Department of Woman's and Child's Health, University Hospital of Padua, Italy.
Department of Neurosciences, University Hospital of Padua, Italy.
Eur J Paediatr Neurol. 2018 Nov;22(6):1042-1053. doi: 10.1016/j.ejpn.2018.06.010. Epub 2018 Jul 3.
The ALDH7A1 gene is known to be responsible for autosomal recessive pyridoxine-dependent epilepsy (OMIM 266100). The phenotypic spectrum of ALDH7A1 mutations is very heterogeneous ranging from refractory epilepsy and neurodevelopmental delay, to multisystem neonatal disorder.
The present study aims at describing the phenotype associated with a novel homozygous ALDH7A1 mutation and the spectrum of brain malformations associated with pyridoxine-dependent epilepsy.
We conducted a literature review on the Internet database Pubmed (up to November 2017) searching for ALDH7A1 mutations associated with brain malformations and brain MRI findings.
We present the case of two siblings, children of related parents. The proband presented neonatal focal seizures not responding to conventional antiepileptic drugs. Electroencephalography showed a suppression burst pattern and several multifocal ictal patterns, responsive to pyridoxine. Brain MRI was normal. Molecular analysis by targeted next-generation sequencing panel for epileptic encephalopathy disclosed a homozygous missense mutation of ALDH7A1. The same mutation was then found in a stored sample of DNA from peripheral blood of an older sister dead 3 years earlier. This girl presented a complex brain malformation diagnosed with a foetal MRI and had neonatal refractory seizures with suppression burst pattern. She died at 6 months of age.
The brain abnormalities most frequently reported in pyridoxine-dependent epilepsy include: agenesia/hypoplasia of the corpus callosum, not specific white matter abnormalities, large cisterna magna, ventriculomegaly, haemorrhages, cerebellum hypoplasia/dysplasia, and, more rarely, dysplasia of the brainstem and hydrocephalus.
ALDH7A1 mutations have been associated to different brain abnormalities, documented by MRI only in few cases. The study cases expand the clinical spectrum of ALDH7A1 associated conditions, suggesting to look for ALDH7A1 mutations not only in classical phenotypes but also in patients with brain malformations, mainly if there is a response to a pyridoxine trial.
已知 ALDH7A1 基因负责常染色体隐性吡哆醇依赖性癫痫（OMIM 266100）。ALDH7A1 突变的表型谱非常异质，从难治性癫痫和神经发育迟缓到多系统新生儿疾病。
本研究旨在描述与新型纯合 ALDH7A1 突变相关的表型以及与吡哆醇依赖性癫痫相关的脑畸形谱。
我们在互联网数据库 Pubmed 上进行了文献综述（截至 2017 年 11 月），搜索与脑畸形和脑 MRI 发现相关的 ALDH7A1 突变。
我们介绍了两例同胞的病例，是相关父母的孩子。先证者表现为新生儿局灶性癫痫，对常规抗癫痫药物无反应。脑电图显示抑制爆发模式和几种多灶性癫痫模式，对吡哆醇有反应。脑 MRI 正常。通过针对癫痫性脑病的靶向下一代测序面板进行分子分析显示 ALDH7A1 纯合错义突变。然后在 3 年前死亡的姐姐的外周血储存 DNA 样本中发现了相同的突变。这个女孩患有复杂的脑畸形，在胎儿 MRI 上诊断，并在新生儿期出现难治性癫痫，伴有抑制爆发模式。她在 6 个月大时死亡。
吡哆醇依赖性癫痫中最常报道的脑异常包括：胼胝体发育不全/发育不良、非特异性白质异常、大后颅窝池、脑室扩大、出血、小脑发育不良/发育不良，以及更罕见的脑干发育不良和脑积水。
ALDH7A1 突变与不同的脑异常有关，仅在少数病例中通过 MRI 证实。研究病例扩展了与 ALDH7A1 相关的疾病的临床谱，表明不仅在典型表型中寻找 ALDH7A1 突变，而且在有脑畸形的患者中也寻找 ALDH7A1 突变，特别是如果对吡哆醇试验有反应的情况下。
