Myotonia congenita in a large consanguineous Arab family: Insight into the clinical spectrum of carriers and double heterozygotes of a novel mutation in the chloride channel CLCN1 gene

The aims of this study were to (1) characterize the clinical phenotype, (2) define the causative mutation, and (3) correlate the clinical phenotype with genotype in a large consanguineous Arab family with myotonia congenita. Twenty‐four family members from three generations were interviewed and examined. Genomic DNA was extracted from peripheral blood samples for sequencing the exons of the CLCN1 gene. Twelve individuals with myotonia congenita transmitted the condition in an autosomal dominant manner with incomplete penetrance. A novel missense mutation [568GG>TC (G190S)] was found in a dose‐dependent clinical phenotype. Although heterozygous individuals were asymptomatic or mildly affected, the homozygous individuals were severely affected. The mutation is a glycine‐to‐serine residue substitution in a well‐conserved motif in helix D of the CLC‐1 chloride channel in the skeletal muscle plasmalemma. A novel mutation, 568GG>TC (G190S) in the CLCN1 gene, is responsible for autosomal dominant myotonia congenita with a variable phenotypic spectrum. Muscle Nerve, 2009     

Novel <Emphasis Type="Italic">CLCN1</Emphasis> mutations in Taiwanese patients with myotonia congenita

Abstract. We have performed genetic screening on the skeletal muscle chloride channel gene (CLCN1) in Taiwanese population. A total of four patients with myotonia congenita (MC) together with 106 normal individuals were examined. All 23 exons of the CLCN1 gene were analysed by direct sequencing of PCR products to detect the nucleotide changes. Five mutations and three polymorphisms were identified in this study. Among these, three missense mutations (S471F, P575S, D644G) and one polymorphism (T736I) are novel and could be unique to the Taiwanese. In addition, a previously documented recessive G482R mutation was identified in a heterozygous patient and his nonsymptomatic father, indicating that this mutation might indeed function recessively or dominantly with incomplete penetrance. In conclusion, this is the first report of MC in Taiwan with proven CLCN1 gene mutations and showing high molecular heterogeneity in Taiwanese MC patients.     

Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia

Nondystrophic myotonias are characterized by muscle stiffness triggered by voluntary movement. They are caused by mutations in either the CLCN1 gene in myotonia congenita or in the SCN4A gene in paramyotonia congenita and sodium channel myotonias. Clinical and electrophysiological phenotypes of these disorders have been well described. No concomitant mutations in both genes have been reported yet. We report five patients from three families showing myotonia with both chloride and sodium channel mutations. Their clinical and electrophysiological phenotypes did not fit with the phenotype known to be associated with the mutation initially found in SCN4A gene, which led us to screen and find an additional mutation in CLCN1 gene. Our electrophysiological and clinical observations suggest that heterozygous CLCN1 mutations can modify the clinical and electrophysiological expression of SCN4A mutation.     

Moroccan consanguineous family with Becker myotonia and review

Myotonia congenita is a genetic muscle disorder characterized by clinical and electrical myotonia, muscle hypertrophy, and stiffness. It is inherited as either autosomal-dominant or –recessive, known as Thomsen and Becker diseases, respectively. These diseases are distinguished by the severity of their symptoms and their patterns of inheritance. Becker disease usually appears later in childhood than Thomsen disease and causes more severe muscle stiffness and pain. Mutations in the muscular voltage-dependent chloride channel gene (CLCN1), located at 7q35, have been found in both types. We report here the case of a Moroccan consanguineous family with a myotonic autosomal-recessive condition in two children. The molecular studies showed that the patients reported here are homozygous for mutation p.Gly482Arg in the CLCN1 gene. The parents were heterozygote carriers for mutation p.Gly482Arg. This diagnosis allowed us to provide an appropriate management to the patients and to make a genetic counselling to their family.     

Asymptomatic myotonia congenita unmasked by severe hypothyroidism

Myotonia congenita is an inherited muscle disorder sustained by mutations in the skeletal muscle chloride channel gene CLCN1. Symptoms vary from mild to severe and generalized myotonia and worsen with cold, stressful events and hormonal fluctuations. Here we report the case of a young woman who sought medical attention because of subacute onset of diffuse and severe limb myotonia. CLCN1 gene sequencing showed a heterozygous transversion (T550M), two polymorphisms and one silent mutation. Thyroid function screening revealed severe hypothyroidism. She was placed on l-thyroxine replacement therapy which dramatically improved myotonia. We conclude that hypothyroidism unmasked a genetically determined, clinically asymptomatic chloride channelopathy. Diagnostic work-up in patients with clinically isolated myotonia should not be limited to genetic screening of non-dystrophic or dystrophic myotonias. Considering the high prevalence of hypothyroidism in females, systematic thyroid function screening by looking for additional hypothyroid symptoms and serum TSH levels measurement is mandatory in these patients.     

