Esmee S B van Kleef, Karlijn Bouman, Joery P F Molenaar, Josine M de Winter, Floor A M Duijkers, Filip Eftimov, Corien C Verschuuren-Bemelmans, Tineke van der Laan, Benno Küsters, Edoardo Malfatti, Erik-Jan Kamsteeg, Baziel G M van Engelen, Coen A C Ottenheijm, Jonne Doorduin, Nicol C Voermans
{"title":"A Likely Pathogenic variant in the KBTBD13 Gene: A Case Series of Three Patients with Nemaline Myopathy Type 6.","authors":"Esmee S B van Kleef, Karlijn Bouman, Joery P F Molenaar, Josine M de Winter, Floor A M Duijkers, Filip Eftimov, Corien C Verschuuren-Bemelmans, Tineke van der Laan, Benno Küsters, Edoardo Malfatti, Erik-Jan Kamsteeg, Baziel G M van Engelen, Coen A C Ottenheijm, Jonne Doorduin, Nicol C Voermans","doi":"10.3233/JND-230196","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Nemaline myopathy type 6 (NEM6) or KBTBD13-related congenital myopathy is the most prevalent type of nemaline myopathy in the Netherlands and is characterised by mild childhood-onset axial, proximal and distal muscle weakness with prominent neck flexor weakness combined with slowness of movements. The most prevalent variant in the Netherlands is the c.1222C > T p.(Arg408Cys) variant in the KBTBD13 gene, also called the Dutch founder variant.</p><p><strong>Objective: </strong>To provide a comprehensive clinical and functional characterisation of three patients to assess the pathogenicity of a newly identified variant in the KBTBD13 gene.</p><p><strong>Results: </strong>We present three cases (Patient 1: female, 76 years old; Patient 2: male, 63 years old; and his brother Patient 3: male, 61 years old) with a c.1222C > A p.(Arg408Ser) variant in the KBTBD13 gene. Patient 1 was also included previously in a histopathological study on NEM6. Symptoms of muscle weakness started in childhood and progressed to impaired functional abilities in adulthood. All three patients reported slowness of movements. On examination, they have mild axial, proximal and distal muscle weakness. None of the patients exhibited cardiac abnormalities. Spirometry in two patients showed a restrictive lung pattern. Muscle ultrasound showed symmetrically increased echogenicity indicating fatty replacement and fibrosis in a subset of muscles and histopathological analyses revealed nemaline rods and cores. Slower muscle relaxation kinetics with in vivo functional tests was observed. This was confirmed by in vitro functional tests showing impaired relaxation kinetics in isolated muscle fibres. We found a genealogic link between patient 1, and patient 2 and 3 nine generations earlier.</p><p><strong>Conclusions: </strong>The c.1222C > A p.(Arg408Ser) variant in the KBTBD13 gene is a likely pathogenic variant causing NEM6.</p>","PeriodicalId":16536,"journal":{"name":"Journal of neuromuscular diseases","volume":null,"pages":null},"PeriodicalIF":3.2000,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of neuromuscular diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3233/JND-230196","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Nemaline myopathy type 6 (NEM6) or KBTBD13-related congenital myopathy is the most prevalent type of nemaline myopathy in the Netherlands and is characterised by mild childhood-onset axial, proximal and distal muscle weakness with prominent neck flexor weakness combined with slowness of movements. The most prevalent variant in the Netherlands is the c.1222C > T p.(Arg408Cys) variant in the KBTBD13 gene, also called the Dutch founder variant.
Objective: To provide a comprehensive clinical and functional characterisation of three patients to assess the pathogenicity of a newly identified variant in the KBTBD13 gene.
Results: We present three cases (Patient 1: female, 76 years old; Patient 2: male, 63 years old; and his brother Patient 3: male, 61 years old) with a c.1222C > A p.(Arg408Ser) variant in the KBTBD13 gene. Patient 1 was also included previously in a histopathological study on NEM6. Symptoms of muscle weakness started in childhood and progressed to impaired functional abilities in adulthood. All three patients reported slowness of movements. On examination, they have mild axial, proximal and distal muscle weakness. None of the patients exhibited cardiac abnormalities. Spirometry in two patients showed a restrictive lung pattern. Muscle ultrasound showed symmetrically increased echogenicity indicating fatty replacement and fibrosis in a subset of muscles and histopathological analyses revealed nemaline rods and cores. Slower muscle relaxation kinetics with in vivo functional tests was observed. This was confirmed by in vitro functional tests showing impaired relaxation kinetics in isolated muscle fibres. We found a genealogic link between patient 1, and patient 2 and 3 nine generations earlier.
Conclusions: The c.1222C > A p.(Arg408Ser) variant in the KBTBD13 gene is a likely pathogenic variant causing NEM6.
期刊介绍:
The Journal of Neuromuscular Diseases aims to facilitate progress in understanding the molecular genetics/correlates, pathogenesis, pharmacology, diagnosis and treatment of acquired and genetic neuromuscular diseases (including muscular dystrophy, myasthenia gravis, spinal muscular atrophy, neuropathies, myopathies, myotonias and myositis). The journal publishes research reports, reviews, short communications, letters-to-the-editor, and will consider research that has negative findings. The journal is dedicated to providing an open forum for original research in basic science, translational and clinical research that will improve our fundamental understanding and lead to effective treatments of neuromuscular diseases.