The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1.
The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1.
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由于ALDH7A1突变引起的吡ido醇依赖性癫痫的基因型和表型光谱。
DOI：
10.1007/s10545-010-9187-2
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发表时间：
2010-10
影响因子：
4.2
通讯作者：
Van Hove JL
中科院分区：
文献类型：
--
作者：
Scharer G;Brocker C;Vasiliou V;Creadon-Swindell G;Gallagher RC;Spector E;Van Hove JL
吡哆醇依赖性癫痫是一种与重度癫痫发作相关的疾病，可能是由ALDH 7A 1基因编码的α-氨基己二酸半醛脱氢酶活性不足引起的，伴随α-氨基己二酸半醛和哌啶-6-羧酸的蓄积。后者与磷酸吡哆醛反应，解释了吡哆醇的有效治疗。我们报告了三名患者的临床表型，他们的突变和我们的临床分子实验室确定的另外12名患者的突变。有六个错义，一个无义，五个剪接位点突变，两个小缺失。突变c.1217_1218delAT、I431 F、IVS-1（+2）T>G、IVS-2（+1）G>A和IVS-12（+1）G>A是新的。一些疾病等位基因重复出现：E399 Q（8次）、G477 R（6次）、R82 X（2次）和c.1217_1218delAT（2次）。对文献中突变的系统回顾表明，错义突变聚集在外显子14、15和16周围。9个突变代表61%的等位基因。错义突变的分子建模允许分为三组：影响NAD+结合或催化的那些，影响底物结合位点的那些，以及影响多聚化的那些。有三种临床表型：吡哆醇完全控制癫痫发作和正常发育结果的患者（第1组），包括我们的第一名患者;吡哆醇完全控制癫痫发作但发育迟缓的患者（第2组），包括我们的其他两名患者;和吡哆醇治疗后持续癫痫发作和发育迟缓的患者（第3组）。有初步证据表明，第1组患者的基因型-表型相关性存在残留活性突变。有证据表明，来自具有相似基因型的患者的非遗传因素有助于表型谱。
Pyridoxine-dependent epilepsy is a disorder associated with severe seizures that may be caused by deficient activity of α-aminoadipic semialdehyde dehydrogenase, encoded by the ALDH7A1 gene, with accumulation of α-aminoadipic semialdehyde and piperideine-6-carboxylic acid. The latter reacts with pyridoxal-phosphate, explaining the effective treatment with pyridoxine. We report the clinical phenotype of three patients, their mutations and those of 12 additional patients identified in our clinical molecular laboratory. There were six missense, one nonsense, and five splice-site mutations, and two small deletions. Mutations c.1217_1218delAT, I431F, IVS-1(+2)T>G, IVS-2(+1)G>A, and IVS-12(+1)G>A are novel. Some disease alleles were recurring: E399Q (eight times), G477R (six times), R82X (two times), and c.1217_1218delAT (two times). A systematic review of mutations from the literature indicates that missense mutations cluster around exons 14, 15, and 16. Nine mutations represent 61% of alleles. Molecular modeling of missense mutations allows classification into three groups: those that affect NAD+binding or catalysis, those that affect the substrate binding site, and those that affect multimerization. There are three clinical phenotypes: patients with complete seizure control with pyridoxine and normal developmental outcome (group 1) including our first patient; patients with complete seizure control with pyridoxine but with developmental delay (group 2), including our other two patients; and patients with persistent seizures despite pyridoxine treatment and with developmental delay (group 3). There is preliminary evidence for a genotype-phenotype correlation with patients from group 1 having mutations with residual activity. There is evidence from patients with similar genotypes for nongenetic factors contributing to the phenotypic spectrum.
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影响因子：
11.2
作者：
Gallagher, Renata C.;Van Hove, Johan L. K.;Jakobs, Cornelis
通讯作者：
Jakobs, Cornelis
影响因子：
3.1
作者：
Millet, A.;Salomons, G. S.;Hamelin, S.
通讯作者：
Hamelin, S.
影响因子：
1.9
作者：
Kaczorowska, Magdalena;Kmiec, Tomasz;Jozwiak, Sergiusz
通讯作者：
Jozwiak, Sergiusz
影响因子：
3.6
作者：
Bok, Levinus A.;Been, Jasper V.;Willemsen, Michel A.
通讯作者：
Willemsen, Michel A.
影响因子：
3.8
作者：
Baxter, P
通讯作者：
Baxter, P