Decrement of compound muscle action potential is related to mutation type in myotonia congenita

Decrement of the compound muscle action potential (CMAP) during 10-HZ repetitive nerve stimulation is thought to be an unusual finding in dominant myotonia congenita, and has not previously been reported in patients with the genetically verified disorder. It was the purpose of the present study to elucidate the relation between decrement and CLCN1 mutation type in myotonia congenita. Decrement and genotypes were studied in eight Danish families with myotonia congenita. Six patients with the known dominant mutation P480L had decrements of 30-84%. Patients heterozygous for the R894X mutation had decrements of 20-47%. Three novel CLCN1 mutations (two dominant and one recessive) were found segregating with the Thomsen/Becker phenotypes. In families with the novel dominant mutations M128V and E193K, decrement was absent in all family members tested. In conclusion, CMAP decrement may be pronounced in dominant myotonia congenita, and the presence of decrement is related to mutation type.     

A novel CLCN1 mutation (G1652A) causing a mild phenotype of thomsen disease

We investigated a 62‐year‐old man who had mild clinical features of myotonia congenita. He was found to have a novel heterozygous G‐to‐A nucleotide substitution at position 1652 in exon 15 of the CLCN1 gene. Clinicogenetic studies performed on his family revealed that his asymptomatic son also shared the mutation. We conclude that a novel chloride channel mutation (G1652A) has caused a mild form of autosomal‐dominant myotonia congenita (Thomsen disease) in this family. Muscle Nerve, 2010     

Extracellular magnesium and calcium reduce myotonia in isolated ClC‐1 chloride channel‐inhibited human muscle

Introduction: Experimental myotonia induced in rat muscle by ClC‐1 chloride channel‐inhibited has been shown to be related inversely to extracellular concentrations of Mg²⁺ and Ca²⁺ ([Mg²⁺]_o and [Ca²⁺]_o) within physiological ranges. Because this implicates a role for [Mg²⁺]_o and [Ca²⁺]_o in the variability of symptoms among myotonia congenita patients, we searched for similar effects of [Mg²⁺]_o and [Ca²⁺]_o on myotonia in human muscle. Methods: Bundles of muscle fibers were isolated from abdominal rectus in patients undergoing abdominal surgery. Myotonia was induced by ClC‐1 inhibition using 9‐anthracene carboxylic acid (9‐AC) and was assessed from integrals of force induced by 5‐Hz stimulation for 2 seconds. Results: Myotonia disappeared gradually when [Mg²⁺]_o or [Ca²⁺]_o were elevated throughout their physiological ranges. These effects of [Mg²⁺]_o and [Ca²⁺]_o were additive and interchangeable. Conclusions: These findings suggest that variations in symptoms in myotonia congenita patients may arise from physiological variations in serum Mg²⁺ and Ca²⁺. Muscle Nerve 51 : 65–71, 2015     

Identification of two mutations and a polymorphism in the chloride channel CLCN-1 in patients with Becker's generalized myotonia

Myotonia congenita is an inherited muscle disorder characterized by muscle stiffness and hypertrophy. Its clinical phenotype depends, in part, on whether it is inherited as a dominant or recessive trait, respectively designated Thomsen's disease or Becker's generalized myotonia (BGM). In either case, it is associated with abnormalities in the muscle currents that are linked to the gene (CLCN-1) on human chromosome 7q35 encoding the skeletal muscle chloride channel. Single-strand conformation polymorphism analysis was used to screen two families with the BGM for mutations in the CLCN-1 gene. Two new mutations were found (G 201ins and A317Q). The latter mutation has been previously described in Thomsen's disease. Accepted: August 14, 1997     

Electrical myotonia in heterozygous carriers of recessive myotonia congenita

We investigated electrophysiologically the unaffected parents of patients with recessive myotonia congenita. We studied 18 families, in nine of which the diagnosis was confirmed by molecular genetics. Brief myotonic discharges were present in at least one parent in 67% of the families. Fathers were more likely than mothers to show these discharges. The difficulty in distinguishing very mildly affected parents with dominant myotonia congenita from the heterozygous carriers of recessive myotonia congenita is stressed. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22: 123–125, 1999     

Clinical Characteristics and Analysis of CLCN1 in Patients with "EMG Disease"

Background and Purpose

While the etiology and clinical features of "EMG disease" - which is characterized by diffusely increased insertional activity on needle electromyography (EMG) in the absence of neuromuscular disease - are not well known, some authorities believe it may be a form of myotonia congenita (MC). The aims of this study were to determine the clinical features of EMG disease and its relationship with CLCN1 mutations in patients.

