[Congenital myotonia. Incidence and presentation of a series of cases]. / Miotonía congénita. Incidencia y presentación de una serie de casos.

INTRODUCTION: Myotonia congenita is the most common form of genetic myotonia and is caused by mutations in the CLCN1 gene. It can be inherited in an autosomal dominant or recessive manner. We present a series of cases to update its incidence in our environment, to describe its phenotype in relation to the genotype found, and we also review the mutations found, among which we provide a new, undescribed alteration. CASES REPORT: The medical records of patients with a diagnosis of congenital myotonia studied and followed up in the pediatric neurology section in a tertiary hospital between the years 2015-2020 were reviewed. Demographic variables (age, sex), disease course (age of onset, symptoms and signs, time elapsed until diagnosis, clinical evolution), family history and evaluation of response to treatment were collected. Five cases with a clinical diagnosis of myotonia congenita were identified (three with Becker's disease and two with Thomsen's disease). The incidence in relation to the number of births is estimated at 1:15,000 newborns for cases with the Becker phenotype and 1:21,000 newborns for the Thomsen phenotypes. We found a probably pathogenic mutation not previously described (CLCN1: c.824T> C). CONCLUSIONS: the approximate incidence in our environment was higher than previously known and we describe a new, undescribed mutation: c.824T> C with pathogenicity predictors that behaved like a Becker recessive phenotype but with an earlier debut.

TITLE: Miotonía congénita. Incidencia y presentación de una serie de casos.Introducción. La miotonía congénita es la forma más común de miotonía de causa genética y se produce por mutaciones en el gen CLCN1. Puede heredarse de manera autosómica dominante o recesiva. Presentamos una serie de casos para actualizar su incidencia en nuestro medio, para describir su fenotipo en relación con el genotipo encontrado y, además, revisamos las mutaciones encontradas, entre las que aportamos una nueva alteración no descrita. Casos clínicos. Se revisaron las historias clínicas de pacientes con diagnóstico de miotonía congénita estudiados y seguidos en la consulta de neurología pediátrica en un hospital de tercer nivel entre los años 2015 y 2020. Se recogieron variables demográficas (edad y sexo), curso de la enfermedad (edad de inicio, síntomas y signos, tiempo transcurrido hasta el diagnóstico y evolución clínica), antecedentes familiares y evaluación de la respuesta al tratamiento. Se identificaron cinco casos con diagnóstico clínico de miotonía congénita (tres con enfermedad de Becker y dos con enfermedad de Thomsen). La incidencia en relación con el número de nacimientos la estimamos en 1:15.000 recién nacidos para los casos con fenotipo Becker y en 1:21.000 recién nacidos para los fenotipos Thomsen. Hallamos una mutación probablemente patogénica no descrita previamente (CLCN1: c.824T>C). Conclusiones. La incidencia aproximada en nuestro medio fue superior a la previamente conocida y describimos una nueva mutación no descrita: c.824T>C, con predictores de patogenicidad, que se comportó como un fenotipo recesivo Becker, pero con inicio más temprano.

Myotonia congenita type Becker in Bulgaria: First genetically proven cases and mutation screening of two presumable endemic regions.

