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

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.

• Authors: 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
• Journal: Journal of the neurological sciences (J Neurol Sci) Vol. 263 Issue 1-2 Pg. 100-6 (Dec 15 2007) ISSN: 0022-510X [Print] Netherlands
• PMID: 17663003 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• BSCL2 protein, human
• Cell Cycle Proteins
• GTP-Binding Protein gamma Subunits
• HSP27 Heat-Shock Proteins
• HSPB1 protein, human
• HSPB8 protein, human
• Heat-Shock Proteins
• MAD2L1BP protein, human
• Molecular Chaperones
• Neoplasm Proteins
• Nuclear Proteins
• Protein Serine-Threonine Kinases

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Adolescent
• Adult
• Aged
• Cell Cycle Proteins (genetics)
• DNA Mutational Analysis
• Family Health
• Female
• GTP-Binding Protein gamma Subunits (genetics)
• Genetic Heterogeneity
• HSP27 Heat-Shock Proteins
• Hand (physiopathology)
• Heat-Shock Proteins (genetics)
• Hereditary Sensory and Motor Neuropathy (complications, genetics)
• Humans
• Male
• Middle Aged
• Molecular Chaperones
• Mutation (genetics)
• Neoplasm Proteins (genetics)
• Nuclear Proteins (genetics)
• Protein Serine-Threonine Kinases (genetics)
• Spastic Paraplegia, Hereditary (complications, genetics)
• Syndrome