Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy
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. 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. 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. Mutations in IGHMBP2 should be considered in the molecular genetic workup of patients with hereditary sensorimotor neuropathies, even in the absence of respiratory symptoms..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:84 |
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| Enthalten in: |
Neurology - 84(2015), 5, Seite 523-531 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schottmann, Gudrun [VerfasserIn] |
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| Links: |
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| RVK: |
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| doi: |
10.1212/WNL.0000000000001220 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy |
| 264 | 1 | |c 2015 | |
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| 520 | |a 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. 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. 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. Mutations in IGHMBP2 should be considered in the molecular genetic workup of patients with hereditary sensorimotor neuropathies, even in the absence of respiratory symptoms. | ||
| 540 | |a Nutzungsrecht: © 2015 American Academy of Neurology. | ||
| 650 | 4 | |a Mutation - genetics | |
| 650 | 4 | |a Peripheral Nervous System Diseases - diagnosis | |
| 650 | 4 | |a Hereditary Sensory and Motor Neuropathy - genetics | |
| 650 | 4 | |a Genes, Recessive - genetics | |
| 650 | 4 | |a Hereditary Sensory and Motor Neuropathy - diagnosis | |
| 650 | 4 | |a DNA-Binding Proteins - genetics | |
| 650 | 4 | |a Transcription Factors - genetics | |
| 650 | 4 | |a Axons - pathology | |
| 650 | 4 | |a Peripheral Nervous System Diseases - genetics | |
| 700 | 1 | |a Jungbluth, Heinz |4 oth | |
| 700 | 1 | |a Schara, Ulrike |4 oth | |
| 700 | 1 | |a Knierim, Ellen |4 oth | |
| 700 | 1 | |a Morales Gonzalez, Susanne |4 oth | |
| 700 | 1 | |a Gill, Esther |4 oth | |
| 700 | 1 | |a Seifert, Franziska |4 oth | |
| 700 | 1 | |a Norwood, Fiona |4 oth | |
| 700 | 1 | |a Deshpande, Charu |4 oth | |
| 700 | 1 | |a von Au, Katja |4 oth | |
| 700 | 1 | |a Schuelke, Markus |4 oth | |
| 700 | 1 | |a Senderek, Jan |4 oth | |
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