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

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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

Fingerprint

Genetic Heterogeneity
Congenital Generalized Lipodystrophy
Hand
Mutation
Hereditary Spastic Paraplegia
Exons
Genes
Glycine-tRNA Ligase
Neuronopathy, Distal Hereditary Motor, Type V
Spastic paraplegia 17
Phenotype
Charcot-Marie-Tooth Disease
Genetic Testing
Mutation Rate
Heat-Shock Proteins

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)

Cite this

Rohkamm, B., Reilly, M. M., Lochmüller, H., Schlotter-Weigel, B., Barisic, N., Schöls, L., ... Auer-Grumbach, M. (2007). Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome. Journal of the Neurological Sciences, 263(1-2), 100-106. https://doi.org/10.1016/j.jns.2007.06.047

Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome. / Rohkamm, Barbara; Reilly, Mary M.; Lochmüller, Hanns; Schlotter-Weigel, Beate; Barisic, Nina; Schöls, Ludger; Nicholson, Garth; Pareyson, Davide; Laurà, Matilde; Janecke, Andreas R.; Miltenberger-Miltenyi, Gabriel; John, Elisabeth; Fischer, Carina; Grill, Franz; Wakeling, William; Davis, Mary; Pieber, Thomas R.; Auer-Grumbach, Michaela.

In: Journal of the Neurological Sciences, Vol. 263, No. 1-2, 15.12.2007, p. 100-106.

Research output: Contribution to journalArticle

Rohkamm, B, Reilly, MM, Lochmüller, H, Schlotter-Weigel, B, Barisic, N, Schöls, L, Nicholson, G, Pareyson, D, Laurà, M, Janecke, AR, Miltenberger-Miltenyi, G, John, E, Fischer, C, Grill, F, Wakeling, W, Davis, M, Pieber, TR & Auer-Grumbach, M 2007, 'Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome', Journal of the Neurological Sciences, vol. 263, no. 1-2, pp. 100-106. https://doi.org/10.1016/j.jns.2007.06.047
Rohkamm, Barbara ; Reilly, Mary M. ; Lochmüller, Hanns ; Schlotter-Weigel, Beate ; Barisic, Nina ; Schöls, Ludger ; Nicholson, Garth ; Pareyson, Davide ; Laurà, Matilde ; Janecke, Andreas R. ; Miltenberger-Miltenyi, Gabriel ; John, Elisabeth ; Fischer, Carina ; Grill, Franz ; Wakeling, William ; Davis, Mary ; Pieber, Thomas R. ; Auer-Grumbach, Michaela. / Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome. In: Journal of the Neurological Sciences. 2007 ; Vol. 263, No. 1-2. pp. 100-106.
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T1 - Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome

AU - Rohkamm, Barbara

AU - Reilly, Mary M.

AU - Lochmüller, Hanns

AU - Schlotter-Weigel, Beate

AU - Barisic, Nina

AU - Schöls, Ludger

AU - Nicholson, Garth

AU - Pareyson, Davide

AU - Laurà, Matilde

AU - Janecke, Andreas R.

AU - Miltenberger-Miltenyi, Gabriel

AU - John, Elisabeth

AU - Fischer, Carina

AU - Grill, Franz

AU - Wakeling, William

AU - Davis, Mary

AU - Pieber, Thomas R.

AU - Auer-Grumbach, Michaela

PY - 2007/12/15

Y1 - 2007/12/15

N2 - 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.

AB - 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.

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KW - Charcot-Marie-Tooth disease type 2D

KW - CMT2

KW - dHMN

KW - Distal hereditary motor neuropathy

KW - GARS

KW - HSPB1, HSPB8

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