Stiffness as a presenting symptom of an odd clinical condition caused by multiple sclerosis and myotonia congenita

A 24-year-old woman complained of a 4-year history of muscle cramps, stiffness of the right lower limb and walking difficulties. After clinical and laboratory investigations, a diagnosis of multiple sclerosis was made. However, her family history revealed that her father and an older sister had lifelong symptoms of impaired muscle relaxation following contraction, improving with physical exercise. Molecular genetic studies in both sisters confirmed the diagnosis of myotonia congenita, due to a c.568GG>TC (Gly190Ser) pathogenic mutation in CLCN1 gene. Occurrence of two different neurological conditions in the same patient, both manifesting with stiffness, is quite unusual and suggests the opportunity of an accurate differential diagnosis.     

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     

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.     

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.     

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.     

Homozygosity for dominant mutations increases severity of muscle channelopathies

Muscle channelopathies caused by mutations in the SCN4A gene that encodes the muscle sodium channel are transmitted by autosomal‐dominant inheritance. We report herein the first cases of homozygous patients for sodium channel mutations responsible for paramyotonia congenita (I1393T) or hypokalemic periodic paralysis (R1132Q). A parallel was drawn between this unprecedented situation and that of myotonia congenita by including patients homozygous or heterozygous for the CLCN1 I556N channel mutation, which is known for incomplete dominance and penetrance. Standardized electromyographic (EMG) protocols combining exercise and cold served as provocative tests to compare homozygotes with heterozygotes for each of the three mutations. Surface‐recorded compound muscle action potentials (CMAPs) were used to monitor muscle electrical activity, and myotonic discharges were evaluated by needle EMG. In heterozygous patients, exercise tests disclosed abnormal patterns of CMAP changes, which matched those previously described for similar dominant sodium and chloride channel mutations. Homozygotes showed much more severe clinical features and CMAP changes. We hypothesized that the presence of 100% defective ion channels in the homozygotes could account for the most severe phenotype. This suggests that the severity of muscle channelopathies depends both on the degree of channel impairment caused by the mutation and on the number of mutant channels engaged in the pathophysiological process. Overall, this study has practical consequences for the diagnosis of muscle channelopathies and raises new questions about their pathophysiology. Muscle Nerve, 2010     

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     

Novel variant in the PYGM gene causing late‐onset limb‐girdle myopathy,ptosis, and camptocormia

Introduction: Mutations in CLCN1 cause recessive or dominant forms of myotonia congenita (MC). Some mutations have been found to exhibit both patterns of inheritance but the mechanism explaining this behavior is unknown. Methods: A known recessive missense mutation, A493E, was identified in a family with dominant MC. The mutant p.A493E alone or in co‐expression with wild‐type (WT) ClC‐1 was expressed in Xenopus oocytes. Currents were measured and biochemical assays were performed. Results: The mutant showed no significant activity and reduced total and plasma membrane (PM) protein levels. Co‐expression with the mutant reduced the activity and PM levels of an engineered lower expression variant of ClC‐1, whereas no effect was observed on a higher expression variant. Discussion: Our results suggest that the dominant effect of some CLCN1 mutations showing recessive or dominant inheritance patterns may be due to a dose‐dependent defect in PM delivery of the WT channel. Muscle Nerve 58 : 157–160, 2018     

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.     

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.     

Becker’s myotonia: novel mutations and clinical variability in patients born to consanguineous parents

Myotonia congenita is an inherited muscle disease present from childhood that is characterized by impaired muscle relaxation after contraction resulting in muscle stiffness; moreover, skeletal striated muscle groups may be involved. Myotonia congenita occurs due to chloride (Cl) channel mutations that reduce the stabilizing Cl conductance, and it is caused by mutations in the CLCN1 gene. This paper describes four patients from two different healthy consanguineous Turkish families with muscle stiffness and easy fatigability. A genetic investigation was performed. Mutation analyses showed a homozygous p.Tyr150* (c.450C > A) mutation in patients 1, 2 and 3 and a homozygous p.Leu159Cysfs*11 (c.475delC) mutation in patient 4 in the CLCN1 gene. These mutations have never been reported before and in silico analyses showed that the mutations were disease causing. They may be predicted to cause nonsense-mediated mRNA decay. Our data expand the spectrum of CLCN1 mutations and provide insights for genotype–phenotype correlations of myotonia congenita.     

