由于 ALDH7A1 中的双等位基因变异，能量产生受损是对吡哆醇依赖性癫痫发病机制的新见解吗？,PLOS ONE

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由于 ALDH7A1 中的双等位基因变异，能量产生受损是对吡哆醇依赖性癫痫发病机制的新见解吗？
PLOS ONE ( IF 2.9 ) Pub Date : 2021-09-08 , DOI: 10.1371/journal.pone.0257073
Anastasia Minenkova ₁ , Erwin E W Jansen ₂ , Jessie Cameron _{3,

4} , Rob Barto ₂ , Thomas Hurd ₁ , Lauren MacNeil _{3,

5} , Gajja S Salomons _{2,

6} , Saadet Mercimek-Andrews _{5,

7,

8}

Affiliation

背景吡哆醇依赖性癫痫 (PDE) 是由 ALDH7A1 (PDE-ALDH7A1) 中的双等位基因变异引起的。ALDH7A1 在赖氨酸分解代谢中编码 α-氨基己二酸半醛脱氢酶。我们研究了人类 PDE-ALDH7A1 及其敲除 aldh7a1 斑马鱼模型中的 γ 氨基丁酸 (GABA) 代谢和能量产生途径。方法我们测量了 PDE-ALDH7A1 患者和敲除 aldh7a1 斑马鱼的 GABA 通路、三羧酸循环代谢物和电子传递链活性。结果我们报告了三名 PDE-ALDH7A1 患者的结果：低配对复合物 I+II 和复合物 II+III 以及患者 1 肌肉活检中的个体复合物 IV 活性（可能更严重的表型）；GABA 通路中的 CSF 谷氨酸盐显着升高，CSF 柠檬酸盐、琥珀酸盐、患者 3 的 TCA 循环中的异柠檬酸和 α-酮戊二酸（可能是更严重的表型）；和正常 CSF GABA 途径和 TCA 循环代谢物对患者 2 的长期吡哆醇治疗（可能较温和的表型）。与野生型斑马鱼相比，纯合敲除的 aldh7a1 斑马鱼的所有 GABA 通路代谢物（γ-羟基丁酸、谷氨酰胺、谷氨酸、总 GABA、琥珀酸半醛）和 TCA 循环代谢物（柠檬酸、苹果酸、富马酸、异柠檬酸、乳酸）显着低. 与野生型斑马鱼相比，纯合敲除 aldh7a1 斑马鱼的电子传递链酶活性降低。讨论我们报告了人类 PDE-ALDH7A1 中电子传递链功能受损、谷氨酸在中枢神经系统中积累和 TCA 循环功能障碍以及 GABA 通路异常，敲除 aldh7a1 斑马鱼中的 TCA 循环和电子传递链。中枢神经系统谷氨酸毒性和能量产生受损可能在人类 PDE-ALDH7A1 的疾病神经发病机制和严重程度中发挥重要作用。

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Is impaired energy production a novel insight into the pathogenesis of pyridoxine-dependent epilepsy due to biallelic variants in ALDH7A1?

BACKGROUND Pyridoxine-dependent epilepsy (PDE) is due to biallelic variants in ALDH7A1 (PDE-ALDH7A1). ALDH7A1 encodes α-aminoadipic semialdehyde dehydrogenase in lysine catabolism. We investigated the gamma aminobutyric acid (GABA) metabolism and energy production pathways in human PDE-ALDH7A1 and its knock-out aldh7a1 zebrafish model. METHODS We measured GABA pathway, and tricarboxylic acid cycle metabolites and electron transport chain activities in patients with PDE-ALDH7A1 and in knock-out aldh7a1 zebrafish. RESULTS We report results of three patients with PDE-ALDH7A1: low paired complex I+II and complex II+III and individual complex IV activities in muscle biopsy in patient 1 (likely more severe phenotype); significantly elevated CSF glutamate in the GABA pathway and elevated CSF citrate, succinate, isocitrate and α-ketoglutarate in the TCA cycle in patient 3 (likely more severe phenotype); and normal CSF GABA pathway and TCA cycle metabolites on long-term pyridoxine therapy in patient 2 (likely milder phenotype). All GABA pathway metabolites (γ-hydroxybutyrate, glutamine, glutamate, total GABA, succinic semialdehyde) and TCA cycle metabolites (citrate, malate, fumarate, isocitrate, lactate) were significantly low in the homozygous knock-out aldh7a1 zebrafish compared to the wildtype zebrafish. Homozygous knock-out aldh7a1 zebrafish had decreased electron transport chain enzyme activities compared to wildtype zebrafish. DISCUSSION We report impaired electron transport chain function, accumulation of glutamate in the central nervous system and TCA cycle dysfunction in human PDE-ALDH7A1 and abnormal GABA pathway, TCA cycle and electron transport chain in knock-out aldh7a1 zebrafish. Central nervous system glutamate toxicity and impaired energy production may play important roles in the disease neuropathogenesis and severity in human PDE-ALDH7A1.

更新日期：2021-09-08

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