Myotonia congenita: mutation spectrum of CLCN1 in Spanish patients

Milla, Carmen Palma; Castro, Carmen Prior de; Gómez-González, Clara; Martínez‐Montero, Paloma; Pascual, Pascual; Mateos, J.

doi:10.1007/s12041-019-1115-0

Cited by 12 publications

(9 citation statements)

References 38 publications

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“…La mutación más frecuentemente encontrada en nuestra serie fue c.180+3A>T, que es la mutación más prevalente en España [ 6 , 9 ]. En general, esta mutación se ha asociado a herencia autosómica recesiva, pero, en nuestra serie, un caso sólo mostraba un alelo afecto, por lo que el segundo alelo se presupone en zona intrónica o con una deleción asociada.…”

Section: Discussionunclassified

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Miotonía congénita. Incidencia y presentación de una serie de casos

et al. 2023

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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.

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Section: Discussionunclassified

“…La mutación que estaba presente en las hermanas, c.1488G>T, la analizó funcionalmente Lorenz et al [ 10 ] y se ha mostrado como recesiva, y se ha descrito en otras series españolas previamente [ 6 , 9 ] en pacientes con comienzo temprano de la clínica, como es nuestro caso.…”

Section: Discussionunclassified

Miotonía congénita. Incidencia y presentación de una serie de casos

et al. 2023

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“…Most worryingly, for several mutations, very different clinical phenotypes have been found in different carriers of the same mutation (23,25,47,101), severely compromising the genotypephenotype correlation in NDM. Another important limitation for the improvement of genotype-phenotype correlations has been the lack of a sufficient number of individuals carrying each mutation (23), in particular in the case of novel mutations [such as the very recent study that described seven novel CLCN1 mutations (68)], which makes the situation even more complex, not without mentioning all those cases that show myotonia or a myotonia-like phenotype but in which the mutation has not been found. It is worth mentioning though, that correlation of mutations with the clinical phenotype gives insights into the pathophysiology of human channelopathies, and although some correlation exists between specific mutations and the associated clinical manifestations, this is vague (47).…”

Section: Complex Genotype-phenotype Relationships In Myotonic Channelmentioning

confidence: 99%

“…The poor correlations are most evident in Cl − channelopathies, where the same mutation can be inherited as dominant or recessive with different clinical manifestations, for example, F167L (39,67,68,102,103), A313T (67, 104), or W433R (44) (see Table 1). By recording and analyzing the ion currents of heterologously expressed mutant channels in different in vitro expression systems (Xenopus oocytes or HEK cells), much progress has been made in understanding how specific mutations affect the function of a particular ion channel, in providing insights onto the mechanism for the inheritance pattern, but also in the role that the voltage-gated ion channels play in excitable tissues (20,25,105).…”

Section: Complex Genotype-phenotype Relationships In Myotonic Channelmentioning

confidence: 99%

An Up-to-Date Overview of the Complexity of Genotype-Phenotype Relationships in Myotonic Channelopathies

Montero

Pusch

2020

Front. Neurol.

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Myotonic disorders are inherited neuromuscular diseases divided into dystrophic myotonias and non-dystrophic myotonias (NDM). The latter is a group of dominant or recessive diseases caused by mutations in genes encoding ion channels that participate in the generation and control of the skeletal muscle action potential. Their altered function causes hyperexcitability of the muscle membrane, thereby triggering myotonia, the main sign in NDM. Mutations in the genes encoding voltage-gated Cl − and Na + channels (respectively, CLCN1 and SCN4A) produce a wide spectrum of phenotypes, which differ in age of onset, affected muscles, severity of myotonia, degree of hypertrophy, and muscle weakness, disease progression, among others. More than 200 CLCN1 and 65 SCN4A mutations have been identified and described, but just about half of them have been functionally characterized, an approach that is likely extremely helpful to contribute to improving the so-far rather poor clinical correlations present in NDM. The observed poor correlations may be due to: (1) the wide spectrum of symptoms and overlapping phenotypes present in both groups (Cl − and Na + myotonic channelopathies) and (2) both genes present high genotypic variability. On the one hand, several mutations cause a unique and reproducible phenotype in most patients. On the other hand, some mutations can have different inheritance pattern and clinical phenotypes in different families. Conversely, different mutations can be translated into very similar phenotypes. For these reasons, the genotype-phenotype relationships in myotonic channelopathies are considered complex. Although the molecular bases for the clinical variability present in myotonic channelopathies remain obscure, several hypotheses have been put forward to explain the variability, which include: (a) differential allelic expression; (b) transacting genetic modifiers; (c) epigenetic, hormonal, or environmental factors; and (d) dominance with low penetrance. Improvements in clinical tests, the recognition of the different phenotypes that result from particular mutations and the understanding of how a mutation affects the structure and function of the ion channel, together with genetic screening, is expected to improve clinical correlation in NDMs.

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“…3 Becker disease may be more common than the dominant form in some populations. [4][5][6] Pathogenic or likely pathogenic variants in the chloride voltage-gated channel 1 (CLCN1) gene, located on chromosome 7q34, cause both types of MC. CLCN1 encodes the voltage-gated chloride channel (ClC-1), which is important for the normal repolarization of muscle action potential 7 and more than 250 variants have been reported to date, including deletions, insertions, splicing, nonsense and missense variants.…”

Section: Introductionmentioning

confidence: 99%

Myotonia congenita in a Greek cohort: Genotype spectrum and impact of the CLCN1:c.501C > G variant as a genetic modifier

Marinakis,

Svingou,

Papadimas

et al. 2024

Muscle and Nerve

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Introduction/AimsMyotonia congenita (MC) is the most common hereditary channelopathy in humans. Characterized by muscle stiffness, MC may be transmitted as either an autosomal dominant (Thomsen) or a recessive (Becker) disorder. MC is caused by variants in the voltage‐gated chloride channel 1 (CLCN1) gene, important for the normal repolarization of the muscle action potential. More than 250 disease‐causing variants in the CLCN1 gene have been reported. This study provides an MC genotype–phenotype spectrum in a large cohort of Greek patients and focuses on novel variants and disease epidemiology, including additional insights for the variant CLCN1:c.501C > G.MethodsSanger sequencing for the entire coding region of the CLCN1 gene was performed. Targeted segregation analysis of likely candidate variants in additional family members was performed. Variant classification was based on American College of Medical Genetics (ACMG) guidelines.ResultsSixty‐one patients from 47 unrelated families were identified, consisting of 51 probands with Becker MC (84%) and 10 with Thomsen MC (16%). Among the different variants detected, 11 were novel and 16 were previously reported. The three most prevalent variants were c.501C > G, c.2680C > T, and c.1649C > G. Additionally, c.501C > G was detected in seven Becker cases in‐cis with the c.1649C > G.DiscussionThe large number of patients in whom a diagnosis was established allowed the characterization of genotype–phenotype correlations with respect to both previously reported and novel findings. For the c.501C > G (p.Phe167Leu) variant a likely nonpathogenic property is suggested, as it only seems to act as an aggravating modifying factor in cases in which a pathogenic variant triggers phenotypic expression.

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Myotonia congenita: mutation spectrum of CLCN1 in Spanish patients

Cited by 12 publications

References 38 publications

Miotonía congénita. Incidencia y presentación de una serie de casos

Miotonía congénita. Incidencia y presentación de una serie de casos

An Up-to-Date Overview of the Complexity of Genotype-Phenotype Relationships in Myotonic Channelopathies

Myotonia congenita in a Greek cohort: Genotype spectrum and impact of the CLCN1:c.501C > G variant as a genetic modifier

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