目的:亨廷顿病(HD)是一种与亨廷顿(HTT)基因中CAG重复扩增相关的神经退行性疾病。在27和35之间的三核苷酸大小被认为是“中间”,不会引起HD的症状和体征。有文章声称否则,然而,仅发表具有HD表型的病例会带来显著的发表偏倚.我们的目标是确定是否有令人信服的证据表明中间重复(IA)引起HD。
方法:对先前发表的关于HTT中间重复序列大小的病例报告和来自荷兰的所有IA病例进行临床症状和体征回顾。
结果:在文献报道的10例病例中,有4例患者有亨廷顿病的临床表现和IA。在2001年至2012年之间,荷兰有1,690名患者接受了HD检测。60例IA中有一例具有类似HD的表型,但已经在病例报告中发表了。
结论:鉴于几个群体中间等位基因的高背景频率,患HD的可能性将对1-7%的正常人群产生巨大影响.IAs可能作为具有后续临床表现潜力的内表型存在。然而,鉴于缺乏令人信服的案例,缺乏令人信服的生物学证据证明中间等位基因的致病性,许多基因仍有待发现,我们发现,现在声称IAs可以导致HD还为时过早。我们建议对这组个体进行系统的随访,并在可能的情况下进行脑部病理学检查以确认或排除HD。
OBJECTIVE: Huntington\'s disease (HD) is a neurodegenerative disease associated with a CAG repeat expansion in the Huntingtin (HTT) gene. A trinucleotide size between 27 and 35 is considered \'intermediate\' and not to cause symptoms and signs of HD. There are articles claiming otherwise, however publishing only the cases that have a HD phenotype introduces a significant publication bias. Our objective is to determine if there is convincing evidence that intermediate repeats (IA) cause HD.
METHODS: Previously published case reports on HTT intermediate repeat sizes and all cases from the Netherlands with an IA were reviewed for clinical symptoms and signs.
RESULTS: Four patients had a clinical presentation of Huntington\'s disease and an IA out of ten reported cases in literature. Between 2001 and 2012, 1,690 patients were tested for HD in the Netherlands. One case out of 60 with an IA had a phenotype resembling HD, but had already been published in a case report.
CONCLUSIONS: Given the high background frequency of intermediate alleles in several populations, the possibility of developing HD would have huge implications for 1-7% of the normal population. It is possible that IAs present as an endophenotype with the potential of subsequent clinical manifestations. However, given the scarcity of convincing cases, the lack of convincing biological evidence for pathogenicity of intermediate alleles, and many genes still to be discovered for HD mimics, we find that it is premature to claim that IAs can cause HD. We recommend systematic follow up of this group of individuals and if possible brain pathology for confirmation or exclusion of HD.