期刊
NEUROCHEMISTRY INTERNATIONAL
卷 99, 期 -, 页码 72-84出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2016.06.009
关键词
GABA (4-aminobutyric acid); GHB (4-hydroxybutyric acid); Knockout mouse model; Neurological disease; Pathophysiology; Oxidative damage; Crystal structure; Autophagy; Mitophagy; Succinic semialdehyde dehydrogenase deficiency (SSADHD); Pathogenic mutations; Polymorphisms; SNP (single nucleotide polymorphism); Multifactorial traits; GWAS; Genome wide association study; GABAergic neurotransmission; Pathophysiology
资金
- NIH [NS 82286, NS 85369]
- SSADH Association
- Speragen, Inc.
Discovered some 35 years ago, succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a rare, autosomal recessively-inherited defect in the second step of the GABA degradative pathway. Some 200 patients have been reported, with broad phenotypic and genotypic heterogeneity. SSADHD represents an unusual neurometabolic disorder in which two neuromodulatory agents, GABA (and the GABA analogue, 4-hydroxybutyrate), accumulate to supraphysiological levels. The unexpected occurrence of epilepsy in several patients is counterintuitive in view of the hyperGABAergic state, in which sedation might be expected. However, the epileptic status of some patients is most likely represented by broader imbalances of GABAergic and glutamatergic neurotransmission. Cumulative research encompassing decades of basic and clinical study of SSADHD reveal a monogenic disease with broad pathophysiological and clinical phenotypes. Numerous metabolic perturbations unmasked in SSADHD include alterations in oxidative stress parameters, dysregulation of autophagy and mitophagy, dysregulation of both inhibitory and excitatory neurotransmitters and gene expression, and unique subsets of SNP alterations of the SSADH gene (so-called ALDH5A1, or aldehyde dehydrogenase 5A1 gene) on the 6p22 chromosomal arm. While seemingly, difficult to collate and interpret, these anomalies have continued to open novel pathways for pharmacotherapeutic considerations. Here, we present an update on selected aspects of SSADHD, the ALDH5A1 gene, and future avenues for research on this rare disorder of GABA metabolism. (C) 2016 Elsevier Ltd. All rights reserved.
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