Beatrix Children's Hospital, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands.
University Children's Hospital in Zurich, Zurich, Switzerland.
Nat Rev Dis Primers. 2021 May 20;7(1):36. doi: 10.1038/s41572-021-00267-0.
Phenylketonuria (PKU; also known as phenylalanine hydroxylase (PAH) deficiency) is an autosomal recessive disorder of phenylalanine metabolism, in which especially high phenylalanine concentrations cause brain dysfunction. If untreated, this brain dysfunction results in severe intellectual disability, epilepsy and behavioural problems. The prevalence varies worldwide, with an average of about 1:10,000 newborns. Early diagnosis is based on newborn screening, and if treatment is started early and continued, intelligence is within normal limits with, on average, some suboptimal neurocognitive function. Dietary restriction of phenylalanine has been the mainstay of treatment for over 60 years and has been highly successful, although outcomes are still suboptimal and patients can find the treatment difficult to adhere to. Pharmacological treatments are available, such as tetrahydrobiopterin, which is effective in only a minority of patients (usually those with milder PKU), and pegylated phenylalanine ammonia lyase, which requires daily subcutaneous injections and causes adverse immune responses. Given the drawbacks of these approaches, other treatments are in development, such as mRNA and gene therapy. Even though PAH deficiency is the most common defect of amino acid metabolism in humans, brain dysfunction in individuals with PKU is still not well understood and further research is needed to facilitate development of pathophysiology-driven treatments.
苯丙酮尿症（PKU；也称为苯丙氨酸羟化酶（PAH）缺乏症）是一种常染色体隐性遗传的苯丙氨酸代谢紊乱，其中特别高的苯丙氨酸浓度会导致大脑功能障碍。如果未经治疗，这种大脑功能障碍会导致严重的智力残疾、癫痫和行为问题。其患病率在全球范围内有所不同，平均每 10,000 名新生儿中就有 1 例。早期诊断基于新生儿筛查，如果早期开始并持续治疗，智力可以处于正常范围内，但平均而言，神经认知功能存在一些不理想的情况。限制苯丙氨酸饮食已经是 60 多年来的主要治疗方法，并且非常成功，尽管治疗效果仍然不理想，而且患者可能难以坚持治疗。目前已有一些药物治疗方法，如四氢生物蝶呤，但其仅对少数患者（通常是病情较轻的 PKU 患者）有效，而聚乙二醇化苯丙氨酸氨裂解酶需要每天皮下注射，且会引起不良反应。鉴于这些方法的缺点，正在开发其他治疗方法，如信使 RNA 和基因治疗。尽管 PAH 缺乏是人类氨基酸代谢中最常见的缺陷，但 PKU 患者的大脑功能障碍仍未得到很好的理解，需要进一步研究以促进基于病理生理学的治疗方法的发展。
