Dierick Ines, Baets Jonathan, Irobi Joy, Jacobs An, De Vriendt Els, Deconinck Tine, Merlini Luciano, Van den Bergh Peter, Rasic Vedrana Milic, Robberecht Wim, Fischer Dirk, Morales Raul Juntas, Mitrovic Zoran, Seeman Pavel, Mazanec Radim, Kochanski Andrzej, Jordanova Albena, Auer-Grumbach Michaela, Helderman-van den Enden A T J M, Wokke John H J, Nelis Eva, De Jonghe Peter, Timmerman Vincent
Peripheral Neuropathy Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium.
Brain. 2008 May;131(Pt 5):1217-27. doi: 10.1093/brain/awn029. Epub 2008 Mar 5.
Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.
远端遗传性运动神经病（HMN）是一组临床和遗传异质性疾病，影响脊髓α运动神经元。自2001年以来，已鉴定出六个不同基因的突变与常染色体显性遗传性远端HMN相关；这些基因分别是甘氨酰 - tRNA合成酶（GARS）、动力蛋白激活蛋白1（DCTN1）、小分子热休克蛋白27 kDa 1（HSPB1）、小分子热休克蛋白22 kDa 8（HSPB8）、贝拉尔迪内利 - 西普先天性脂肪营养不良（BSCL2）和senataxin（SETX）。此外，在几个患有复杂和非典型常染色体显性遗传性运动神经元疾病的巴西家族中发现了与（VAMP）相关蛋白B和C（VAPB）的突变。我们在一组112例诊断为远端运动神经病的家族性和散发性患者中研究了这七个基因的突变分布，在17例患者中发现了HSPB8、HSPB1、BSCL2和SETX中的九种不同致病突变，其中10种先前已有报道。在GARS、DCTN1和VAPB中未发现突变。HSPB8、HSPB1、BSCL2和SETX突变患者的表型特征符合远端HMN分类，只有一个例外；HSPB1 C末端突变与上运动神经元体征相关。此外，我们提供了传递HSPB1突变时存在遗传镶嵌现象的证据。这项在大量家族性和散发性远端HMN患者队列中进行的研究，明确证实了远端HMN的遗传和表型异质性，并为开发该组疾病诊断性突变筛查算法提供了基础。
