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     

Whole‐body high‐field MRI shows no skeletal muscle degeneration in young patients with recessive myotonia congenita

Kornblum C, Lutterbey GG, Czermin B, Reimann J, von Kleist‐Retzow J‐C, Jurkat‐Rott K, Wattjes MP. Whole‐body high‐field MRI shows no skeletal muscle degeneration in young patients with recessive myotonia congenita.
Acta Neurol Scand: 2010: 121: 131–135.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Background – Muscle magnetic resonance imaging (MRI) is the most sensitive method in the detection of dystrophic and non‐dystrophic abnormalities within striated muscles. We hypothesized that in severe myotonia congenita type Becker muscle stiffness, prolonged transient weakness and muscle hypertrophy might finally result in morphologic skeletal muscle alterations reflected by MRI signal changes. Aim of the study – To assess dystrophic and/or non‐dystrophic alterations such as fatty or connective tissue replacement and muscle edema in patients with severe recessive myotonia congenita. Methods – We studied three seriously affected patients with myotonia congenita type Becker using multisequence whole‐body high‐field MRI. All patients had molecular genetic testing of the muscle chloride channel gene (CLCN1). Results – Molecular genetic analyses demonstrated recessive CLCN1 mutations in all patients. Two related patients were compound heterozygous for two novel CLCN1 mutations, Q160H and L657P. None of the patients showed skeletal muscle signal changes indicative of fatty muscle degeneration or edema. Two patients showed muscle bulk hypertrophy of thighs and calves in line with the clinical appearance. Conclusions – We conclude that (i) chloride channel dysfunction alone does not result in skeletal muscle morphologic changes even in advanced stages of myotonia congenita, and (ii) MRI skeletal muscle alterations in myotonic dystrophy must be clear consequences of the dystrophic disease process.     

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.     

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.     

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     

Novel chloride channel mutations leading to mild myotonia among Chinese

We describe two Chinese families with a mild form of the myotonia congenita due to novel chloride channel (ClCN1) mutations. In one case, heterozygous I553F and H555N mutations were found. The patient shared the I553F mutation with his healthy father, and his mother had a history of mild myotonia when she was younger. In another family, autosomal dominant myotonia congenita was due to a L844F change. The physiological effects of the mutations were examined by using the two-electrode voltage-clamp technique after expression of the channels in Xenopus oocytes. All mutations drastically shifted the voltage required for half-maximal activation, more under conditions mimicking the homozygous situation, than under conditions mimicking the heterozygous situation. The larger effect was seen in the compound heterozygous situation combining the I553F and the H555N mutations. Our data suggest that myotonia congenita caused by CLCN1 mutations in Chinese have similar variable features to those found in the West.     

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.     

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.     

Truncating CLCN1 mutations in myotonia congenita: Variable patterns of inheritance

Introduction: Myotonia congenita due to protein truncating CLCN1 mutations is associated with variable patterns of inheritance. Methods: Three family kindreds are described, all of whom possess protein truncating mutations (Y33X, fs503X, R894X). One lineage also has coexistent R894X, A313T, and A320V mutations. Results: The Y33X mutation kinship has autosomal recessive inheritance and a severe phenotype when homozygous. The fs503X family has autosomal dominant inheritance and a moderate‐to‐severe phenotype. The A313T mutation kindred also has autosomal dominant inheritance but expresses a mild phenotype, except for the more severely affected compound heterozygotes. Conclusions: Early truncating mutations precluding dimerization are expected to be autosomal recessive and express a severe phenotype, while later mutations may be variable. The pedigrees presented here demonstrate that intrafamilial phenotypic variability may result from a dosage effect of an additional mutation, not necessarily variable expressivity. Mutations that have unexpected patterns of inheritance may represent allelic variability. Muscle Nerve 49:593–600, 2014     

The dominant chloride channel mutant G200R causing fluctuating myotonia: Clinical findings,electrophysiology, and channel pathology

Clinical, electrophysiological, and molecular findings are reported for a family with dominant myotonia congenita in which all affected members have experienced long-term fluctuations of the symptom of myotonia. In some patients myotonia is combined with myalgia. The myotonia-causing mutation in this family is in the gene encoding the muscular chloride channel, hClC-1, predicting the amino acid exchange G200R. We have constructed recombinant DNA vectors for expression of the mutant protein in tsA201 cells and investigation of the properties of the mutant channel. The most prominent alteration was a +100-mV shift of the midpoint of the activation curve. Therefore, within the physiological range the open probability of the mutant channel is markedly smaller than in wild-type. This shift is likely to be responsible for the myotonia in the patients. The fluctuating symptoms of this chloride channelopathy are discussed with respect to short-term fluctuations of myotonia in the sodium channelopathy of potassium-aggravated myotonia. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1122–1128, 1998.     

