PROGRESSION OF 6-PYRUVOYL-TETRAHYDROPTERIN SYNTHASE DEFICIENCY FROM A PERIPHERAL INTO A CENTRAL PHENOTYPE
PROGRESSION OF 6-PYRUVOYL-TETRAHYDROPTERIN SYNTHASE DEFICIENCY FROM A PERIPHERAL INTO A CENTRAL PHENOTYPE
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DOI：
10.1007/bf01799379
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发表时间：
1990-01-01
影响因子：
4.2
通讯作者：
ENDRES, W
中科院分区：
文献类型：
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作者：
PONZONE, A;BLAU, N;ENDRES, W
四氢生物蝶呤（BH4）是芳香氨基酸羟化酶的辅助因子，在苯丙氨酸（PHE）的降解和血清素和儿茶酚胺的生物合成中是必不可少的。辅助因子缺乏可由三种常染色体隐性遗传的酶缺陷引起，即GTP环水解酶I、6-pyruvoyl-tetrahydropterin synthase （6-PPH4S）和二氢蝶啶还原酶。相关的高苯丙氨酸血症和生物胺缺乏症在临床上会导致严重的进行性神经系统疾病，通常被称为“非典型”或“恶性”苯丙酮尿症，因为它对限制phe的饮食没有反应（Blau, 1988）。患有6-PPH4S缺陷的患者是BH4缺乏症最常见的变体。由于该酶能催化由三磷酸7,8 -二氢蝶呤生成不稳定的中间体6-吡咯叶- 5,6,7,8 -四氢蝶呤，这类患者在尿中排出的生物蝶呤(B)量极低，新蝶呤(N)量极高，其% B值（B/B+ N）通常低于5%。通过肝活检或红细胞检测6-PPH4S活性也可以诊断（Niederwieser et al., 1985; Shintaku et al., 1988）。然而，6-PPH4S缺乏症是一种异质性疾病，有典型、部分、中间和短暂等不同的临床表现，但尚未完全了解。它们的表征需要分析尿液、血清和脑脊液（CSF）中的蝶呤，测量CSF生物胺代谢物，以及评估PHE饮食耐受性和对合成辅因子负荷试验的反应（Niederw~ ieser et at）。, 1987)。评估病人的虚型是治疗的关键，可以决定病人是否需要治疗，治疗的类型和方法
Tetrahydrobiopterin (BH4), a cofactor of aromatic amino acid hydroxylases, is essential in the degradation of phenylalanine (PHE) and in the biosynthesis of serotonin and catecholamines. Cofactor deficiency can be caused by three autosomal recessively inherited enzyme defects in its synthetic or salvage pathways, namely GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase (6-PPH4S) and dihydropteridine reductase. Associated hyperphenylalaninaemia and biogenic amine deficiency will result clinically in a severe and progressive neurological disorder, often called'atypical'or'malignant'phenylketonuria, since it is unresponsive to a PHE-restricted diet (Blau, 1988). Patients suffering from a defect in 6-PPH4S represent the most frequent variant of BH4 deficiency. Since the enzyme catalyses the formation of the labile intermediate 6-pyruvoyl-5, 6, 7, 8-tetrahydropterin from 7, 8-dihydroneopterin triphosphate, such patients excrete in urine very low amounts of biopterin (B) and very high amounts of neopterin (N), with% B values (B/B+ N) usually below 5%. Diagnosis is also possible through the measurement of 6-PPH4S activity in liver biopsy or in erythrocytes (Niederwieser et al., 1985; Shintaku et al., 1988). However, 6-PPH4S deficiency is a heterogeneous disorder, and different clinical forms such as typical, partial, intermediate and transient have been described, but are not yet fully tmderstood. Their characterization requires the analysis of pterins in urine, serum and cerebrospinal fluid (CSF), and the measurement of CSF biogenic amine metabolites, as well as evaluation of the PHE dietary tolerance and of the response to a synthetic cofactor loading test (Niederw~ ieser et at., 1987). The assessment of the form of deficiency to which a patient belongs is a crucial point for therapeutic purposes, to determine whether or not he needs treatment, the type of treatment and