Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase
Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase
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DOI：
10.1038/ng727
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发表时间：
2001-10-01
期刊：
影响因子：
30.8
通讯作者：
Gibson, KM
中科院分区：
文献类型：
--
作者：
Hogema, BM;Gupta, M;Gibson, KM
琥珀酸半醛脱氢酶（ALDH 5A 1，编码SSADH缺乏症）是4-氨基丁酸（GABA）降解的缺陷，其在人类中表现为4-羟基丁酸（γ-羟基丁酸，GHB）酸尿症。其特征在于非特异性神经障碍，包括精神发育迟滞、语言延迟、癫痫发作、张力减退和共济失调。目前的治疗，氨己烯酸（VGB），并不是一致成功的（1）。在这里，我们报告了Aldh 5a 1缺陷小鼠的发展。在出生后第16-22天，Aldh 5a 1（-/-）小鼠表现出共济失调，并出现全身性癫痫发作，导致快速死亡。我们观察到尿、脑和肝匀浆中GHB和总GABA的量增加，并在Aldh 5a 1（-/-）小鼠的海马中检测到显著的神经胶质增生。我们发现用苯巴比妥或菲妥英治疗干预无效，而用氨己烯酸或GABA（B）受体拮抗剂CGP 35348（参考文献2）干预可预防强直-阵挛性惊厥，并显著提高突变小鼠的存活率。由于神经功能恶化与断奶同时发生，我们假设母乳中存在一种保护性化合物。事实上，用氨基酸牛磺酸治疗突变小鼠拯救了Aldh 5a 1（-/-）小鼠。这些发现提供了深入了解病理机制，并可能对人类SSADH缺乏症和GHB过量和毒性具有治疗意义。
Succinate semialdehyde dehydrogenase (ALDH5A1, encoding SSADH deficiency is a defect of 4-aminobutyric acid (GABA) degradation that manifests in humans as 4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria. It is characterized by a non-specific neurological disorder including psychomotor retardation, language delay, seizures, hypotonia and ataxia. The current therapy, vigabatrin (VGB), is not uniformly successful(1). Here we report the development of Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1(-/-) mice display ataxia and develop generalized seizures leading to rapid death. We observed increased amounts of GHB and total GABA in urine, brain and liver homogenates and detected significant gliosis in the hippocampus of Aldh5a1(-/-) mice. We found therapeutic intervention with phenobarbital or pherytoin ineffective, whereas intervention with vigabatrin or the GABA(B) receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and significantly enhanced survival of the mutant mice. Because neurologic deterioration coincided with weaning, we hypothesized the presence of a protective compound in breast milk. Indeed, treatment of mutant mice with the amino acid taurine rescued Aldh5a1(-/-) mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity.