RESUMO
KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although KBTBD13 is expressed in cardiac muscle, cardiac involvement in NEM6 is unknown. Here, we constructed pedigrees of three families with the KBTBD13 p.R408C variant. In 65 evaluated patients, 12% presented with left ventricle dilatation, 29% with left ventricular ejection fraction< 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Five patients received an implantable cardioverter defibrillator, three cases of sudden cardiac death were reported. Linkage analysis confirmed cosegregation of the KBTBD13 p.R408C variant with the cardiac phenotype. Mouse studies revealed that (1) mice harboring the Kbtbd13 p.R408C variant display mild diastolic dysfunction; (2) Kbtbd13-deficient mice have systolic dysfunction. Hence, (1) KBTBD13 is associated with cardiac dysfunction and cardiomyopathy; (2) KBTBD13 should be added to the cardiomyopathy gene panel; (3) NEM6 patients should be referred to the cardiologist.
Assuntos
Cardiomiopatias , Proteínas Musculares , Animais , Humanos , Camundongos , Arritmias Cardíacas , Cardiomiopatias/genética , Morte Súbita Cardíaca/etiologia , Desfibriladores Implantáveis , Proteínas Musculares/genética , Volume Sistólico/fisiologia , Função Ventricular EsquerdaRESUMO
Nemaline myopathy (NEM) is a congenital myopathy that typically presents with proximal muscle weakness and hypotonia. To date, 13 genes have been associated with NEM. The Kelch repeat and BTB domain-containing protein 13 (KBTBD13) gene (KBTBD13)-related NEM is a rarely reported condition, and not a single case has been reported in Asia. Here, we report the case of a mother and daughter in China with NEM caused by a mutation (c.1222C>T) in KBTBD13. Their shared clinical phenotype is symmetrical muscle weakness in the arms and legs with childhood onset. Muscle magnetic resonance imaging showed the unique replacement mode of muscle with fibro-fatty tissue. Histopathological examination revealed the presence of fibers containing rod-shaped structures in the cytoplasm or under the sarcolemma. DNA sequencing analysis detected a heterozygous mutation (c.1222C>T) in KBTBD13 in this family. A founder effect for the variant may exist in the Low Countries of Belgium and the Netherlands, and the mutation may be a hotspot mutation in Europe, as it has not been reported in Asia. Our case study expands the spectrum of KBTBD13-related NEM.
Assuntos
Proteínas Musculares/genética , Mutação/genética , Miopatias da Nemalina/diagnóstico por imagem , Miopatias da Nemalina/genética , China , Feminino , Humanos , Pessoa de Meia-Idade , LinhagemRESUMO
Background: Congenital myopathies (CMs) are a diverse group of inherited muscle disorders with broad genotypic and phenotypic heterogeneity. While the literature on CM is available from European countries, comprehensive data from the Indian subcontinent is lacking. Objectives: This study aims to describe the clinical and histopathological characteristics of a cohort of genetically confirmed CMs from India and attempts to do phenotype-genotype correlation. Methods: A retrospective chart review of genetically confirmed CMs was evaluated between January 2016 and December 2020 at the neuromuscular clinic. The clinical, genetic, and follow-up data were recorded in a pre-structured proforma as per the medical records, and the data was analyzed. Results: A total of 31(M: Fâ=â14â:â17) unrelated patients were included. The median age at onset and duration of illness are 2.0(IQR:1-8) years and 6.0(IQR:3-10) years respectively. Clinical features observed were proximodistal weakness (54.8%), facial weakness (64.5%), and myopathic facies (54.8%), followed by ptosis (33.3%), and ophthalmoplegia (19.4%). Muscle histopathology was available in 38.7% of patients, and centronuclear myopathy was the most common histopathology finding. The pathogenic genetic variants were identified in RYR1 (29.0%), DNM2 (19.4%), SELENON (12.9%), KBTBD13 (9.7%), NEB (6.5%), and MYPN (6.5%) genes. Novel mutations were observed in 30.3% of the cohort. Follow-up details were available in 77.4% of children, and the median duration of follow-up and age at last follow-up was 4.5 (Range 0.5-11) years and 13 (Range 3-35) years, respectively. The majority were ambulant with minimal assistance at the last follow-up. Mortality was noted in 8.3% due to respiratory failure in Centronuclear myopathy 1 and congenital myopathy 3 with rigid spines (SELENON). Conclusion: This study highlights the various phenotypes and patterns of genetic mutations in a cohort of pediatric patients with congenital myopathy from India. Centronuclear myopathy was the most common histological classification and the mutations in RYR1 followed by DNM2 gene were the common pathogenic variants identified. The majority were independent in their activities of daily living during the last follow-up, highlighting the fact that the disease has slow progression irrespective of the genotype.
Assuntos
Miopatias Congênitas Estruturais , Humanos , Índia , Masculino , Criança , Feminino , Estudos Retrospectivos , Pré-Escolar , Lactente , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/fisiopatologia , Estudos de Associação Genética , Fenótipo , Adolescente , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Estudos de Coortes , MutaçãoRESUMO
Nemaline myopathy type 6 (NEM6), KBTBD13-related congenital myopathy is caused by mutated KBTBD13 protein that interacts improperly with thin filaments/actin, provoking impaired muscle-relaxation kinetics. We describe muscle morphology in 18 Dutch NEM6 patients and correlate it with clinical phenotype and pathophysiological mechanisms. Rods were found in in 85% of biopsies by light microscopy, and 89% by electron microscopy. A peculiar ring disposition of rods resulting in ring-rods fiber was observed. Cores were found in 79% of NEM6 biopsies by light microscopy, and 83% by electron microscopy. Electron microscopy also disclosed granulofilamentous protein material in 9 biopsies. Fiber type 1 predominance and prominent nuclear internalization were found. Rods were immunoreactive for α-actinin and myotilin. Areas surrounding the rods showed titin overexpression suggesting derangement of the surrounding sarcomeres. NEM6 myopathology hallmarks are prominent cores, rods including ring-rods fibers, nuclear clumps, and granulofilamentous protein material. This material might represent the histopathologic epiphenomenon of altered interaction between mutated KBTBD13 protein and thin filaments. We claim to classify KBTBD13-related congenital myopathy as rod-core myopathy.