Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.
Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.
Mol Genet Metab. 2022 Jan;135(1):42-46. doi: 10.1016/j.ymgme.2021.11.355. Epub 2021 Dec 3.
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited inborn error of the γ-aminobutyric acid (GABA) metabolism pathway. It results from mutations in the ALDH5A1 gene leading to elevated GABA, γ-hydroxybutyric acid (GHB), succinic semialdehyde (SSA), decreased glutamine and alterations in several other metabolites. The phenotype includes developmental and cognitive delays, hypotonia, seizures, neuropsychiatric morbidity and other nervous system pathologies. The composition of the intestinal flora of patients with SSADHD has not been characterized, and dysbiosis of the gut microbiome may unveil novel treatment paradigms. We investigated the gut microbiome in SSADHD using 16S ribosomal DNA sequencing and unmasked evidence of dysbiosis in both aldh5a1-deficient mice and patients with SSADHD. In the murine model, there was a reduction in α-diversity measurements, and there were 4 phyla, 3 classes, 5 orders, 9 families, and 15 genera that differed, with a total of 17 predicted metabolic pathways altered. In patients, there were changes in Fusobacterium, 3 classes, 4 orders, 11 families, and a predicted alteration in genes associated with the digestive system. We believe this is the first evaluation of microbiome structure in an IEM with a neurometabolic phenotype that is not treated dietarily.
琥珀酸半醛脱氢酶缺乏症（SSADHD）是一种γ-氨基丁酸（GABA）代谢途径的遗传性先天性错误。它是由 ALDH5A1 基因突变引起的，导致 GABA、γ-羟基丁酸（GHB）、琥珀酸半醛（SSA）升高，谷氨酰胺降低，以及其他几种代谢物的改变。表型包括发育和认知迟缓、张力减退、癫痫发作、神经精神发病率和其他神经系统病变。SSADHD 患者的肠道菌群组成尚未得到描述，肠道微生物组的失调可能揭示出新的治疗模式。我们使用 16S 核糖体 DNA 测序研究了 SSADHD 的肠道微生物组，并在 aldh5a1 缺陷型小鼠和 SSADHD 患者中揭示了微生物失调的证据。在小鼠模型中，α-多样性测量值降低，有 4 个门、3 个纲、5 个目、9 个科和 15 个属存在差异，共有 17 个预测的代谢途径发生改变。在患者中，梭杆菌属发生了变化，有 3 个纲、4 个目、11 个科和一个与消化系统相关的基因预测发生了改变。我们相信，这是首次对未经饮食治疗的具有神经代谢表型的 IEM 进行微生物组结构评估。