Methods

The detailed clinical and electrophysiological features of EMG disease were evaluated in six patients. All 23 coding exons and exon-intron boundaries in CLCN1 gene were analyzed by direct sequencing to detect nucleotide changes.

Results

The common clinical symptoms of EMG disease were chronic muscle stiffness or generalized myalgia, which were aggravated in a cold environment. Four patients complained of action myotonia several times a year. Short trains of provoked positive sharp waves were documented on needle EMG, but myotonic discharges, fibrillation potentials, and fasciculations were not. Increased insertional activity was identified at the asymptomatic muscles studied. One novel heterozygous mutation was identified in one patient following genetic testing for CLCN1 mutations (c.1679T>C, p.Met560Thr).

Conclusions

The clinical features of EMG disease might be quite similar to those of MC, but CLCN1 mutation was found in only one subject. It is thus difficult to accept that EMG disease lies within the phenotypic spectrum of MC. Additional testing is needed to verify the pathogenetic cause of the diffusely increased insertional activity associated with this condition.     

Muscle MRI reveals distinct abnormalities in genetically proven non-dystrophic myotonias

We assessed the presence, frequency and pattern of MRI abnormalities in non-dystrophic myotonia patients. We reviewed T1-weighted and STIR (short-tau-inversion-recovery) 3T MRI sequences of lower limb muscles at thigh and calf level in 21 patients with genetically confirmed non-dystrophic myotonia: 11 with CLCN1 mutations and 10 with SCN4A mutations, and 19 healthy volunteers. The MRI examinations of all patients showed hyperintensity within muscles on either T1-weighted or STIR images. Mild extensive or marked T1-weighted changes were noted in 10/21 patients and no volunteers. Muscles in the thigh were equally likely to be affected but in the calf there was sparing of tibialis posterior. Oedema was common in calf musculature especially in the medial gastrocnemius with STIR hyperintensity observed in 18/21 patients. In 10/11 CLCN1 patients this included a previously unreported “central stripe”, also present in 3/10 SCN4A patients but no volunteers. Degree of fatty infiltration correlated with age (rho = 0.46, p < 0.05). Muscle MRI is frequently abnormal in non-dystrophic myotonia providing evidence of fatty infiltration and/or oedema. The pattern is distinct from other myotonic disorders; in particular the “central stripe” has not been reported in other conditions. Correlations with clinical parameters suggest a potential role for MRI as a biomarker.     

Painful cramps and giant myotonic discharges in a family with the Nav1.4‐G1306A mutation

Introduction: Two previously reported Norwegian patients with painful muscle cramps and giant myotonic discharges were genotyped and compared with those of members of 21 families harboring the same mutation. Methods: Using primers specific for SCN4A and CLCN1, the DNA of the Norwegian family members was amplified and bidirectionally sequenced. Clinical and neurophysiological features of other families harboring the same mutation were studied. Results: A G1306A mutation in the Nav1.4 voltage‐gated sodium channel of skeletal muscle was identified. This mutation is known to cause myotonia fluctuans. No giant myotonic discharges or painful muscle cramps were found in the other G1306A families. Conclusions: Ephaptic transmission between neighboring muscle fibers may not only cause the unusual size of the myotonic discharges in this family, but also a more severe type of potassium‐aggravated myotonia than myotonia fluctuans. Muscle Nerve 52: 680–683, 2015     

Transient weakness and compound muscle action potential decrement in myotonia congenita

Twenty-five Turkish patients with recessive myotonia congenita (RMC), 16 of whom had genetic confirmation, were studied. Nineteen had transient weakness. In the upper extremities, onset age of transient weakness was usually in the early teens. All untreated RMC patients had a compound muscle action potential decrement of ⩾25%, usually above 50%, with repetitive nerve stimulation at 10/s for 5 s. Patients with other nondystrophic diseases with myotonia, except 1 patient with dominant myotonia congenita, had no transient weakness and a CMAP decrement below 25%. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1334–1337, 1998.     

Guidelines on clinical presentation and management of nondystrophic myotonias

The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.     