Myotonia congenita type Becker is an autosomal recessive nondystrophic skeletal muscle disorder, caused by mutations in the CLCN1 gene. The disease is characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction. Here we report the results from molecular genetic testing of 6 families, referred for sequencing of the CLCN1 gene. The disease causing mutations were detected in 5 of the cases, representing diverse type of nucleotide changes: nonsense (p.Arg894*), splice-site (c.1471+1G>A), missense (p.Val273Met; p.Tyr524Cys). Two additional changes were detected in an asymptomatic individual (c.2284+5C>T and p.Phe167Leu). Two of the detected mutations are interesting from population point of view. The novel missense mutation p.Tyr524Cys was found in a large Bulgarian family with affected individuals in both vertical and horizontal pedigree directions, all of them carrying the mutation in homozygous form. They populate a village located in the northwest part of the country. Endogamous marriages are very unusual for the Bulgarian population, supposing a high carrier frequency in this subpopulation. Screening of 154 residents of the corresponding region showed a significant carrier frequency for the p.Tyr524Cys mutation of about 0.65% (1/154). The second interesting region in the context of Myotonia congenita type Becker is the southwest part of the country, where we found a large family of Bulgarian Turkish origin. The disease causing missense mutation p.Val273Met was again present in homozygous state. Surprisingly, the genetic testing of newborns from southwest Bulgaria showed an even higher carrier status of about 2.6% (3/116), disproving our initial hypothesis of endogamous marriages (traditionally common in this subpopulation) being the cause of the disease in these patients. However the probability of consanguineous marriages being the cause for further exaggeration of the anyway very high carrier frequency cannot be excluded.

Prevalence and phenotypes of congenital myopathy due to α-actin 1 gene mutations.

INTRODUCTION: Congenital myopathy due to mutations in the α-actin 1 gene (ACTA1) was identified in 1999, but knowledge of prevalence and phenotype in patients who survive 5 years is lacking. METHODS: A national cohort of 91 patients aged ≥5 years and diagnosed with congenital myopathy was assessed for ACTA1 mutations and investigated clinically. RESULTS: Four patients with ACTA1 mutations were identified, yielding a prevalence of 4.4%. Patients were 10-23 years of age, and all but 1 were ambulatory. Vital capacity ranged from 47% to 70% predicted, and 1 patient needed nocturnal bi-level positive airway pressure. Limb flexor/extensor muscles and upper and lower extremities were affected equally. Pronounced neck flexor weakness was noted. CONCLUSIONS: Congenital myopathy caused by ACTA1 mutations is fatal in infancy in most cases. This study shows that the prevalence of α-actin myopathy in older patients with congenital myopathy is not negligible and that phenotypes can be quite mild.

A comprehensive genetic diagnosis of Chinese muscular dystrophy and congenital myopathy patients by targeted next-generation sequencing.

Muscular dystrophies and congenital myopathies are a large group of heterogeneous inherited muscle disorders. The spectrum of muscular dystrophies and congenital myopathies extends to more than 50 diseases today, even excluding the common forms Duchenne Muscular Dystrophy, Myotonic Dystrophy and Facioscapulohumeral Dystrophy. Unfortunately, even by critical clinical evaluation and muscle pathology, diagnosis is still difficult. To potentially remediate this difficulty, we applied a microarray-based targeted next-generation sequencing (NGS) technology to diagnose these patients. There were 55 consecutive unrelated patients who underwent the test, 36 of which (65%) were found to have a causative mutation. Our result shows the accuracy and efficiency of next-generation sequencing in clinical circumstances and reflects the features and relative distribution of inherited myopathies in the Chinese population.

Frequency and phenotype of patients carrying TPM2 and TPM3 gene mutations in a cohort of 94 patients with congenital myopathy.

Congenital myopathies are difficult to classify correctly through molecular testing due to the size and heterogeneity of the genes involved. Therefore, the prevalence of the various genetic causes of congenital myopathies is largely unknown. In our cohort of 94 patients with congenital myopathy, two related female patients and two sporadic, male patients were found to carry mutations in the tropomyosin 2 (TPM2) and tropomyosin 3 (TPM3) genes, respectively. This indicates a low (4.3%) frequency of TPM2 and TPM3 mutations as a cause of congenital myopathy. Compared to previously described patients carrying the same mutations as found in our study (c.503G>A, and c.502C>T in TPM3, and c.415_417delGAG in TPM2), clinical presentation and muscle morphological findings differed in our patients. Differences included variation in distribution of muscle weakness, presence of scoliosis and ptosis, physical performance and joint contractures. The variation in clinical profiles emphasizes the phenotypic heterogeneity. However, common features were also present, such as onset of symptoms in infancy or childhood, musculoskeletal deformities and normal or low plasma levels of creatine kinase. One patient had nemaline myopathy and fiber size disproportion, while three patients had congenital fiber type disproportion (CFTD) on muscle biopsies. TPM2-related CFTD has only been described in two cases, indicating that mutations in TPM2 are rare causes of CFTD.

