Tetrahydrobiopterin (BH₄) deficiency is caused by genetic variants in the three genes involved in de novo cofactor biosynthesis, GTP cyclohydrolase I (GTPCH/GCH1), 6-pyruvoyl-tetrahydropterin synthase (PTPS/PTS), sepiapterin reductase (SR/SPR), and the two genes involved in cofactor recycling, carbinolamine-4α-dehydratase (PCD/PCBD1) and dihydropteridine reductase (DHPR/QDPR). Dysfunction in BH₄ metabolism leads to reduced cofactor levels and may result in systemic hyperphenylalaninemia and/or neurological sequelae due to secondary deficiency in monoamine neurotransmitters in the central nervous system. More than 1100 patients with BH₄ deficiency and 800 different allelic variants distributed throughout the individual genes are tabulated in database of pediatric neurotransmitter disorders PNDdb. Here we provide an update on the molecular-genetic analysis and structural considerations of these variants, including the clinical courses of the genotypes. From a total of 324 alleles, 11 are associated with the autosomal recessive form of GTPCH deficiency presenting with hyperphenylalaninemia (HPA) and neurotransmitter deficiency, 295 GCH1 variant alleles are detected in the dominant form of L-dopa-responsive dystonia (DRD or Segawa disease) while phenotypes of 18 alleles remained undefined. Autosomal recessive variants observed in the PTS (199 variants), PCBD1 (32 variants), and QDPR (141 variants) genes lead to HPA concomitant with central monoamine neurotransmitter deficiency, while SPR deficiency (104 variants) presents without hyperphenylalaninemia. The clinical impact of reported variants is essential for genetic counseling and important for development of precision medicine.

四氢生物蝶呤 (BH ₄ ) 缺乏症是由参与从头辅助因子生物合成的三个基因的遗传变异引起的，即 GTP 环化水解酶 I (GTPCH/ GCH1 )、6-丙酮酰四氢蝶呤合酶 (PTPS/ PTS )、sepipterin 还原酶 (SR/ SPR ) ，以及参与辅因子循环的两个基因，甲醇胺-4α-脱水酶（PCD/ PCBD1）和二氢蝶啶还原酶（DHPR/ QDPR）。BH ₄功能障碍代谢导致辅因子水平降低，并可能导致全身性高苯丙氨酸血症和/或由于中枢神经系统中单胺类神经递质继发性缺乏引起的神经系统后遗症。在儿科神经递质疾病 PNDdb 数据库中列出了 1100多名BH ₄缺陷患者和分布在各个基因中的 800 种不同等位基因变异。在这里，我们提供了这些变异的分子遗传分析和结构考虑的更新，包括基因型的临床过程。在总共 324 个等位基因中，11 个与常染色体隐性遗传的 GTPCH 缺陷相关，表现为高苯丙氨酸血症 (HPA) 和神经递质缺陷，295 GCH1在左旋多巴反应性肌张力障碍（DRD 或 Segawa 病）的显性形式中检测到变异等位基因，而 18 个等位基因的表型仍未确定。在PTS（199 个变体）、PCBD1（32 个变体）和QDPR（141 个变体）基因中观察到的常染色体隐性变异导致 HPA 伴有中枢单胺类神经递质缺乏，而SPR缺乏（104 个变体）则没有高苯丙氨酸血症。报告变异的临床影响对遗传咨询至关重要，对精准医学的发展也很重要。