Sara Nagy, Alistair T Pagnamenta, Elisa Cali, Hilde M H Braakman, Juerd Wijntjes, Benno Kusters, Marc Gotkine, Orly Elpeleg, Vardiella Meiner, Jerica Lenberg, Kristen Wigby, Jennifer Friedman, Luke D Perry, Alexander M Rossor, Anna Uhrova Meszarosova, Dana Thomasova, Saiju Jacob, Mary O'Driscoll, Lenika De Simone, Dorothy K Grange, Richard Sommerville, Zahra Firoozfar, Shahryar Alavi, Mahta Mazaheri, Jevin M Parmar, Phillipa J Lamont, Veronica Pini, Anna Sarkozy, Francesco Muntoni, Gianina Ravenscroft, Eppie Jones, Declan O'Rourke, Melissa Nel, Jeannine M Heckmann, Michelle Kvalsund, Musambo M Kapapa, Somwe Wa Somwe, David R Bearden, Arman Çakar, Anne-Marie Childs, Rita Horvath, Mary M Reilly, Henry Houlden, Reza Maroofian
{"title":"Autosomal recessive <i>VWA1</i>-related disorder: comprehensive analysis of phenotypic variability and genetic mutations.","authors":"Sara Nagy, Alistair T Pagnamenta, Elisa Cali, Hilde M H Braakman, Juerd Wijntjes, Benno Kusters, Marc Gotkine, Orly Elpeleg, Vardiella Meiner, Jerica Lenberg, Kristen Wigby, Jennifer Friedman, Luke D Perry, Alexander M Rossor, Anna Uhrova Meszarosova, Dana Thomasova, Saiju Jacob, Mary O'Driscoll, Lenika De Simone, Dorothy K Grange, Richard Sommerville, Zahra Firoozfar, Shahryar Alavi, Mahta Mazaheri, Jevin M Parmar, Phillipa J Lamont, Veronica Pini, Anna Sarkozy, Francesco Muntoni, Gianina Ravenscroft, Eppie Jones, Declan O'Rourke, Melissa Nel, Jeannine M Heckmann, Michelle Kvalsund, Musambo M Kapapa, Somwe Wa Somwe, David R Bearden, Arman Çakar, Anne-Marie Childs, Rita Horvath, Mary M Reilly, Henry Houlden, Reza Maroofian","doi":"10.1093/braincomms/fcae377","DOIUrl":null,"url":null,"abstract":"<p><p>A newly identified subtype of hereditary axonal motor neuropathy, characterized by early proximal limb involvement, has been discovered in a cohort of 34 individuals with biallelic variants in von Willebrand factor A domain-containing 1 (<i>VWA1</i>). This study further delineates the disease characteristics in a cohort of 20 individuals diagnosed through genome or exome sequencing, incorporating neurophysiological, laboratory and imaging data, along with data from previously reported cases across three different studies. Newly reported clinical features include hypermobility/hyperlaxity, axial weakness, dysmorphic signs, asymmetric presentation, dystonic features and, notably, upper motor neuron signs. Foot drop, foot deformities and distal leg weakness followed by early proximal leg weakness are confirmed to be initial manifestations. Additionally, this study identified 11 novel <i>VWA1</i> variants, reaffirming the 10 bp insertion-induced p.Gly25ArgfsTer74 as the most prevalent disease-causing allele, with a carrier frequency of ∼1 in 441 in the UK and Western European population. Importantly, VWA1-related pathology may mimic various neuromuscular conditions, advocating for its inclusion in diverse gene panels spanning hereditary neuropathies to muscular dystrophies. The study highlights the potential of lower quality control filters in exome analysis to enhance diagnostic yield of VWA1 disease that may account for up to 1% of unexplained hereditary neuropathies.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535570/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain communications","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/braincomms/fcae377","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
A newly identified subtype of hereditary axonal motor neuropathy, characterized by early proximal limb involvement, has been discovered in a cohort of 34 individuals with biallelic variants in von Willebrand factor A domain-containing 1 (VWA1). This study further delineates the disease characteristics in a cohort of 20 individuals diagnosed through genome or exome sequencing, incorporating neurophysiological, laboratory and imaging data, along with data from previously reported cases across three different studies. Newly reported clinical features include hypermobility/hyperlaxity, axial weakness, dysmorphic signs, asymmetric presentation, dystonic features and, notably, upper motor neuron signs. Foot drop, foot deformities and distal leg weakness followed by early proximal leg weakness are confirmed to be initial manifestations. Additionally, this study identified 11 novel VWA1 variants, reaffirming the 10 bp insertion-induced p.Gly25ArgfsTer74 as the most prevalent disease-causing allele, with a carrier frequency of ∼1 in 441 in the UK and Western European population. Importantly, VWA1-related pathology may mimic various neuromuscular conditions, advocating for its inclusion in diverse gene panels spanning hereditary neuropathies to muscular dystrophies. The study highlights the potential of lower quality control filters in exome analysis to enhance diagnostic yield of VWA1 disease that may account for up to 1% of unexplained hereditary neuropathies.