Masruha Marcelo R, Caboclo Luis O S F, Carrete Henrique, Cendes Iscia L, Rodrigues Murilo G, Garzon Eliana, Yacubian Elza M T, Sakamoto Américo C, Sheen Volney, Harney Megan, Neal Jason, Hill R Sean, Bodell Adria, Walsh Christopher, Vilanova Luiz C P
Department of Neurology, Federal University of Sao Paulo, Sao Paulo, Brazil.
Epilepsia. 2006 Jan;47(1):211-4. doi: 10.1111/j.1528-1167.2006.00390.x.
Familial periventricular heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray-matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant pattern. Heterozygotic female patients usually remain asymptomatic until the second or third decade of life, when they may have predominantly focal seizures, whereas hemizygotic male fetuses typically die in utero. Recent studies have also reported mutations in FLNA in male patients with PH who are cognitively normal. We describe PH in three male siblings with PH due to FLNA, severe developmental regression, and West syndrome.
The study includes the three affected brothers and their parents. Video-EEG recordings and magnetic resonance image (MRI) scanning were performed on all individuals. Mutations for FLNA were detected by using polymerase chain reaction (PCR) on genomic DNA followed by single-stranded conformational polymorphism (SSCP) analysis or sequencing.
Two of the siblings are monozygotic twins, and all had West syndrome with hypsarrhythmia on EEG. MRI of the brain revealed periventricular nodules of cerebral gray-matter intensity, typical for PH. Mutational analyses demonstrated a cytosine-to-thymidine missense mutation (c. C1286T), resulting in a threonine-to-methionine amino acid substitution in exon 9 of the FLNA gene.
The association between PH and West syndrome, to our knowledge, has not been previously reported. Males with PH have been known to harbor FLNA mutations, although uniformly, they either show early lethality or survive and have a normal intellect. The current studies show that FLNA mutations can cause periventricular heterotopia, developmental regression, and West syndrome in male patients, suggesting that this type of FLNA mutation may contribute to severe neurologic deficits.
家族性室周异位（PH）是一种神经元迁移障碍疾病，会导致沿侧脑室壁出现多个灰质结节。先前的研究表明，细丝蛋白A（FLNA）基因突变可通过X连锁显性模式导致PH。杂合子女性患者通常在生命的第二个或第三个十年之前无症状，此时她们可能主要出现局灶性癫痫发作，而半合子男性胎儿通常在子宫内死亡。最近的研究还报告了认知正常的PH男性患者中存在FLNA基因突变。我们描述了三名因FLNA基因突变导致PH、严重发育倒退和韦斯特综合征的男性同胞。
该研究包括三名受影响的兄弟及其父母。对所有个体进行了视频脑电图记录和磁共振成像（MRI）扫描。通过对基因组DNA进行聚合酶链反应（PCR），随后进行单链构象多态性（SSCP）分析或测序，检测FLNA基因突变。
其中两名同胞是同卵双胞胎，所有人脑电图均显示有高峰失律的韦斯特综合征。脑部MRI显示脑室周围有灰质密度的结节，这是PH的典型表现。突变分析显示存在一个胞嘧啶到胸腺嘧啶的错义突变（c.C1286T），导致FLNA基因第9外显子中的苏氨酸到蛋氨酸的氨基酸替换。
据我们所知，PH与韦斯特综合征之间的关联此前尚未见报道。已知患有PH的男性携带FLNA基因突变，尽管他们要么表现为早期致死，要么存活且智力正常。目前的研究表明，FLNA基因突变可导致男性患者出现室周异位、发育倒退和韦斯特综合征，提示这种类型的FLNA突变可能导致严重的神经功能缺陷。
