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
Institute of Human Genetics, Medical University Graz, Austria.
J Neurol Sci. 2007 Dec 15;263(1-2):100-6. doi: 10.1016/j.jns.2007.06.047. Epub 2007 Jul 30.
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.
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.
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.
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.
Ⅴ型远端遗传性运动神经病（dHMN-Ⅴ）以及主要累及手部的夏科-马里-图斯综合征（CMT）2型，即CMT2D和西尔弗综合征（SS），是罕见的表型重叠疾病，可由贝拉尔迪内利-塞普先天性脂肪营养不良2（BSCL2）基因和甘氨酰-tRNA合成酶编码（GARS）基因突变引起。热休克蛋白HSPB1和HSPB8的突变可导致相关的远端遗传性运动神经病（dHMN），被认为是dHMN-Ⅴ、CMT2和SS的候选致病基因。
为确定GARS、BSCL2、HSPB1和HSPB8基因的突变频率及分布，我们对33例诊断为dHMN-Ⅴ、CMT2D或SS的散发性和家族性非亲缘患者进行了筛查。对另外69例未分类的dHMN表型或诊断为遗传性痉挛性截瘫（HSP）合并纯运动神经病的个体，筛查了BSCL2基因的第3外显子。
4例诊断为dHMN-Ⅴ或SS的患者携带已知的杂合BSCL2突变（N88S和S90L）。在1例dHMN-Ⅴ患者中，我们检测到一个假定的GARS突变（A57V）。未在HSPB1和HSPB8中检测到突变。在33例先证者系列中，BSCL2突变的诊断率为12%，GARS突变为3%。在未分类的dHMN和复杂HSP病例系列中未发现突变。
我们的数据证实，BSCL2基因第3外显子中很可能只有两个突变（N88S、S90L）可导致dHMN-Ⅴ或SS表型。GARS、HSPB1和HSPB8的突变并非dHMN-Ⅴ、SS和CMT2D的常见病因。因此，我们建议对dHMN-Ⅴ和SS患者进行基因检测时，应首先筛查BSCL2基因的第3外显子。对主要累及手部的CMT2和dHMN-Ⅴ患者，筛查GARS基因是有用的。dHMN-Ⅴ、CMT2D和SS患者中BSCL2、GARS、HSPB1和HSPB8突变的频率较低，这强烈表明这些相关疾病存在进一步的遗传异质性。