A large cohort of myotonia congenita probands: novel mutations and a high-frequency mutation region in exons 4 and 5 of the CLCN1 gene.

Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction (myotonia) and caused by mutations in the chloride channel voltage-sensitive 1 (CLCN1) gene, encoding the voltage-gated chloride channel of skeletal muscle (ClC-1). In a large cohort of clinically diagnosed unrelated probands, we identified 75 different CLCN1 mutations in 106 individuals, among which 29 were novel mutations and 46 had already been reported. Despite the newly described mutations being scattered throughout the gene, in our patients, mutations were mostly found in exons 4 and 5. Most of the novel mutations located in the region comprising the intramembrane helices are involved in the ion-conducting pathway and predicted to affect channel function. We report for the first time that two mutations, inherited on the same allele as a heterozygous trait, abrogate disease expression, although when inherited singularly they were pathogenic. Such a mode of inheritance might explain the incomplete penetrance reported for autosomal dominant mutations in particular families.

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.

Congenital myopathy with focal loss of cross-striations revisited.

In 1977 Wijngaarden et al. reported a Dutch family with a congenital myopathy characterized by external ophthalmoplegia and a remarkable histological feature, focal loss of cross-striations. A small number of other families with similar clinical and pathological features led to the consideration of this congenital myopathy as a distinct entity. Here we present more than 30years of follow-up from the Dutch family and report recently identified compound heterozygous mutations in the skeletal muscle ryanodine receptor (RYR1) gene, c.10627-2A>G and p.Arg3539His (c.10616G>A). Focal loss of cross-striations on muscle biopsy is another histopathological feature that should raise the possibility of RYR1 involvement.

Genotype and phenotype characterization in a large dystrophinopathic cohort with extended follow-up.

Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) are allelic disorders with different clinical presentations and severity determined by mutations in the gene DMD, which encodes the sarcolemmal protein dystrophin. Diagnosis is based on clinical aspects and muscle protein analysis, followed by molecular confirmation. We revised the main aspects of the natural history of dystrophinopathies to define genotype-phenotype correlations in large patient cohorts with extended follow-up. We also specifically explored subjects carrying nucleotide substitutions in the DMD gene, a comparatively less investigated DMD/BMD subgroup. We studied 320 dystrophinopathic patients (205 DMD and 115 BMD), defining muscular, cardiac, respiratory, and cognitive involvement. We also subdivided patients according to the kind of molecular defect (deletions, duplications, nucleotide substitutions or other microrearrangements) and the mutation sites (proximal/distal to exon 45), studying phenotype-genotype correlations for each group. In DMD, mutation type did not influence clinical evolution; mutations located in distal regions (irrespective of their nature) are more likely to be associated with lower IQ levels (p = 0.005). BMD carrying proximal deletions showed a higher degree of cardiac impairment than BMD with distal deletions (p = 0.0046). In the BMD population, there was a strong correlation between the entity of muscle dystrophin deficiency and clinical course (p = 0.002). An accurate knowledge of natural history may help in the clinical management of patients. Furthermore, several clinical trials are ongoing or are currently planned, some of which aim to target specific DMD mutations: a robust natural history is therefore essential to correctly design these experimental trials.

Normalización transitoria de CK en un paciente con distrofia de Becker y tumor germinal testicular; ¿un efecto de la quimioterapia? / Transient normalisation of CK in a patient with Becker muscular dystrophy and testicular germ cell tumor: an effect of chemotherapy?

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[Prevalence of myotonic dystrophy in Iceland]. / Spennuvisnun (Dystrophia Myotonica): almennt yfirlit og algengi á Islandi.

