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1.
Medicine (Baltimore) ; 99(28): e21117, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664137

RESUMO

INTRODUCTION: we report on the first case of a woman affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and recessive myotonia congenita (MC), treated with mexiletine. We aimed at describing the possible role of mexiletine in CIDP management. PATIENT CONCERNS: A 44-year-old female affected by CIDP and MC, gained beneficial effects for CIDP symptoms (muscle weakness, cramps, and fatigue) and relapses, after mexiletine intake (200 mg twice a day). The patient presented with detrimental effects after mexiletine drop out, with a worsening of CIDP symptoms. INTERVENTIONS: The patient reported a nearly complete remission of muscle stiffness and weakness up to 3 years since mexiletine intake. Then, she developed an allergic reaction with glottis edema, maybe related to mexiletine intake, as per emergency room doctors' evaluation, who suggested withdrawing the drug. OUTCOMES: The patient significantly worsened after the medication drop out concerning both CIDP and MC symptoms. CONCLUSION: This is the first report on the association of CIDP and MC in the same patient. Such diseases may share some clinical symptoms related to a persistent sodium currents increase, which maybe due either to the over-expression of sodium channels following axonal damage due to demyelination or to the chloride channel genes mutations. This is the possible reason why mexiletine maybe promising to treat CIDP symptoms.


Assuntos
Mexiletina/uso terapêutico , Miotonia Congênita/complicações , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Adulto , Doença Crônica , Feminino , Seguimentos , Humanos , Miotonia Congênita/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/complicações , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Recidiva , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Suspensão de Tratamento
2.
PLoS One ; 15(5): e0233017, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407401

RESUMO

Myotonia congenita and hypokalemic periodic paralysis type 2 are both rare genetic channelopathies caused by mutations in the CLCN1 gene encoding voltage-gated chloride channel CLC-1 and the SCN4A gene encoding voltage-gated sodium channel Nav1.4. The patients with concomitant mutations in both genes manifested different unique symptoms from mutations in these genes separately. Here, we describe a patient with myotonia and periodic paralysis in a consanguineous marriage pedigree. By using whole-exome sequencing, a novel F306S variant in the CLCN1 gene and a known R222W mutation in the SCN4A gene were identified in the pedigree. Patch clamp analysis revealed that the F306S mutant reduced the opening probability of CLC-1 and chloride conductance. Our study expanded the CLCN1 mutation database. We emphasized the value of whole-exome sequencing for differential diagnosis in atypical myotonic patients.


Assuntos
Canais de Cloreto/genética , Paralisia Periódica Hipopotassêmica/complicações , Paralisia Periódica Hipopotassêmica/genética , Miotonia Congênita/complicações , Miotonia Congênita/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , China , Canais de Cloreto/química , Canais de Cloreto/metabolismo , Consanguinidade , Sequência Conservada , Diagnóstico Diferencial , Feminino , Células HEK293 , Humanos , Paralisia Periódica Hipopotassêmica/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação , Miotonia Congênita/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo , Linhagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sequenciamento Completo do Exoma , Adulto Jovem
3.
Int J Mol Sci ; 21(7)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276507

RESUMO

Myotonia congenita (MC) is a rare disorder characterized by stiffness and weakness of the limb and trunk muscles. Mutations in the SCN4A gene encoding the alpha-subunit of the voltage-gated sodium channel Nav1.4 have been reported to be responsible for sodium channel myotonia (SCM). The Nav1.4 channel is expressed in skeletal muscles, and its related channelopathies affect skeletal muscle excitability, which can manifest as SCM, paramyotonia and periodic paralysis. In this study, the missense mutation p.V445M was identified in two individual families with MC. To determine the functional consequences of having a mutated Nav1.4 channel, whole-cell patch-clamp recording of transfected Chinese hamster ovary cells was performed. Evaluation of the transient Na+ current found that a hyperpolarizing shift occurs at both the activation and inactivation curves with an increase of the window currents in the mutant channels. The Nav1.4 channel's co-expression with the Navß4 peptide can generate resurgent Na+ currents at repolarization following a depolarization. The magnitude of the resurgent currents is higher in the mutant than in the wild-type (WT) channel. Although the decay kinetics are comparable between the mutant and WT channels, the time to the peak of resurgent Na+ currents in the mutant channel is significantly protracted compared with that in the WT channel. These findings suggest that the p.V445M mutation in the Nav1.4 channel results in an increase of both sustained and resurgent Na+ currents, which may contribute to hyperexcitability with repetitive firing and is likely to facilitate recurrent myotonia in SCM patients.


