A novel genetic locus for benign familial infantile seizures maps to chromosome 1p36.12‐p35.1
A novel genetic locus for benign familial infantile seizures maps to chromosome 1p36.12‐p35.1
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良性家族性婴儿癫痫发作的新基因位点映射到染色体 1p36.12-p35.1
DOI：
10.1111/j.1399-0004.2008.01092.x
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发表时间：
2008
影响因子：
3.5
通讯作者：
B. Tang
中科院分区：
文献类型：
--
作者：
Hy Li;Nan Li;Hong Jiang;Lu Shen;Jifeng Guo;Ruxu Zhang;Kun Xia;Q. Pan;X. Zi;B. Tang
致编辑：良性家族性婴儿惊厥（Benign familial infant seizures，BFIS）是一种常染色体显性遗传的特发性癫痫综合征，以无热性部分性惊厥伴或不伴继发全身强直阵挛性惊厥为特征，起病年龄3 ~ 10个月，病程良性，精神发育正常。受BFIS影响的患者通常神经系统检查正常，生化和神经放射学检查无变化（1，2）。迄今为止，已经确定了三个BFIS易感位点，19 q12-q13.1，16 p12-q12和2 q24。进一步的研究表明可能存在其他基因座（3-5）。我们在这里报告一个家庭的中国血统的影响与BFIS和映射到一个不同的致病基因座从以前建立的研究。所有患者和未受影响的家庭成员都对临床和遗传研究给予了知情同意。该家庭的8名成员（4名女性和4名男性）被诊断为BFIS。神经系统检查、血清生化测定（总蛋白、电解质、葡萄糖、乳酸脱氢酶、尿酸等），对所有现有的家庭成员进行脑电图（EEG）、脑计算机断层扫描（CT）和/或磁共振成像（MRI）检查。癫痫发作时的年龄为3 ~ 10个月。先证者（图1，III：6），31岁，正常妊娠后足月出生。在6个月大时，他发生了无热性惊厥，包括凝视、眼睛偏斜、面部局灶性阵挛，随后是继发性全身性阶段伴肌张力亢进、四肢阵挛、发绀和尿失禁。发作时间为30 s ~ 2 min，多为丛集性发作，每天发作3-10次。发作间期EEG、脑CT和MRI均正常。血清生化及染色体核型正常。丙戊酸钠治疗有效。他的癫痫在3岁时自发缓解。从可用的家庭成员中采集血液样本。外周血淋巴细胞G显带核型分析正常。从外周血白细胞中提取基因组DNA样品，首先用位于染色体19 q12 -13.1、16 p12-q12和2 q24的微卫星标记进行检测。连锁分析显示，两点对数比值（LOD）评分为负（表1），从而排除了该BFIS家族与三个已知易感基因座的连锁。随后使用ABI Prism Linkage Mapping Set第2版（Applied Biosystems，Foster City，CA）的382个荧光标记的微卫星标记进行全基因组扫描。在重组分数y 1/4 0时，在标记D1 S2674处获得的最大两点LOD评分为3.14（表1）。利用标记D1 S2702-D1 S2674-D1 S2830在性别平均连锁图上进行的多点连锁分析证实了这一连锁关系，在D1 S2674处的最大LOD值为3.27。在所有受影响的个体中，一个特定的单倍型被鉴定为与疾病表型共分离（图1）。基于重组事件，通过参考NCBI Map Viewer Build 34，将潜在致病基因定位到从D1 S2864延伸至D1 S2830的12.4-cM区间，对应于1p36.12-p35.1。1996年，Auburger等人（6）证实了一种常染色体显性形式的阵发性舞蹈徐动症/痉挛，发病年龄在2 - 15岁之间，由体育锻炼和情绪压力等因素引起。它也位于D1 S443和D1 S197之间的1 p，但距离基因座1p36.12-p35.1约11.07 cM。发病年龄、临床特征和遗传图谱的差异表明它们可能是两种不同的疾病。一个中国人BFIS家系定位于1p36.12-p35.1位点
To the Editor: Benign familial infantile seizures (BFIS), formerly named benign familial infantile convulsions, is an autosomal dominant idiopathic epilepsy syndrome characterized by afebrile partial seizures with or without secondary generalized tonic-clonic seizures, age at onset from3 to 10 months, a benign course and normal psychomotor development. Patients affected with BFIS usually have a normal neurological examination and no changes in biochemical and neuroradiological investigations (1, 2). To date, three susceptibility loci of BFIS have been identified, 19q12-q13.1, 16p12-q12 and 2q24. Further investigations have indicated that other loci may exist (3–5). We report here a family of Chinese origin affected with BFIS and mapped to a different causative locus from previously established studies. All patients and unaffected members of the family gave informed consent to the clinical and genetic studies. Eight individuals (four female and four male) of the family were diagnosed as having BFIS. Neurological examination, serum biochemical determination (total protein, electrolytes, glucose, lactic dehydrogenase, uric acid, etc.), electroencephalogram (EEG), brain computed tomography (CT) and/or magnetic resonance imaging (MRI) were performed for all existing familymembers. No demonstrable underlying pathologywas observed.Age at seizure onset ranged from 3 to 10 months of life. The proband (Fig. 1, III:6), 31 years old at the timeof our study, was born at full term after normal pregnancy. At age 6 months, he experienced afebrile seizures, including staring, eye deviation, focal clonus of the face, followed by secondarily generalized phase with hypertonia, extremities clonus, cyanosis and urinary incontinence. The seizures, lasting from 30 s to 2 min in one attack, occurred mainly in clusters with 3–10 episodes per day. Interictal EEG, brain CT and MRI were classified as normal. Serum biochemical determination and chromosome karyotype were normal. Treatment with sodium valproate was effective. His seizures spontaneously remitted by 3 years of age. Blood samples were collected from available family members. Karyotype analysis of peripheral lymphocytes by G-banding was normal. Genomic DNA samples were extracted from peripheral blood leukocytes and tested first with microsatellite markers situated at chromosome 19q12-13.1, 16p12-q12 and 2q24. Linkage analysis showed that two-point logarithm of odds (LOD) scores were negative (Table 1), thereby excluding this BFIS family from linkage to the three known susceptibility loci. Genome-wide scan was subsequently performed using 382 fluorescencelabeled microsatellite markers of the ABI Prism Linkage Mapping Set, version 2 (Applied Biosystems, Foster City, CA). At recombination fraction y 1⁄4 0, a maximum two-point LOD score of 3.14 was obtained at marker D1S2674 (Table 1). Multipoint linkage analyses with markers D1S2702-D1S2674-D1S2830 on the sexaveraged linkage map confirmed the linkage, with a maximum LOD score of 3.27 at D1S2674. A particular single haplotype was identified to cosegregate with the disease phenotype in all affected individuals (Fig. 1). Based on recombination events, the underlying causative gene was mapped to a 12.4-cM interval extending from D1S2864 to D1S2830, corresponding to 1p36.12-p35.1 by referring to NCBI Map Viewer Build 34. In 1996,Auburger et al. (6) reportedanautosomal dominant form of paroxysmal choreo-athetosis/ spasticity,withonset age ranging from2 to15 years, precipitated by factors such as physical exercise and emotional stress. It was alsomapped to 1p, between D1S443 and D1S197, but about 11.07 cM distant to locus 1p36.12-p35.1. Differences in onset age, clinical features and genetic mapping indicate that they are likely to be two different disorders. The Chinese family affected with pure BFIS is identified to map to 1p36.12-p35.1, a novel locus