OBJECTIVE: Epidemiologic studies of Myotonic Dystrophy (Dystrophic Myotony, DM) have shown variable regional prevalence from 0,46 to 189/105. We carried out a total population survey of DM in Iceland in 2004 having Oct. 31 as the day of prevalence. MATERIAL AND METHODS: Patients were collected from multiple sources, including Landspitali University Hospital registry and through contact with neurologists, neuropaediatricians, paediatricians and rehabilitation specialists. All EMGs of DM patients were reviewed. Information was gathered about age, age of onset, family history of DM and clinical symptoms. RESULTS: Eighty-two patients were ascertained giving a crude prevalence of 28.2/105. The prevalence of the congenital form of DM was 7.9/105 (23 patients, 26%). Affected females outnumbered males with a gender ratio of 1.2:1 (NS). Mean age of onset of symptoms for those, who didn't have the congenital form was 27.5 years (range 5-70 years). Ten families with DM were identified and all prevalent patients belonged to those families. CONCLUSION: The prevalence of DM is high in Iceland and higher than generally reported. This study showed a three times higher total prevalence and a seven times higher prevalence of congenital DM than found in a previous study in Iceland. We believe that this increase in prevalence probably reflects increased awareness of inherited diseases in neonates and better detection of patients who have mild symptoms.

Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia.

Myotonia congenita is a non-dystrophic muscle disorder affecting the excitability of the skeletal muscle membrane. It can be inherited either as an autosomal dominant (Thomsen's myotonia) or an autosomal recessive (Becker's myotonia) trait. Both types are characterised by myotonia (muscle stiffness) and muscular hypertrophy, and are caused by mutations in the muscle chloride channel gene, CLCN1. At least 50 different CLCN1 mutations have been described worldwide, but in many studies only about half of the patients showed mutations in CLCN1. Limitations in the mutation detection methods and genetic heterogeneity might be explanations. In the current study, we sequenced the entire CLCN1 gene in 15 Northern Norwegian and three Northern Swedish MC families. Our data show a high prevalence of myotonia congenita in Northern Norway similar to Northern Finland, but with a much higher degree of mutation heterogeneity. In total, eight different mutations and three polymorphisms (T87T, D718D, and P727L) were detected. Three mutations (F287S, A331T, and 2284+5C>T) were novel while the others (IVS1+3A>T, 979G>A, F413C, A531V, and R894X) have been reported previously. The mutations F413C, A531V, and R894X predominated in our patient material. Compound heterozygosity for A531V/R894X was the predominant genotype. In two probands, three mutations cosegregated with myotonia. No CLCN1 mutations were identified in two families. Our data support the presence of genetic heterogeneity and additional modifying factors in myotonia congenita.

Founder mutations and the high prevalence of myotonia congenita in northern Finland.

OBJECTIVE AND BACKGROUND: To find an explanation at the molecular level for the high prevalence of myotonia congenita in northern Finland and the exceptional pattern of inheritance of the disease in many families, and to study genotype-phenotype correlation in the patients. METHODS: Forty-six patients with myotonia congenita and 16 unaffected relatives from 24 families were studied. All 23 exons and their flanking regions of the gene for the chloride channel protein (ClC-1) were sequenced from at least one patient from all families. RESULTS: There were three different mutations of ClC-1 in the patients: one in exon 11, a T-to-G transversion that resulted in the substitution of cysteine for phenylalanine at amino acid position 413 (F413C); one in exon 15, a C-to-T transition that resulted in the substitution of valine for alanine at amino acid position 531 (A531V); and one in exon 23, a C-to-T transition that resulted in the substitution of a stop codon for an arginine codon at amino acid position 894 (R894X). CONCLUSIONS: Molecular studies showed that even in families with apparent dominant inheritance, the actual mode of inheritance was autosomal recessive. This was explained not only by the observed consanguinity in some families but by an enrichment of three different mutations of the ClC-1 gene and a consequent high number of compound heterozygotes in the population. One of the mutations is unique to northern Finland. The conspicuous enrichment of the mutations is likely due to the founder effect and isolation by distance, as in other diseases in the Finnish heritage.

