Gudrun Schottmann1, Heinz Jungbluth1, Ulrike Schara1, Ellen Knierim1, Susanne Morales Gonzalez1, Esther Gill1, Franziska Seifert1, Fiona Norwood1, Charu Deshpande1, Katja von Au1, Markus Schuelke2, Jan Senderek1. 1. From the Department of Neuropediatrics and the NeuroCure Clinical Research Center (G.S., E.K., S.M.G., E.G., F.S., M.S.), and Department of Neuropediatrics/SPZ (K.v.A.), Charité-Universitätsmedizin Berlin, Germany; Department of Paediatric Neurology-Neuromuscular Service (H.J.), Evelina Children's Hospital, St Thomas' Hospital, the Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section and the Department of Clinical Neuroscience, IoP, King's College, London, UK; Department of Neuropediatrics, Developmental Neurology and Social Pediatrics (U.S.), University of Essen, Germany; Department of Neurology (F.N.), King's College Hospital, London; Department of Clinical Genetics (C.D.), Guy's Hospital, London, UK; and Friedrich Baur Institute (J.S.), Department of Neurology, Ludwig Maximilians University Munich, Germany. 2. From the Department of Neuropediatrics and the NeuroCure Clinical Research Center (G.S., E.K., S.M.G., E.G., F.S., M.S.), and Department of Neuropediatrics/SPZ (K.v.A.), Charité-Universitätsmedizin Berlin, Germany; Department of Paediatric Neurology-Neuromuscular Service (H.J.), Evelina Children's Hospital, St Thomas' Hospital, the Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section and the Department of Clinical Neuroscience, IoP, King's College, London, UK; Department of Neuropediatrics, Developmental Neurology and Social Pediatrics (U.S.), University of Essen, Germany; Department of Neurology (F.N.), King's College Hospital, London; Department of Clinical Genetics (C.D.), Guy's Hospital, London, UK; and Friedrich Baur Institute (J.S.), Department of Neurology, Ludwig Maximilians University Munich, Germany. markus.schuelke@charite.de.
Abstract
OBJECTIVE: To identify the cause of sensorimotor neuropathy in a cohort of patients with genetically unsolved neuropathies (57 families with a total of 74 members) in whom hitherto known disease genes had been excluded. METHODS: We used autozygosity mapping or haplotype analysis to delineate potential disease loci in informative families. For mutation detection, we used either whole-exome sequencing or Sanger sequencing of positional candidates. Subsequently, a larger cohort was specifically screened for IGHMBP2 mutations. The pathogenicity of a splice-site mutation was verified in cultured patient skin fibroblasts on the messenger RNA level and by Western blot. RESULTS: We report on 5 patients with neuropathy from 3 families who carried truncating mutations in IGHMBP2. Contrary to the "classic" phenotype, they did not manifest with respiratory distress, but with progressive sensorimotor neuropathy. Only one patient required nocturnal mask ventilation, while 4 others maintained normal respiratory function by the age of 14, 18, 22, and 37 years. Three patients were still able to walk independently. All patients had a predominantly axonal sensorimotor neuropathy with subsequent muscle atrophy, but without obvious sensory symptoms. Two patients had signs of autonomic neuropathy. CONCLUSIONS: Mutations in IGHMBP2 should be considered in the molecular genetic workup of patients with hereditary sensorimotor neuropathies, even in the absence of respiratory symptoms.
OBJECTIVE: To identify the cause of sensorimotor neuropathy in a cohort of patients with genetically unsolved neuropathies (57 families with a total of 74 members) in whom hitherto known disease genes had been excluded. METHODS: We used autozygosity mapping or haplotype analysis to delineate potential disease loci in informative families. For mutation detection, we used either whole-exome sequencing or Sanger sequencing of positional candidates. Subsequently, a larger cohort was specifically screened for IGHMBP2 mutations. The pathogenicity of a splice-site mutation was verified in cultured patient skin fibroblasts on the messenger RNA level and by Western blot. RESULTS: We report on 5 patients with neuropathy from 3 families who carried truncating mutations in IGHMBP2. Contrary to the "classic" phenotype, they did not manifest with respiratory distress, but with progressive sensorimotor neuropathy. Only one patient required nocturnal mask ventilation, while 4 others maintained normal respiratory function by the age of 14, 18, 22, and 37 years. Three patients were still able to walk independently. All patients had a predominantly axonal sensorimotor neuropathy with subsequent muscle atrophy, but without obvious sensory symptoms. Two patients had signs of autonomic neuropathy. CONCLUSIONS: Mutations in IGHMBP2 should be considered in the molecular genetic workup of patients with hereditary sensorimotor neuropathies, even in the absence of respiratory symptoms.
Authors: Thomas A Cassini; Laura Duncan; Lynette C Rives; John H Newman; John A Phillips; Mary E Koziura; Jennifer Brault; Rizwan Hamid; Joy Cogan Journal: Mol Genet Genomic Med Date: 2019-04-25 Impact factor: 2.183
Authors: Pedro J Tomaselli; Alejandro Horga; Alexander M Rossor; Zane Jaunmuktane; Andrea Cortese; Julian C Blake; Natalia Zarate-Lopez; Henry Houlden; Mary M Reilly Journal: Neuromuscul Disord Date: 2018-08-29 Impact factor: 4.296