University of Groningen, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
Mol Genet Metab. 2022 Sep-Oct;137(1-2):9-17. doi: 10.1016/j.ymgme.2022.07.001. Epub 2022 Jul 8.
Tyrosinemia type 1 (HT1) is a rare metabolic disorder caused by a defect in the tyrosine catabolic pathway. Since HT1 patients are treated with NTBC, outcome improved and life expectancy greatly increased. However extensive neurocognitive and behavioural problems have been described, which might be related to treatment with NTBC, the biochemical changes induced by NTBC, or metabolites accumulating due to the enzymatic defect characterizing the disease.
To study the possible pathophysiological mechanisms of brain dysfunction in HT1, we assessed blood and brain LNAA, and brain monoamine neurotransmitter metabolite levels in relation to behavioural and cognitive performance of HT1 mice.
C57BL/6 littermates were divided in three different experimental groups: HT1, heterozygous and wild-type mice (n = 10; 5 male). All groups were treated with NTBC and underwent cognitive and behavioural testing. One week after behavioural testing, blood and brain material were collected to measure amino acid profiles and brain monoaminergic neurotransmitter levels.
Irrespective of the genetic background, NTBC treatment resulted in a clear increase in brain tyrosine levels, whereas all other brain LNAA levels tended to be lower than their reference values. Despite these changes in blood and brain biochemistry, no significant differences in brain monoamine neurotransmitter (metabolites) were found and all mice showed normal behaviour and learning and memory.
Despite the biochemical changes, NTBC and genotype of the mice were not associated with poorer behavioural and cognitive function of the mice. Further research involving dietary treatment of FAH-/- are warranted to investigate whether this reveals the cognitive impairments that have been seen in treated HT1 patients.
I 型酪氨酸血症（HT1）是一种罕见的代谢紊乱疾病，由酪氨酸分解代谢途径中的缺陷引起。由于 HT1 患者接受 NTBC 治疗，其预后得到改善，预期寿命大大延长。然而，已经描述了广泛的神经认知和行为问题，这些问题可能与 NTBC 的治疗、NTBC 诱导的生化变化或由于疾病特征的酶缺陷而积累的代谢物有关。
为了研究 HT1 脑功能障碍的可能病理生理机制，我们评估了 HT1 小鼠的血液和大脑必需氨基酸（LNAA）以及大脑单胺神经递质代谢物水平与行为和认知表现的关系。
C57BL/6 同窝仔鼠分为三组不同的实验组：HT1、杂合子和野生型仔鼠（n = 10；5 只雄性）。所有组均接受 NTBC 治疗并进行认知和行为测试。行为测试一周后，收集血液和脑组织，以测量氨基酸谱和大脑单胺神经递质水平。
无论遗传背景如何，NTBC 治疗均导致大脑酪氨酸水平明显升高，而所有其他大脑必需氨基酸水平均趋于低于参考值。尽管血液和大脑生物化学发生了这些变化，但未发现大脑单胺神经递质（代谢物）的显著差异，所有小鼠均表现出正常的行为和学习记忆能力。
尽管存在生化变化，但 NTBC 和小鼠的基因型与小鼠的行为和认知功能较差无关。进一步研究涉及 FAH-/- 的饮食治疗，以研究这是否会揭示已在治疗的 HT1 患者中观察到的认知障碍。