Assuntos
Mutação de Sentido Incorreto , Miotonia Congênita/genética , Miotonia Congênita/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.4/fisiologia , Sequência de Aminoácidos , Animais , Grupo com Ancestrais do Continente Asiático , Células CHO , Canalopatias/genética , Canalopatias/metabolismo , Canalopatias/fisiopatologia , Cricetulus , Feminino , Humanos , Masculino , Miotonia Congênita/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.4/química , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo , Técnicas de Patch-Clamp , Linhagem
4.
Brain ; 143(2): 452-466, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32040565

RESUMO

Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.


Assuntos
Doenças Musculares/genética , Mutação/genética , Miotonia Congênita/genética , Retículo Sarcoplasmático/metabolismo , Adolescente , Adulto , ATPases Transportadoras de Cálcio/genética , Criança , Feminino , Humanos , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Fenótipo , Adulto Jovem
5.
Muscle Nerve ; 61(4): 491-495, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31944327

RESUMO

INTRODUCTION: Brody myopathy (BM) is a recessive condition caused by mutations in the ATP2A1 gene and usually induces impaired muscle relaxation during and after exercise. Diagnosis relies on needle electromyography showing electrical silence, muscle biopsy with decreased sarcoplasmic reticulum calcium adenosine triphosphatase activity, and genetic analysis. Electrodiagnostic functional analyses are useful in the diagnosis of channelopathies, and thus may be impaired in BM. METHODS: We performed exercise tests and repetitive nerve stimulation (RNS; 10 supramaximal stimuli at 3 Hz) in 10 patients with BM. RESULTS: All participants showed incremental responses on RNS. Compound muscle action potential amplitude was increased and duration was decreased, especially in the ulnar nerve (+30.2 ± 7.1% and - 30.3 ± 2.8%, respectively; both P < .001). DISCUSSION: Easily accessible, this sign, referred to as the Arzel sign, could prove to be a very useful tool in BM diagnosis and in broadening its phenotype.


Assuntos
Potenciais de Ação/fisiologia , Eletrodiagnóstico/métodos , Músculo Esquelético/fisiopatologia , Miotonia Congênita/diagnóstico , Nervo Ulnar/fisiopatologia , Estimulação Elétrica , Eletromiografia , Teste de Esforço , Feminino , Humanos , Masculino , Mutação , Miotonia Congênita/genética , Miotonia Congênita/fisiopatologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética
6.
Am J Case Rep ; 21: e919867, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31915326

RESUMO

BACKGROUND Congenital myotonic dystrophy is a subtype of type 1 myotonic dystrophy presenting in the neonatal period. Cardiac involvement is commonly seen in patients with type 1 myotonic dystrophy beyond the neonatal period. Brugada syndrome is a conduction abnormality associated with a mutation in the sodium voltage-gated channel alpha subunit 5 (SCN5A) gene and has been described in adult patients with type 1 myotonic dystrophy. Two cases are presented of type 1 myotonic dystrophy in neonates, one who had family members with a confirmed diagnosis of Brugada syndrome. CASE REPORT Case 1: A female infant at 40 weeks gestational age, birth weight of 3,395 grams was born to a 40-year-old gravida 4, para 3 (G4P3) mother. The mother had previously been diagnosed with Brugada syndrome. Multiple family members were identified and diagnosed with type 1 myotonic dystrophy and Brugada syndrome. The infant is being monitored closely with a plan to perform genetic testing for Brugada syndrome if she develops cardiac conduction abnormalities. Case 2: A male infant at 37 weeks gestational age, with a birth weight of 2,900 grams, was born to a 24-year-old gravida 2, para 1 (G2P1) mother. He was admitted to the neonatal intensive care unit (NICU) secondary to poor respiratory effort and generalized hypotonia. Severe polyhydramnios was diagnosed during pregnancy. The mother had previously been diagnosed with type 1 myotonic dystrophy. CONCLUSIONS Infants with congenital myotonic dystrophy should be carefully monitored for both structural and conduction abnormalities of the heart, supported by genetic testing.