Clinical characteristics of myotonia congenita in China★ Literature analysis of the past 30 years

AIM： To understand the distinct, clinical features of myotonia congenita in China.
METHODS： Case reports of myotonia congenita were retrieved from the Chinese Journal Full-text database, dating between 1980 and 2007, and analyzed for clinical characteristics of myotonia congenita.
RESULTS： There were 35 published reports and 258 cases about myotonia congenita. Six reports （62 cases） were excluded due to lack of clinical data, imprecise diagnosis, or duplication. Finally, 29 published reports and 196 cases （140 males and 56 females） were included in this analysis. About 78.6% of patients were diagnosed with myotonia congenita before the age of 20, and among these, 86.1% were classified as dominant inheritance. Lower and upper extremities were frequently affected with severe symptoms. Eyelids, mouth and lingual muscles, and trunk muscles and cervical muscles were less frequently involved. However, muscles for swallowing, sphincter muscles, and smooth muscles were not involved. There were no reports of cataracts, cardiac conduction block, or dyscrinism. myotonia congenita symptoms were induced or aggravated by cold temperatures in 71.9% of the patients and warming-up effect occurred in 95.6% of the patients. Muscle hypertrophy was observed in 69.6% and percussion of muscles in 76.5% of the patients. Myotonia potential or myotonia-like potential was detected in all patients using electromyography. Muscle fiber swelling or hypertrophy was frequently detected through muscular biopsy.
CONCLUSION： Myotonia congenita frequently occurs in males before the age of 20, in particular as the autosomal dominant form of myotonia congenita. Skeletal muscles throughout the body, especially the lower and upper extremities, are involved. However, muscles for swallowing, sphincter muscles, and smooth muscles are not involved. Warming-up effect is the main characteristic of myotonia congenita.     

Limbic encephalitis with anti‐GAD antibodies and Thomsen myotonia: a casual or causal association?

The association between hereditary myotonic disorders and epilepsy is seldom described in the literature. To date, few reports have dealt with dystrophic myotonias, whereas a single case demonstrating an association between sporadic congenital myotonia and epilepsy was recently reported in a patient carrying a de novo mutation of the CLCN1 gene. Additional evidence for a role of CLCN1 in the pathogenesis of epilepsy is derived from large‐scale exome analysis of ion channel variants and expression studies. Here, we describe the first case of association between familial Thomsen myotonia and epilepsy. All the affected members of a two‐generation family presented myotonia and disclosed a pathogenic mutation in CLCN1. In addition, one individual experienced epileptic seizures due to limbic encephalitis (LE) with anti‐GAD antibodies. The occurrence of the two diseases in this patient could be a chance association, however, CLCN1 mutation, as a susceptibility factor for epilepsy through dysfunction of GABA_a inhibitory signalling, cannot be ruled out as a possible influence.     

Phenotypic variability in myotonia congenita

Myotonia congenita is a hereditary chloride channel disorder characterized by delayed relaxation of skeletal muscle (myotonia). It is caused by mutations in the skeletal muscle chloride channel gene CLCN1 on chromosome 7. The phenotypic spectrum of myotonia congenita ranges from mild myotonia disclosed only by clinical examination to severe and disabling myotonia with transient weakness and myopathy. The most severe phenotypes are seen in patients with two mutated alleles. Heterozygotes are often asymptomatic but for some mutations heterozygosity is sufficient to cause pronounced myotonia, although without weakness and myopathy. Thus, the phenotype depends on the mutation type to some extent, but this does not explain the fact that severity varies greatly between heterozygous family members and may even vary with time in the individual patient. In this review, existing knowledge about phenotypic variability is summarized, and the possible contributing factors are discussed.     

Novel chloride channel gene mutations in two unrelated Japanese families with Becker's autosomal recessive generalized myotonia

We investigated the skeletal muscle voltage-gated chloride channel gene (CLCN1) in two unrelated Japanese patients with Becker's myotonia congenita. The non-myotonic parents of each patient were consanguineous. The proband of each family shares generalized myotonia, transient weakness after rest, and leg muscle hypertrophy. However, the disease severity related to the degree of myotonia differed, even in view of the response to long train nerve stimulation tests. CLCN1 gene analysis revealed a novel Ala659Val missense mutation identified to be homozygous in the more severe patient, while a novel Gln445Stop nonsense mutation was present in the other patient. Both mutations were absent in 90 Japanese normal controls. This is the first report of Japanese cases of Becker's myotonia congenita with CLCN1 gene mutations.