Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene
Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene
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DOI：
10.1002/humu.20433
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发表时间：
2007-01-01
期刊：
影响因子：
3.9
通讯作者：
Erwa, Wolfgang
中科院分区：
文献类型：
--
作者：
Plecko, Barbara;Paul, Karl;Erwa, Wolfgang
吡哆醇依赖性癫痫（PDE）患者出现对常见抗惊厥药耐药的早发性癫痫发作。根据吡哆醇（维生素B-6）的获益和吡哆醇停药后癫痫发作的复发，迄今为止已将患者分为明确、很可能或可能的PDE。最近，PDE已被证明是由大脑赖氨酸降解途径中的α-氨基己二酸半醛（AASA）脱氢酶（antiquitin）缺陷引起的。积累化合物哌啶6-羧酸（P6 C）被证明通过Knoevenagel缩合反应使磷酸吡哆醛（PLP）缩合。哌可酸（PA）和AASA在尿液、血浆和脑脊液（CSF）中显著升高，因此可用作该疾病的生物标志物。我们调查了18例新生儿癫痫发作患者，他们被分类为确诊（11例）、很可能（4例）或可能（3例）PDE。所有患者在接受个体剂量吡哆醇治疗时血浆（和尿液）中PA和AASA均升高。在该队列中，分子分析在antiquitin基因的高度保守区域内鉴定出10个新突变（6个错义突变，1个无义突变，2个剪接位点突变）。7个突变位于外显子序列，2个位于内含子7和17。此外，还发现了一种新的外显子7缺失。研究的36个等位基因中有2个需要进一步研究。一个已知的突变（p.Glu399Gln）被发现有显着的患病率，占我们的队列中的36个等位基因（33%）的12。不再需要停用吡哆醇来确定“明确”PDE的诊断。在PDE中给予吡哆醇不仅可以纠正继发性PLP缺乏症，而且还可能导致AASA（和P6 C）减少，这可能是有毒化合物。(c)2006威利-利斯公司
Patients with pyridoxine dependent epilepsy (PDE) present with early-onset seizures resistant to common anticonvulsants. According to the benefit of pyridoxine (vitamin B-6) and recurrence of seizures on pyridoxine withdrawal, patients so far have been classified as having definite, probable, or possible PDE. Recently, PDE has been shown to be caused by a defect of alpha-amino adipic semialdehyde (AASA) dehydrogenase (antiquitin) in the cerebral lysine degradation pathway. The accumulating compound piperideine 6-carboxylic acid (P6C) was shown to inactivate pyridoxalphosphate (PLP) by a Knoevenagel condensation. Pipecolic acid (PA) and AASA are markedly elevated in urine, plasma, and cerebrospinal fluid (CSF) and thus can be used as biomarkers of the disease. We have investigated 18 patients with neonatal seizure onset, who have been classified as having definite (11), probable (four), or possible (three) PDE. All patients had elevated PA and AASA in plasma (and urine) while on treatment with individual dosages of pyridoxine. Within this cohort, molecular analysis identified 10 novel mutations (six missense mutations, one nonsense mutation, two splice site mutations) within highly conserved regions of the antiquitin gene. Seven mutations were located in exonic sequences and two in introns 7 and 17. Furthermore, a novel deletion of exon 7 was identified. Two of the 36 alleles investigated require further investigation. A known mutation (p.Glu399Gln) was found with marked prevalence, accounting for 12 out of 36 alleles (33%) within our cohort. Pyridoxine withdrawal is no longer needed to establish the diagnosis of "definite" PDE. Administration of pyridoxine in PDE may not only correct secondary PLP deficiency, but may also lead to a reduction of AASA (and P6C) as presumably toxic compounds. (c) 2006 Wiley-Liss, Inc.