Assuntos
Síndrome de Brugada/diagnóstico , Miotonia Congênita/diagnóstico , Distrofia Miotônica/diagnóstico , Adulto , Síndrome de Brugada/genética , Feminino , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido/genética , Masculino , Mutação , Miotonia Congênita/genética , Miotonia Congênita/patologia , Distrofia Miotônica/genética , Distrofia Miotônica/patologia , Miotonina Proteína Quinase/genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Gravidez
7.
Med Sci (Paris) ; 35 Hors série n° 2: 15-17, 2019 Nov.
Artigo em Francês | MEDLINE | ID: mdl-31859625

RESUMO

Congenital myopathies represent a quite heterogeneous group of neuromuscular disorders both at the clinical and genetic level. High-throughput sequencing (NGS), targeted or not, combined with muscle pathology, greatly facilitate their accurate characterization and occasionally lead to unexpected discoveries like in the case reported here in a Kuwaiti family facing a long diagnostic odyssey.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Fissura Palatina/diagnóstico , Hipertermia Maligna/diagnóstico , Mutação de Sentido Incorreto , Miotonia Congênita/diagnóstico , Miotonia Congênita/genética , Adolescente , África , Grupo com Ancestrais do Continente Africano/genética , Substituição de Aminoácidos , Criança , Fissura Palatina/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Kuweit , Masculino , Hipertermia Maligna/genética , Miotonia Congênita/patologia , Fenótipo , Catar , Arábia Saudita , Irmãos
8.
Genes (Basel) ; 10(11)2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31752120

RESUMO

Duchenne muscular dystrophy (DMD) is a progressive hereditary muscular disease with X-linked recessive inheritance, that leads patients to premature death. The loss of dystrophin determines membrane instability, causing cell damage and inflammatory response. Macrophage migration inhibitory factor (MIF) is a cytokine that exerts pleiotropic properties and is implicated in the pathogenesis of a variety of diseases. Recently, converging data from independent studies have pointed to a possible role of MIF in dystrophic muscle disorders, including DMD. In the present study, we have investigated the modulation of MIF and MIF-related genes in degenerative muscle disorders, by making use of publicly available whole-genome expression datasets. We show here a significant enrichment of MIF and related genes in muscle samples from DMD patients, as well as from patients suffering from Becker's disease and limb-girdle muscular dystrophy type 2B. On the other hand, transcriptomic analysis of in vitro differentiated myotubes from healthy controls and DMD patients revealed no significant alteration in the expression levels of MIF-related genes. Finally, by analyzing DMD samples as a time series, we show that the modulation of the genes belonging to the MIF network is an early event in the DMD muscle and does not change with the increasing age of the patients, Overall, our analysis suggests that MIF may play a role in vivo during muscle degeneration, likely promoting inflammation and local microenvironment reaction.


Assuntos
Redes Reguladoras de Genes/imunologia , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Distrofia Muscular de Duchenne/imunologia , Transdução de Sinais/genética , Estudos de Casos e Controles , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/imunologia , Fibras Musculares Esqueléticas/imunologia , Fibras Musculares Esqueléticas/patologia , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/imunologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia , Miotonia Congênita/genética , Miotonia Congênita/imunologia , Miotonia Congênita/patologia , Transdução de Sinais/imunologia
9.
J Neuromuscul Dis ; 6(4): 467-473, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31609695

RESUMO

BACKGROUND: The phenotypic spectrum of the skeletal muscle voltage-gated sodium channel gene (SCN4A) mutations has been expanding dramatically with advancements in genetic testing. Previously only known to cause autosomal dominant myotonia or periodic paralysis, now recessive mutations have been found causing congenital myopathies and congenital myasthenic syndromes. CASE PRESENTATION: A 27-year-old woman who was born with Arnold-Chiari malformation, hydrocephalus, high-arched palate, bilateral hip dysplasia, and severe scoliosis presented for evaluation of episodic muscle stiffness and weakness. Electrodiagnostic studies revealed myopathy and widespread myotonia. Muscle histopathology showed marked fiber size variability, type I fiber predominance with minimal scattered necrosis and regeneration which was typical of a congenital myopathy with an additional finding of a lobulated structural pattern in type I fibers. Sequential individual gene testing revealed a novel de novo heterozygous c.2386 C > G, p.Leu796Val missense mutation in the SCN4A gene. DISCUSSION: To the best of our knowledge, this is the first report of a dominant, heterozygous mutation in SCN4A causing a complex phenotype of congenital myopathy and myotonia with multiple congenital anomalies and unique muscle pathology findings. This case is another addition to the ever expanding phenotype of SCN4A mutations.


