Central nervous system involvement in severe congenital neutropenia:: neurological and neuropsychological abnormalities associated with specific HAX1 mutations
Central nervous system involvement in severe congenital neutropenia:: neurological and neuropsychological abnormalities associated with specific HAX1 mutations
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DOI：
10.1111/j.1365-2796.2008.01982.x
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发表时间：
2008-10-01
影响因子：
11.1
通讯作者：
Henter, J-I
中科院分区：
文献类型：
--
作者：
Carlsson, G.;van't Hooft, I.;Henter, J-I
目标.最近在瑞典北方Kostmann家族的严重先天性中性粒细胞减少症患者中发现了HAX 1基因的纯合突变。我们的观察结果表明，这些患者也发展神经和神经心理学障碍。对Kostmann家族的存活患者和两名与该家族无关的患者进行了详细的临床研究和突变分析，沿着对HAX 1剪接变异体在正常人体组织中表达的研究。6名Kostmann家族患者中的5名和另1名来自瑞典北方的患者携带纯合HAX 1突变（568 C-> T，Q190 X），1名携带杂合ELA 2基因突变。一名库尔德血统的瑞典患者携带替代纯合HAX 1突变（131 G-> A，W 44 X）。所有三名Q190 X突变的患者都存活并可进行评估，他们都患有神经系统疾病，认知功能下降，四名达到10岁的患者中有三名患有癫痫。相反，ELA 2和W 44 X HAX 1突变的患者分别没有表现出明显的神经系统异常。此外，在正常人体组织（包括大脑）中鉴定了两种可选的HAX 1剪接变体。两个转录本都含有外显子5，含有Q190 X突变，而外显子2的5'端含有W 44 X突变，从第二个转录本中剪接出来。我们首次描述了Kostmann病患者的神经系统和神经心理学异常。这些中枢神经系统症状似乎与特定的HAX 1突变有关。
Objectives. Homozygous mutations in the HAX1 gene were recently identified in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden. Our observations suggested that these patients also develop neurological and neuropsychological symptoms.Methods. Detailed clinical studies and mutation analyses were performed in the surviving patients belonging to the Kostmann kindred and in two patients not related to this family, along with studies of HAX1 splice variant expression in normal human tissues.Results. Five of six Kostmann family patients and one other patient from northern Sweden harboured homozygous HAX1 mutations (568C -> T, Q190X) and one carried a heterozygous ELA2 gene mutation. One Swedish patient of Kurdish extraction carried alternative homozygous HAX1 mutations (131G -> A, W44X). All the three patients with Q190X mutations who were alive and available for evaluation developed neurological disease with decreased cognitive function, and three of four patients who reached 10 years developed epilepsy. In contrast, the patients with the ELA2 and W44X HAX1 mutations, respectively, showed no obvious neurological abnormalities. Moreover, two alternative HAX1 splice variants were identified in normal human tissues, including the brain. Both transcripts contained exon 5, harbouring the Q190X mutation, whereas the 5' end of exon 2 containing the W44X mutation was spliced out from the second transcript.Conclusions. We describe neurological and neuropsychological abnormalities for the first time in Kostmann disease patients. These central nervous system symptoms appear to be associated with specific HAX1 mutations.