Knerr I, Pearl P L, Bottiglieri T, Snead O Carter, Jakobs C, Gibson K M
Children's and Adolescents' Hospital, University of Erlangen-Nuremberg, Erlangen, Germany.
J Inherit Metab Dis. 2007 Jun;30(3):279-94. doi: 10.1007/s10545-007-0574-2. Epub 2007 Apr 24.
We overview the pathophysiological bases, clinical approaches and potential therapeutic options for succinate semialdehyde dehydrogenase (SSADH; EC1.2.1.24) deficiency (gamma-hydroxybutyric aciduria, OMIM 271980, 610045) in relation to studies on SSADH gene-deleted mice, outcome data developed from 25 years of patient evaluation, and characterization of gamma-hydroxybutyric acid (GHB) pharmacology in different species. The clinical picture of this disorder encompasses a wide spectrum of neurological and psychiatric dysfunction, such as psychomotor retardation, delayed speech development, epileptic seizures and behavioural disturbances, emphasizing the multifactorial pathophysiology of SSADH deficiency. The murine SSADH-/- (e.g. Aldh5a1-/-) mouse model suffers from epileptic seizures and succumbs to early lethality. Aldh5a1-/- mice accumulate GHB and gamma-aminobutyric acid (GABA) in the central nervous system, exhibit alterations of amino acids such as glutamine (Gln), alanine (Ala) and arginine (Arg), and manifest disturbances in other systems including dopamine, neurosteroids and antioxidant status. Therapeutic concepts in patients with SSADH deficiency and preclinical therapeutic experiments are discussed in light of data collected from research in Aldh5a1-/- mice and animal studies of GHB pharmacology; these studies are the foundation for novel working approaches, including pharmacological and dietary trials, which are presented for future evaluation in this disease.
我们结合对琥珀酸半醛脱氢酶（SSADH；EC1.2.1.24）基因敲除小鼠的研究、25年患者评估得出的结果数据以及不同物种中γ-羟基丁酸（GHB）药理学特征，概述了SSADH缺乏症（γ-羟基丁酸尿症，OMIM 271980，610045）的病理生理基础、临床方法和潜在治疗选择。这种疾病的临床表现包括广泛的神经和精神功能障碍，如精神运动发育迟缓、语言发育延迟、癫痫发作和行为障碍，突出了SSADH缺乏症的多因素病理生理学。小鼠SSADH-/-（如Aldh5a1-/-）模型患有癫痫发作并早期死亡。Aldh5a1-/-小鼠在中枢神经系统中积累GHB和γ-氨基丁酸（GABA），表现出氨基酸如谷氨酰胺（Gln）、丙氨酸（Ala）和精氨酸（Arg）的变化，并在包括多巴胺、神经甾体和抗氧化状态在内的其他系统中出现紊乱。根据从Aldh5a1-/-小鼠研究和GHB药理学动物研究中收集的数据，讨论了SSADH缺乏症患者的治疗概念和临床前治疗实验；这些研究是新工作方法的基础，包括药理学和饮食试验，本文提出以供未来对该疾病进行评估。
