Glutaric aciduria type I (GA-I, OMIM # 231670) is an inborn error of metabolism caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). Patients develop acute encephalopathic crises (AEC) with striatal injury most often triggered by catabolic stress. The pathophysiology of GA-I, particularly in brain, is still not fully understood.

We generated the first knock-in rat model for GA-I by introduction of the mutation p.R411W, the rat sequence homologue of the most common Caucasian mutation p.R402W, into the Gcdh gene of Sprague Dawley rats by CRISPR/CAS9 technology. Homozygous Gcdh^ki/ki rats revealed a high excretor phenotype, but did not present any signs of AEC under normal diet (ND). Exposure to a high lysine diet (HLD, 4.7%) after weaning resulted in clinical and biochemical signs of AEC.

A significant increase of plasmatic ammonium concentrations was found in Gcdh^ki/ki rats under HLD, accompanied by a decrease of urea concentrations and a concomitant increase of arginine excretion. This might indicate an inhibition of the urea cycle. Gcdh^ki/ki rats exposed to HLD showed highly diminished food intake resulting in severely decreased weight gain and moderate reduction of body mass index (BMI). This constellation suggests a loss of appetite. Under HLD, pipecolic acid increased significantly in cerebral and extra-cerebral liquids and tissues of Gcdh^ki/ki rats, but not in WT rats. It seems that Gcdh^ki/ki rats under HLD activate the pipecolate pathway for lysine degradation. Gcdh^ki/ki rat brains revealed depletion of free carnitine, microglial activation, astroglyosis, astrocytic death by apoptosis, increased vacuole numbers, impaired OXPHOS activities and neuronal damage. Under HLD, Gcdh^ki/ki rats showed imbalance of intra- and extracellular creatine concentrations and indirect signs of an intracerebral ammonium accumulation.

We successfully created the first rat model for GA-I. Characterization of this Gcdh^ki/ki strain confirmed that it is a suitable model not only for the study of pathophysiological processes, but also for the development of new therapeutic interventions. We further brought up interesting new insights into the pathophysiology of GA-I in brain and periphery.

I 型戊二酸尿症 (GA-I, OMIM # 231670) 是由戊二酰辅酶 A 脱氢酶 (GCDH) 缺乏引起的先天性代谢错误。患者出现急性脑病危象 (AEC)，纹状体损伤最常由分解代谢压力引发。GA-I 的病理生理学，特别是在大脑中，仍未完全了解。

我们通过 CRISPR/CAS9 技术将突变 p.R411W（最常见的白种人突变 p.R402W 的大鼠序列同源物）引入Sprague Dawley 大鼠的Gcdh基因，从而生成了第一个 GA-I 敲入大鼠模型。纯合Gcdh ^ki/ki大鼠显示出高排泄表型，但在正常饮食 (ND) 下没有出现任何 AEC 迹象。断奶后暴露于高赖氨酸饮食（HLD，4.7%）导致 AEC 的临床和生化症状。

在 HLD 下，Gcdh ^ki/ki大鼠的血浆铵浓度显着增加，伴随着尿素浓度的降低和精氨酸排泄量的增加。这可能表明尿素循环受到抑制。暴露于 HLD 的Gcdh ^ki/ki大鼠表现出高度减少的食物摄入量，导致体重增加严重减少和体重指数 (BMI) 中度降低。这个星座表明食欲不振。在 HLD 下，哌可酸在Gcdh ^ki/ki大鼠的脑和脑外液和组织中显着增加，但在 WT 大鼠中没有。似乎Gcdh ^ki/kiHLD 下的大鼠激活哌可酸途径以降解赖氨酸。Gcdh ^ki/ki大鼠大脑显示游离肉碱消耗、小胶质细胞活化、星形胶质细胞增生、细胞凋亡导致的星形细胞死亡、液泡数量增加、OXPHOS 活性受损和神经元损伤。在 HLD 下，Gcdh ^ki/ki大鼠表现出细胞内和细胞外肌酸浓度的不平衡以及脑内铵积累的间接迹象。

我们成功地为 GA-I 创建了第一个大鼠模型。这种Gcdh ^ki/ki菌株的表征证实，它不仅是研究病理生理过程的合适模型，而且是开发新治疗干预措施的合适模型。我们进一步对大脑和外周 GA-I 的病理生理学提出了有趣的新见解。