Hereditary tyrosinemia Type 1 (HT-1) is a rare metabolic disease where the enzyme catalyzing the final step of tyrosine breakdown is defect, leading to accumulation of toxic metabolites. Nitisinone inhibits the degradation of tyrosine and thereby the production of harmful metabolites, however, the concentration of tyrosine also increases. We investigated the relationship between plasma tyrosine concentrations and cognitive functions and how tyrosine levels affected enzyme activities of human tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2). Eight Norwegian children between 6 and 18 years with HT-1 were assessed using questionnaires measuring Attention Deficit Hyperactivity Disorder (ADHD)-symptoms and executive functioning. Recent and past levels of tyrosine were measured and the enzyme activities of TH and TPH2 were studied at conditions replicating normal and pathological tyrosine concentrations. We observed a significant positive correlation between mean tyrosine levels and inattention symptoms. While TH exhibited prominent substrate inhibition kinetics, TPH2 activity also decreased at elevated tyrosine levels. Inhibition of both enzymes may impair syntheses of dopamine, noradrenaline, and serotonin in brain tissue. Inattention in treated HT-1 patients may be related to decreased production of these monoamines. Our results support recommendations of strict guidelines on plasma tyrosine levels in HT-1. ADHD-related deficits, particularly inattention, should be monitored in HT-1 patients to determine whether intervention is necessary.

中文翻译：

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1型酪氨酸血症和ADHD症状：生化机制及其对治疗和预后的影响。

遗传性1型酪氨酸血症（HT-1）是一种罕见的代谢疾病，其中催化酪氨酸分解的最后一步的酶是缺陷，导致有毒代谢产物的积累。尼替尼酮抑制酪氨酸的降解，从而抑制有害代谢产物的产生，但是，酪氨酸的浓度也会增加。我们调查了血浆酪氨酸浓度与认知功能之间的关系，以及酪氨酸水平如何影响人类酪氨酸羟化酶（TH）和色氨酸羟化酶2（TPH2）的酶活性。使用测量注意缺陷多动障碍（ADHD）症状和执行功能的问卷，对8名6至18岁的HT-1挪威儿童进行了评估。在复制正常和病理性酪氨酸浓度的条件下，测量了酪氨酸的最近和过去水平，并研究了TH和TPH2的酶活性。我们观察到平均酪氨酸水平和注意力不集中症状之间存在显着的正相关。尽管TH表现出显着的底物抑制动力学，但是TPH2活性在酪氨酸水平升高时也降低了。两种酶的抑制都可能损害脑组织中多巴胺，去甲肾上腺素和5-羟色胺的合成。接受治疗的HT-1患者注意力不集中可能与这些单胺的产生减少有关。我们的结果支持对HT-1中血浆酪氨酸水平的严格指导原则的建议。应监测HT-1患者的ADHD相关缺陷，特别是注意力不集中，以确定是否有必要进行干预。