Assuntos
Doenças Musculares/genética , Mutação/genética , Miotonia Congênita/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Adulto , Feminino , Testes Genéticos , Heterozigoto , Humanos , Músculo Esquelético/fisiopatologia , Miotonia Congênita/diagnóstico , Linhagem , Fenótipo
10.
Medicina (B Aires) ; 79 Suppl 3: 82-86, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31603850

RESUMO

Important advances have been made in the field of congenital myopathies in recent years, forcing clinicians to constantly review and update this group of diseases. The increasing identification of new genes and phenotypes associated with already known genes has been possible to a great extent thanks to the development accomplished in next generation sequencing techniques, which are increasingly accessible. Knowing better the phenotypic spectrum of these entities allows to establish a phenotype/genotype correlation in some subgroups. The best understanding of the pathophysiology and natural history of these diseases are fundamental to design new therapies. The first clinical trials in the field of gene therapy are already a reality and are showing positive results, creating a new expectation for patients, families and specialists, which will be reflected in the need to adapt the protocols of care, diagnosis and treatment of some of these entities. It is essential that pediatric neurologists, pediatricians, physiotherapists and other professionals involved in the care of these patients are informed and updated on the advances in this group of diseases.


Assuntos
Miotonia Congênita/patologia , Miotonia Congênita/terapia , Genótipo , Humanos , Músculos/patologia , Músculos/fisiopatologia , Miotonia Congênita/classificação , Miotonia Congênita/genética , Fenótipo
11.
J Electromyogr Kinesiol ; 49: 102362, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31610484

RESUMO

INTRODUCTION: Myotonia congenita (MC) is caused by pathogenic variants in the CLCN1 gene coding the chloride channel protein. METHODS: To test the hypothesis that needle EMG could be helpful in distinguishing between the recessive and dominant MC, we performed EMG examination in 36 patients (23 men) aged 4-61 years with genetically proven MC: in 30 patients with autosomal recessive MC (Becker MC) and in 6 with autosomal dominant MC (Thomsen MC). RESULTS: Myotonic discharges were recorded in 95.8% of examined muscles. For the whole MC group we observed a significant positive correlation between parameters of motor unit activity potentials (MUAPs) in vastus lateralis and tibialis anterior muscles and the duration of the disease. Similar correlation for biceps brachii also was found in Becker MC subgroup only. DISCUSSION: EMG could still be helpful in diagnosis of MC and together with provocative tests might be useful in differentiation between recessive and autosomal MC.


Assuntos
Eletromiografia/métodos , Potencial Evocado Motor , Mutação , Miotonia Congênita/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Genes Dominantes , Genes Recessivos , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Miotonia Congênita/diagnóstico , Miotonia Congênita/genética
12.
Neurol Res ; 41(12): 1069-1074, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31566103

RESUMO

Objectives: Myotonia congenita (MC) is a rare genetic muscular disorder caused by CLCN1 mutations, which codes for skeletal muscle chloride channel CLC1. MC is characterized by impaired muscle relaxation after contraction resulting in muscle stiffness. This study aimed to identify the genetic etiology of a Chinese family affected with recessive MC. Methods: Whole exome sequencing was performed to identify the disease-associated variants. The candidate causal genes discovered by WES were then confirmed by Sanger sequencing and co-segregation analyses were also conducted. Results: Two novel compound heterozygous mutations in CLCN1 gene, p.D94Y (paternal allele) and p.Y206* (maternal allele), were successfully identified as the pathogenic mutations by whole-exome sequencing (WES). The mutations were confirmed with Sanger sequencing in the family members and cosegregated with the MC phenotype. The two mutations have not been reported in the HGMD, dbSNP, 1000 Genomes project, ClinVar database, ExAC, and gnomAD previously. Mutation p.D94Y is predicted to be deleterious by using in silico tools and p.Y206* is a nonsense mutation, causing protein synthesis termination. Conclusions: Molecular genetics analysis offers an accurate method for diagnosing MC. Our results expand the mutational spectrum of recessive MC.


