CMT2D and Silver Syndrome

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J Neurol Sci. 2007 Jul 27

Further evidence for genetic heterogeneity of distal HMN type V,

CMT2 with predominant hand involvement and Silver syndrome.

Rohkamm B, Reilly MM, Lochmüller H, Schlotter-Weigel B, Barisic N,

Schöls L, Nicholson G, Pareyson D, Laurà M, Janecke AR, Miltenberger-

Miltenyi G, E, Fischer C, Grill F, Wakeling W, M, Pieber

TR, Auer-Grumbach M.

Institute of Human Genetics, Medical University Graz, Austria;

Department of Internal Medicine, Diabetes and Metabolism, Medical

University Graz, Austria.

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.