Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with pred

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J Neurol Sci. 2007 Dec 15;263(1-2):100-6.

Further evidence for genetic heterogeneity of distal HMN type V, CMT2

with predominant hand involvement and Silver syndrome.

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

Schols L, Nicholson G, Pareyson D, 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.

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.