Assuntos
Canais de Cloreto/genética , Miotonia Congênita/genética , Adulto , Feminino , Heterozigoto , Humanos , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Mutação , Miotonia Congênita/diagnóstico , Miotonia Congênita/patologia , Linhagem , Sequenciamento Completo do Exoma
13.
J Genet ; 982019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31544778

RESUMO

Myotonia congenita (MC) is a Mendelian inherited genetic disease caused by the mutations in the CLCN1 gene, encoding the main skeletal muscle ion chloride channel (ClC-1). The clinical diagnosis of MC should be suspected in patients presenting myotonia, warm-up phenomenon, a characteristic electromyographic pattern, and/or family history. Here, we describe the largest cohort of MC Spanish patients including their relatives (up to 102 individuals). Genetic testing was performed by CLCN1 sequencing and multiplex ligation-dependent probe amplification (MLPA). Analysis of selected exons of the SCN4A gene, causing paramyotonia congenita, was also performed. Mutation spectrum and analysis of a likely founder effect of c.180+3A>T was achieved by haplotype analysis and association tests. Twenty-eight different pathogenic variants were found in the CLCN1 gene, of which 21 were known mutations and seven not described. Gross deletions/duplications were not detected. Four probands had a pathogenic variant in SCN4A. Two main haplotypes were detected in c.180+3A>T carriers and no statistically significant differences were detected between case and control groups regarding the type of haplotype and its frequencies. A diagnostic yield of 51% was achieved; of which 88% had pathogenic variants in CLCN1 and 12% in SCN4A. The existence of a c.180+3A>T founder effect remains unsolved.


Assuntos
Canais de Cloreto/genética , Miotonia Congênita/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Estudos de Coortes , Éxons , Feminino , Efeito Fundador , Haplótipos , Humanos , Masculino , Músculo Esquelético/metabolismo , Mutação , Miotonia Congênita/diagnóstico , Polimorfismo de Nucleotídeo Único , Espanha
14.
J Neuromuscul Dis ; 6(3): 377-384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31227654

RESUMO

Dihydropyridine receptor congenital myopathy is a recently described congenital myopathy caused by dominant or recessive mutations in the CACNA1S gene. To date, only 11 cases from 7 families were described in a single report. Here, we describe a consanguineous family with three affected children, presenting congenital hypotonia, contractures, ophthalmoplegia and respiratory insufficiency, with a novel homozygous mutation in the CACNA1S gene. They also showed cognitive delay, pes equinovarus deformity and neurogenic changes that have not been associated with this myopathy in the previous reports. This report expands the phenotypic spectrum of dihydropyridine receptor congenital myopathy and underscores the importance of whole exome sequencing in early onset neuromuscular disorders.


Assuntos
Canais de Cálcio Tipo L/genética , Miotonia Congênita/genética , Pré-Escolar , Feminino , Homozigoto , Humanos , Lactente , Masculino , Músculo Esquelético/patologia , Mutação de Sentido Incorreto , Miotonia Congênita/patologia , Linhagem , Fenótipo , Turquia
15.
Skelet Muscle ; 9(1): 14, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133047

RESUMO

BACKGROUND: Myopalladin (MYPN) is a component of the sarcomere that tethers nebulin in skeletal muscle and nebulette in cardiac muscle to alpha-actinin at the Z lines. Autosomal dominant MYPN mutations cause hypertrophic, dilated, or restrictive cardiomyopathy. Autosomal recessive MYPN mutations have been reported in only six families showing a mildly progressive nemaline or cap myopathy with cardiomyopathy in some patients. CASE PRESENTATION: A consanguineous family with congenital to adult-onset muscle weakness and hanging big toe was reported. Muscle biopsy showed minimal changes with internal nuclei, type 1 fiber predominance, and ultrastructural defects of Z line. Muscle CT imaging showed marked hypodensity of the sartorius bilaterally and MRI scattered abnormal high-intensity areas in the internal tongue muscle and in the posterior cervical muscles. Cardiac involvement was demonstrated by magnetic resonance imaging and late gadolinium enhancement. Whole exome sequencing analysis identified a homozygous loss of function single nucleotide deletion in the exon 11 of the MYPN gene in two siblings. Full-length MYPN protein was undetectable on immunoblotting, and on immunofluorescence, its localization at the Z line was missed. CONCLUSIONS: This report extends the phenotypic spectrum of recessive MYPN-related myopathies showing: (1) the two patients had hanging big toe and the oldest one developed spine and hand contractures, none of these signs observed in the previously reported patients, (2) specific ultrastructural changes consisting in Z line fragmentation, but (3) no nemaline or caps on muscle pathology.