Dominant myotonia congenita: Pedigree with skipping of one generation

Summary The skipping of one generation in a family pedigree with dominant myotonia congenita is reported. It is suggested that non-penetrance in this condition occurs and should be considered in genetic counselling as a rare, but realistic possibility.Dedicated to Prof. A. Prader on the occasion of his 60th birthday     

Thomsen or Becker myotonia? A novel autosomal recessive nonsense mutation in the CLCN1 gene associated with a mild phenotype

We describe a large Brazilian consanguineous kindred with 3 clinically affected patients with a Thomsen myotonia phenotype. They carry a novel homozygous nonsense mutation in the CLCN1 gene (K248X). None of the 6 heterozygote carriers show any sign of myotonia on clinical evaluation or electromyography. These findings confirm the autosomal recessive inheritance of the novel mutation in this family, as well as the occurrence of phenotypic variability in the autosomal recessive forms of myotonia.     

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.     

Mutation in the S4 segment of the adult skeletal sodium channel gene in an Italian Paramyotonia Congenita (PC) family

The periodic paralyses are a group of autosomal dominant muscle diseases sharing the common feature of episodic stiffness and weakness, usually occurring with muscle cooling (as in the case of paramyotonia congenita, PC pheno-type) or changes in extracellular K+ levels resulting from various precipitating factors (hyperkalemic periodic paralysis, HYPP and hypokalemic periodic paralysis, Hypo PP). It is now known that HYPP maps to chromosome 17q, and that PC and a form of myotonia congenita without periodic paralysis also map to the 17q locus, thus indicating that they derive from allelic variants. So far, these disorders have been described in various ethnic groups but, to our knowledge, have never been reported in Italy. We describe a mutation in an S4 segment of the adult skeletal muscle sodium channel in a clinically-defined Italian family that leads to the paramyotonia congenita (PC) phenotype with dominant autosomal inheritance and temperature-related symptoms (regional weakness following cooling and exercise), present since childhood in all of the affected family members. This study was supported by a grant from MURST 60% given to Prof. G. Meola.     

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     

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.     

New mutation of the Na channel in the severe form of potassium‐aggravated myotonia

Myotonia manifests in several hereditary diseases, including hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita (PMC), and potassium‐aggravated myotonia (PAM). These are allelic disorders originating from missense mutations in the gene that codes the skeletal muscle sodium channel, Nav1.4. Moreover, a severe form of PAM has been designated as myotonia permanens. A new mutation of Nav1.4, Q1633E, was identified in a Japanese family presenting with the PAM phenotype. The proband suffered from cyanotic attacks during infancy. The mutated amino acid residue is located on the EF‐hand calcium‐binding motif in the intracellular C‐terminus. A functional analysis of the mutant channel using the voltage‐clamp method revealed disruption of fast inactivation, a slower rate of current decay, and a depolarized shift in the voltage dependence of availability. This study has identified a new mutation of PAM with a severe phenotype and emphasizes the importance of the C‐terminus for fast inactivation of the sodium channel. Muscle Nerve 39: 666–673, 2009     

A large German kindred with cold-aggravated myotonia and a heterozygous A1481D mutation in the SCN4A gene

Muscle sodium-channel disorders cover a spectrum of rare myotonic diseases. In a German family with 17 affected individuals in four generations, we identified a heterozygous missense mutation in exon 24 A1481D (c.4442 C>A) of the voltage-gated sodium channel gene (SCN4A) alpha subunit. Phenotypes of 12 family members were characterized by a mild myotonia with cold sensitivity but without paramyotonia. The index patient presented with fluctuating cold- and exercise-induced stiffness of ocular, facial, and distal muscles. The myotonia became more severe at the age of 22 years. His father had had cold- and exercise-induced periodic weakness with fluctuating myotonia since age 10. Later he developed a more severe, purely exercise- and cold-aggravated myotonia of arms, hands, and facial muscles. The father's mother presented with cold-induced myotonia until age 65, when progressive weakness of proximal limb muscles developed. Her muscle biopsies revealed considerable myopathic changes with a variety of fine structural alterations. This study presents a family with cold-aggravated myotonia and progression of myopathic changes in the muscle biopsy with increasing age. In older patients, sodium channelopathies may mimic the phenotypic features of myotonic dystrophy type 2.     

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