade of life [6]. Symptoms of myotonia are prominent at the initiation of movement and often improve with repeated activity – a phenomenon known as ‘warm up.’ Patients with recessively inherited myotonia congenita tend to have more severe symptoms compared to patients with dominant mutations [5] and additionally, some patients with recessive MC have transient weakness at the initiation of movement. Hundreds of pathogenic mutations have been identified in CLCN1, the majority of CLCN1 mutations are missense, with Gly230Glu the most common [2,7].
Identification of two novel compound heterozygous CLCN1 mutations associated with autosomal recessive myotonia congenita
Published in Neurological Research, 2019
Zhang Wei, Meng Huaxing, Wang Xiaomei, Wang Juan, Chang Xueli, Zhang Jing, Guo Junhong
CLC-1, a 988 amino acid membrane protein, is the principal skeletal muscle voltage-gated chloride channel, encoded by the 23 exon CLCN1 gene on chromosome 7q35[6]. This channel plays an important role in stabilizing muscle resting potentials and promoting repolarization after action potentials[5]. Dysfunction of the channel leads to muscle membrane hyperexcitability and myotonia. By the end of 2013, there had been more than 160 pathogenic mutations in CLCN1 associated with MC [5,7]. Most mutations are recessive and in patients with recessive MC inheritance of a different mutant allele from each parent (compound heterozygosity) is common[5]. The CLC-1 channel is a homodimer[8]. In recessive MC both subunits carry mutations, resulting in total loss of CLC-1 currents[5]. While, in dominant MC the mutant subunit interferes with the normal function of the wildtype subunit, leading to dominant inheritance[5].