Assuntos
Proteínas Musculares/deficiência , Proteínas Musculares/genética , Miotonia Congênita/genética , Adulto , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Consanguinidade , Éxons , Feminino , Genes Recessivos , Homozigoto , Humanos , Mutação com Perda de Função , Masculino , Microscopia Eletrônica de Transmissão , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Miotonia Congênita/diagnóstico por imagem , Miotonia Congênita/fisiopatologia , Linhagem , Deleção de Sequência , Dedos do Pé/diagnóstico por imagem
16.
Pract Neurol ; 19(5): 417-419, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30996034

RESUMO

A 56-year-old man presented with painless impairment of muscle relaxation on vigorous contraction (eg, eyelid closure, hand grip, running). There were no episodes of paralysis, symptom progression, weakness or extramuscular symptoms. Five of his fifteen siblings had similar complaints. His serum creatine kinase was normal. Electromyography showed electrical silence on muscle relaxation, without myotonic discharges. DMPK, ClCN1 and SCN4A genetic testing was normal, but he had a homozygous pathogenic variant of ATP2A1 (c.1315G>A; pGlu439Lys). Brody disease is a rare autosomal recessive myopathy due to ATP2A1 mutations that reduce sarcoplasmic reticulum calcium-ATPase1 activity, hence delaying muscle relaxation.


Assuntos
Doenças Musculares/genética , Miotonia Congênita/genética , Miotonia/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Eletromiografia/métodos , Testes Genéticos , Força da Mão/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/diagnóstico , Mutação/genética , Miotonia/diagnóstico , Miotonia Congênita/diagnóstico
19.
Acta Neuropathol ; 137(3): 501-519, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30701273

RESUMO

The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-lines. Deeper analysis of the missense mutation revealed mutant alpha-actinin-2 properly localized to the Z-line in differentiating myotubes and its level was not altered in muscle biopsy. Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients. Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice. In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies. The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects. Dominant ACTN2 mutations were previously associated with cardiomyopathies, and our data demonstrate that specific mutations in the well-known Z-line regulator alpha-actinin-2 can cause a skeletal muscle disorder.


Assuntos
Actinina/genética , Músculo Esquelético/patologia , Miotonia Congênita/genética , Miotonia Congênita/patologia , Animais , Feminino , Humanos , Masculino , Camundongos , Mutação , Peixe-Zebra
20.
Exp Neurol ; 315: 52-59, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30738808

RESUMO

Patients with myotonia congenita suffer from muscle stiffness caused by muscle hyperexcitability. Although loss-of-function mutations in the ClC-1 muscle chloride channel have been known for 25 years to cause myotonia congenita, this discovery has led to little progress on development of therapy. Currently, treatment is primarily focused on reducing hyperexcitability by blocking Na+ current. However, other approaches such as increasing K+ currents might also be effective. For example, the K+ channel activator retigabine, which opens KCNQ channels, is effective in treating epilepsy because it causes hyperpolarization of the resting membrane potential in neurons. In this study, we found that retigabine greatly reduced the duration of myotonia in vitro. Detailed study of its mechanism of action revealed that retigabine had no effect on any of the traditional measures of muscle excitability such as resting potential, input resistance or the properties of single action potentials. Instead it appears to shorten myotonia by activating K+ current during trains of action potentials. Retigabine also greatly reduced the severity of myotonia in vivo, which was measured using a muscle force transducer. Despite its efficacy in vivo, retigabine did not improve motor performance of mice with myotonia congenita. There are a number of potential explanations for the lack of motor improvement in vivo including central nervous system side effects. Nonetheless, the striking effectiveness of retigabine on muscle itself suggests that activating potassium currents is an effective method to treat disorders of muscle hyperexcitability.


Assuntos
Carbamatos/uso terapêutico , Moduladores de Transporte de Membrana/uso terapêutico , Miotonia Congênita/tratamento farmacológico , Fenilenodiaminas/uso terapêutico , Potenciais de Ação/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Técnicas In Vitro , Canais de Potássio KCNQ/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Miotonia Congênita/psicologia , Desempenho Psicomotor/efeitos dos fármacos
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