Genetic malformations of cortical development
Genetic malformations of cortical development
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DOI：
10.1007/s00221-006-0501-z
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发表时间：
2006-08-01
影响因子：
2
通讯作者：
Marini, Carla
中科院分区：
文献类型：
--
作者：
Guerrini, Renzo;Marini, Carla
大脑皮层的畸形是发育障碍、严重癫痫和生殖缺陷的主要原因。高分辨率MRI技术的出现，促进了在体内鉴定的一大群皮质畸形表型。已经认识到由异常皮质发育引起的几种畸形综合征，并且已经鉴定出特定的致病基因缺陷。脑室周围结节性异位（PNH）是一种神经元迁移畸形，其中一部分神经元不能迁移到发育中的大脑皮质。X连锁PNH主要见于女性，常与局灶性癫痫有关。在所有家族性病例和约25%的散发性患者中均报告了FLNA突变。在患有小头畸形、严重延迟和早期癫痫发作的儿童中也报告了ARGEF2基因突变引起的PNH的罕见隐性形式。Lissencephaly-pachygyria和皮质下带状异位（SBH）是神经元迁移的疾病，代表了由LIS1或DCX基因突变引起的畸形谱。LIS1突变导致大脑后部区域更严重的畸形。大多数儿童有严重的发育迟缓和婴儿痉挛症，但记录在案的表型较轻，包括由于LIS1嵌合突变引起的后部SBH。DCX突变通常导致男性患者的前部优势无脑畸形和女性患者的SBH。DCX的突变也被发现在男性前SBH患者和女性亲属与正常的脑磁共振成像。常染色体隐性遗传无脑畸形伴小脑发育不全，伴有严重的延迟、张力减退和癫痫发作，与reelin（reelin）基因突变有关。基因型男性X连锁无脑畸形伴胼胝体发育不全和生殖器不清与ARX基因突变有关受影响的男孩有严重的延迟和癫痫发作与抑制爆发脑电图。过早死亡是常见的。携带者女性患者可出现孤立性胼胝体发育不全。在几种以多脑回为特征的综合征中，双侧大脑外侧裂周多脑回显示出遗传异质性，包括一些谱系与染色体Xq 28连锁，另一些谱系与常染色体显性或隐性遗传，以及一些患者与染色体22 q11.2缺失相关。大约65%的患者患有严重的癫痫。隐性双侧额顶叶多微回症与GPR56基因突变有关。癫痫通常存在于皮质畸形的患者中，并且往往是严重的，尽管其发病率和类型在不同的畸形中有所不同。据估计，高达40%的耐药性癫痫儿童有皮质畸形。然而，有关皮质畸形癫痫的病理生理机制仍然难以捉摸。
The malformations of the cerebral cortex represent a major cause of developmental disabilities, severe epilepsy and reproductive disadvantage. The advent of high-resolution MRI techniques has facilitated the in vivo identification of a large group of cortical malformation phenotypes. Several malformation syndromes caused by abnormal cortical development have been recognised and specific causative gene defects have been identified. Periventricular nodular heterotopia (PNH) is a malformation of neuronal migration in which a subset of neurons fails to migrate into the developing cerebral cortex. X-linked PNH is mainly seen in females and is often associated with focal epilepsy. FLNA mutations have been reported in all familial cases and in about 25% of sporadic patients. A rare recessive form of PNH due ARGEF2 gene mutations has also been reported in children with microcephaly, severe delay and early seizures. Lissencephaly-pachygyria and subcortical band heterotopia (SBH) are disorders of neuronal migration and represent a malformative spectrum resulting from mutations of either LIS1 or DCX genes. LIS1 mutations cause a more severe malformation in the posterior brain regions. Most children have severe developmental delay and infantile spasms, but milder phenotypes are on record, including posterior SBH owing to mosaic mutations of LIS1. DCX mutations usually cause anteriorly predominant lissencephaly in males and SBH in female patients. Mutations of DCX have also been found in male patients with anterior SBH and in female relatives with normal brain magnetic resonance imaging. Autosomal recessive lissencephaly with cerebellar hypoplasia, accompanied by severe delay, hypotonia, and seizures, has been associated with mutations of the reelin (RELN) gene. X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia in genotypic males is associated with mutations of the ARX gene. Affected boys have severe delay and seizures with suppression-burst EEG. Early death is frequent. Carrier female patients can have isolated corpus callosum agenesis. Among several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria shows genetic heterogeneity, including linkage to chromosome Xq28 in some pedigrees, autosomal dominant or recessive inheritance in others, and an association with chromosome 22q11.2 deletion in some patients. About 65% of patients have severe epilepsy. Recessive bilateral frontoparietal polymicrogyria has been associated with mutations of the GPR56 gene. Epilepsy is often present in patients with cortical malformations and tends to be severe, although its incidence and type vary in different malformations. It is estimated that up to 40% of children with drug-resistant epilepsy have a cortical malformation. However, the physiopathological mechanisms relating cortical malformations to epilepsy remain elusive.