Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females
Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females
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DOI：
10.1093/brain/awf248
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发表时间：
2002-11-01
期刊：
影响因子：
14.5
通讯作者：
Andermann, E
中科院分区：
文献类型：
--
作者：
D'Agostino, MD;Bernasconi, A;Andermann, E
皮质下带异位 (SBH) 或双皮质综合征是一种神经元迁移障碍，在男性中很少发生：迄今为止，至少有 110 例女性报道，但只有 11 例男性报道。该综合征通常与双皮质素 (DCX) (Xq22.3-q23) 基因突变相关，而与 LIS1 (17p13.3) 基因突变相关的情况则少得多。为了确定男性 SBH 的表型谱、遗传基础和基因型-表型相关性是否与女性相似，我们比较了 30 名个人评估的 SBH 男性和 60 名先前报道的 SBH 女性的临床、影像和分子特征。根据 MRI 结果，我们定义了以下带亚型：部分带，涉及一或两个脑叶；中间，涉及两个叶和第三个叶的一部分；弥漫性，严重累及三个或更多肺叶；厚脑回-SBH，其中后部 SBH 与前部厚脑回合并。分别对 23 名和 24 名患者进行了 DCX 和/或 LIS1 的核型分型和突变分析。男性 SBH 的临床表型范围与女性有很大重叠。 MRI 研究显示，SBH 的一些解剖亚型，例如部分和中间后部、厚回型 SBH 和以后部为主的弥漫带，更常见或仅出现在男性中。相反，经典弥漫性 SBH 和以前部为主的弥漫性条带在女性中更为常见。男性具有轻度或最严重的带亚型，这些亚型分别与正常/边缘智力和严重精神发育迟滞的过度表现相关。相反，以弥漫性带为主的女性大多表现出轻度或中度智力低下。 7 名患者 (29%) 存在 DCX 错义突变；其中四种是种系突变，而三种则有体细胞嵌合的证据。各一名患者 (4%) 发现了 LIS1 种系错义突变和 9p 染色体部分三体性。一名男性的 DCX 和 LIS1 基因中各有一个可能致病性内含子碱基变化。我们的研究表明，男性 SBH 是一种临床异质性综合征，大多是偶发性的。临床谱与女性 SBH 相似。然而，男性 DCX 和 LIS1 基因编码序列中更大的认知和神经放射学异质性以及迄今为止发现的少量突变与女性的研究结果不同。这表明了其他遗传机制，例如 DCX 或 LIS1 基因非编码区的突变、性腺或体细胞嵌合，以及其他基因的突变。
Subcortical band heterotopia (SBH) or double cortex syndrome is a neuronal migration disorder, which occurs very rarely in males: to date, at least 110 females but only 11 in males have been reported. The syndrome is usually associated with mutations in the doublecortin (DCX) (Xq22.3-q23) gene, and much less frequently in the LIS1 (17p13.3) gene. To determine whether the phenotypic spectrum, the genetic basis and genotype-phenotype correlations of SBH in males are similar to those in females, we compared the clinical, imaging and molecular features in 30 personally evaluated males and 60 previously reported females with SBH. Based on the MRI findings, we defined the following band subtypes: partial, involving one or two cerebral lobes; intermediate, involving two lobes and a portion of a third; diffuse, with substantial involvement of three or more lobes; and pachygyria-SBH, in which posterior SBH merges with anterior pachygyria. Karyo typing and mutation analysis of DCX and/or LIS1 were performed in 23 and 24 patients, respectively. The range of clinical phenotypes in males with SBH greatly overlapped that in females. MRI studies revealed that some anatomical subtypes of SBH, such as partial and intermediate posterior, pachygyria-SBH and diffuse bands with posterior predominance, were more frequently or exclusively present in males. Conversely, classical diffuse SBH and diffuse bands with anterior predominance were more frequent in females. Males had either mild or the most severe band subtypes, and these correlated with the over-representation of normal/borderline intelligence and severe mental retardation, respectively. Conversely, females who had predominantly diffuse bands exhibited mostly mild or moderate mental retardation. Seven patients (29%) had missense mutations in DCX; in four, these were germline mutations, whereas in three there was evidence for somatic mosaicism. A germline missense mutation of LIS1 and a partial trisomy of chromosome 9p were identified in one patient (4%) each. One male each had a possible pathogenic intronic base change in both DCX and LIS1 genes. Our study shows that SBH in males is a clinically heterogeneous syndrome, mostly occurring sporadically. The clinical spectrum is similar to that of females with SBH. However, the greater cognitive and neuroradiological heterogeneity and the small number of mutations identified to date in the coding sequences of the DCX and LIS1 genes in males differ from the findings in females. This suggests other genetic mechanisms such as mutations in the non-coding regions of the DCX or LIS1 genes, gonadal or somatic mosaicism, and finally mutations of other genes.