Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome

Barbara Rohkamm, Mary M. Reilly, Hanns Lochmüller, Beate Schlotter-Weigel, Nina Barisic, Ludger Schöls, Garth Nicholson, Davide Pareyson, Matilde Laurà, Andreas R. Janecke, Gabriel Miltenberger-Miltenyi, Elisabeth John, Carina Fischer, Franz Grill, William Wakeling, Mary Davis, Thomas R. Pieber, Michaela Auer-Grumbach

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Distal hereditary motor neuropathy type V (dHMN-V) and Charcot-Marie-Tooth syndrome (CMT) type 2 presenting with predominant hand involvement, also known as CMT2D and Silver syndrome (SS) are rare phenotypically overlapping diseases which can be caused by mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) and in the glycyl-tRNA synthetase encoding (GARS) genes. Mutations in the heat-shock proteins HSPB1 and HSPB8 can cause related distal hereditary motor neuropathies (dHMN) and are considered candidates for dHMN-V, CMT2, and SS. Design: To define the frequency and distribution of mutations in the GARS, BSCL2, HSPB1 and HSPB8 genes we screened 33 unrelated sporadic and familial patients diagnosed as either dHMN-V, CMT2D or SS. Exon 3 of the BSCL2 gene was screened in further 69 individuals with an unclassified dHMN phenotype or diagnosed as hereditary spastic paraplegia (HSP) complicated by pure motor neuropathy. Results: Four patients diagnosed with dHMN-V or SS carried known heterozygous BSCL2 mutations (N88S and S90L). In one dHMN-V patient we detected a putative GARS mutation (A57V). No mutations were detected in HSPB1 and HSPB8. The diagnostic yield gained in the series of 33 probands was 12% for BSCL2 mutations and 3% for GARS mutations. In the series of unclassified dHMN and complicated HSP cases no mutations were found. Conclusions: Our data confirm that most likely only two mutations (N88S, S90L) in exon 3 of BSCL2 may lead to dHMN-V or SS phenotypes. Mutations in GARS, HSPB1 and HSPB8. are not a common cause of dHMN-V, SS and CMT2D. We would therefore suggest that a genetic testing of dHMN-V and SS patients should begin with screening of exon 3 of the BSCL2 gene. Screening of the GARS gene is useful in patients with CMT2 with predominant hand involvement and dHMN-V. The rather low frequencies of BSCL2, GARS, HSPB1 and HSPB8 mutations in dHMN-V, CMT2D and SS patients strongly point to further genetic heterogeneity of these related disorders.

Original languageEnglish
Pages (from-to)100-106
Number of pages7
JournalJournal of the Neurological Sciences
Volume263
Issue number1-2
DOIs
Publication statusPublished - Dec 15 2007

Keywords

  • BSCL2
  • Charcot-Marie-Tooth disease type 2D
  • CMT2
  • dHMN
  • Distal hereditary motor neuropathy
  • GARS
  • HSPB1, HSPB8

ASJC Scopus subject areas

  • Ageing
  • Clinical Neurology
  • Surgery
  • Developmental Neuroscience
  • Neurology
  • Neuroscience(all)

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