Myotonia congenita in northern Finland: an epidemiological and genetic study.

An epidemiological and genetic investigation of myotonia congenita was carried out in northern Finland. Altogether 58 patients were identified (of whom 54 lived in the study area) in 23 families, with a prevalence of 7.3 per 100000. The majority of the families originated from a sparsely populated area in western Lapland. The mean age at onset of the disease was 11 years with a range of 2 to 45 years. The mean time that had passed before verification of the clinical disease was 18 (SD 14) years. The sex ratio M/F was 2.2/1.0. Forty-seven cases were familial and 11 were sporadic. In six families/pedigrees the inheritance was compatible with autosomal recessive and in two families with autosomal dominant inheritance. In five additional families, in which autosomal recessive inheritance seemed most plausible, vertical transmission was also noticed. This could be explained either by consanguinity of the parents or by variant expression of the mutation(s) involved. Our results suggest that myotonia congenita is unusually frequent in northern Finland, most probably as a consequence of an enrichment of the gene mutation(s) in the population.

[The clinico-epidemiological characteristics of myotonias in Saratov Province]. / Kliniko-épidemiologicheskaia kharakteristika miotonii v Saratovskoi oblasti.

The paper summarizes data on the epidemiology and clinical polymorphism of the major types of myotonias. Presents both familial and sporadic cases of myotonia congenita, atrophica, dystrophica, and Eulenburg's [correction of Eilenburg's] paramyotonias. Describes the clinical picture of Thomsen's disease in childhood. Discusses the types of disease inheritance and nosological entities of myotonias. The material has been obtained from the studies performed over 25 years, which allows the course of the disease to be followed up in families and in individuals, and enables the patients' migration in the region and outside to be traced.

[Regional clinico-genetic features of myotonias]. / O regional'nykh kliniko-geneticheskikh osobennostiakh miotonii.

The incidence of myotonia in the South-West regions of Uzbekistan is 1.6:100000 of the population. Its proportion among other hereditary diseases of the nervous system is 8.2% and among neuromuscular abnormalities--2.6%. Furthermore, it has been also established that an autosomal-recessive form of non-atrophic myotonia is rather prevalent in this region. It has a number of clinical characteristics which differentiate it from a generalized recessive form prevalent in West Europe.

Myotonia congenita and myotonic dystrophy: descriptive epidemiological investigation in Turin, Italy (1955-1979).

A descriptive epidemiological survey of Myotonia Congenita (MC) and Myotonic Dystrophy (MD) was carried out on the resident population of the City of Turin, Italy. Cases were collected from the Archives of the Neurological Clinic, University of Turin, and from other neurological departments in the city's hospitals. Every patient (and the "healthy" relatives of MD subjects) underwent clinical and EMG re-examination, in order to confirm the initial diagnosis and to investigate the familial distribution of the diseases. The point prevalence rate was 0.9 (+/- 0.6) X 10(-5) for MC and 2.1 (+/- 0.8) X 10(-5) for MD. During the period 1955-1979 the mean annual incidence was 0.3 (+/- 0.2) X 10(-6) for MC and 0.7 (+/- 0.3) X 10(-6) for MD. The incidence-at-birth rate was 1.4 (+/- 1.2) X 10(-5) for MC and 2.9 (+/- 1.8) X 10(-5) for MD. The modalities of inheritance and sex distribution of MC and MD were also studied. Knowledge of epidemiological features of these myopathies is of vital importance for genetic counselling.

Paramyotonia congenita (von Eulenburg) in Denmark.

Paramyotonia congenita (von Eulenburg) (PMC) is described in a Danish family in seven generations and 39 persons. PMC has not previously been described in Denmark and an epidemiological description of the family is given. The diagnostic difficulties versus hyperkalemic familial periodic paralysis with myotonia, adynamia episodica hereditaria and myotonia congenita (Thomsen) are discussed.