Dosage effect of a dominant CLCN1 mutation: a novel syndrome

Multiple mutations in the CLCN1 gene coding for the voltage-gated chloride channel have been documented to cause myotonia congenita. We report a kindred featuring an index patient who possesses 2 copies of a dominantly inherited mutated CLCN1 allele with a resulting novel phenotypic presentation. The index patient is a boy who presented initially for evaluation at the age of 5 years with a 2-year history of gait problems. Both parents and 3 male siblings were entirely well. Examination revealed a striking diffuse muscular hypertrophy, diffuse mild to moderate weakness, Gower sign, percussion, and grip myotonia. Electromyography confirmed myotonia, and molecular analysis revealed 2 copies of the T310M mutation on the CLCN1 gene. Testing of family members revealed a normal neurological examination without clinical myotonia in all and electromyographic evidence of myotonia and a single copy of the T310M mutation in both parents and 2 siblings. Our kindred is the initial demonstration of the dosage effect of a dominant mutated allele in the CLCN1 gene.     

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     

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 <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.     

Novel mutations in the muscle chloride channel CLCN1 gene causing myotonia congenita in Spanish families

Mutations in the muscular voltage-dependent chloride channel gene (CLCN1), located at 7q35, lead to recessive and dominant myotonia congenita. We report four novel mutations identified in this gene, after clinical, electromyographic, and genetic studies performed on 13 unrelated families. Two of the four mutations (2512insCTCA and A218T) were identified in families with Thomsen’s disease, one (Q658X) in a family with Becker’s disease, and the fourth (R669C) in a presumably sporadic patient with the Becker phenotype. Although identification of the mutations allows us to establish some genotype/phenotype correlations, this does not wholly account for the clinical heterogenity and the inheritance patterns of the disease. Received: 27 June 1998 Received in revised form: 11 November 1998 Accepted: 16 November 1998     

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     

Myotonia congenita in a Labrador Retriever with truncated CLCN1

An eight week old Labrador Retriever puppy presented with stiff-legged robotic gait. Abnormal gait was most evident after rest and improved with prolonged activity. On occasions, initiation of sudden movements would result in collapse with rigidity of the trunk and stiff extended limbs for several seconds. Other clinical signs were excitement-induced upper airway stridor and oropharyngeal dysphagia. Myotonia congenita was diagnosed based on clinical signs, abundant myotonic discharges on electromyography and exclusion of structural myopathies on histology. Whole exome sequencing revealed a case-specific homozygous variant in CLCN1, c.2275A > T resulting in a premature stop codon, p.R759X. The CLCN1 variant was absent from the genomes of 127 Labrador Retriever controls and 474 control dogs from other breeds. This study expands the spectrum of identified canine CLCN1 mutations and the list of affected breeds in myotonia congenita and highlights the potential value of dogs as translational large animal models of human genetic diseases.     

先天性肌强直一家系的临床特点及CLCN1基因突变筛查

目的 探讨先天性肌强直一家系的临床特点及CLCN1基因突变情况。方法 对一先天性肌强直家系中的22例患者的临床资料进行分析。结果 该家系5代68名成员,连续4代共24例发病,男女均有累及;多于婴幼儿期起病,肌强直见于所有患者,16例伴有肌肥大。全部患者肌酶学检查及血电解质正常;2例肌电图检查见自发性肌强直电位;先证者肌活检见肌纤维排列疏松,大小不一,横纹不清,部分肌纤维增生与肥大,肌细胞轻度变性,周围有少量炎性细胞浸润;3例基因检测未发现CLCN1基因的23对外显子突变。结论 该家系为常染色体显性遗传的Thomsen病,患者均有典型的临床表现。CLCN1基因23对外显子筛查未发现突变,表明可能存在遗传异质性。