Butler I J, Koslow S H, Krumholz A, Holtzman N A, Kaufman S
Ann Neurol. 1978 Mar;3(3):224-30. doi: 10.1002/ana.410030307.
A severe deficiency of dihydropteridine reductase (DHPR) in liver, brain, and cultured skin fibroblasts was demonstrated in a child with hyperphenylalaninemia and an atypical form of phenylketonuria. DHPR is required for regeneration of the cofactor, tetrahydrobiopterin. The cofactor is essential in hydroxylation of aromatic amino acid precursors in the biosynthesis of neurotransmitters, serotonin, dopamine, and norepinephrine. In gray tissue at brain biopsy, dopamine was low at 3 ng per gram of tissue, serotonin was barely detected, and norepinephrine appeared high at 1600 ng per gram. In cerebrospinal fluid, homovanillic acid (HVA) was low normal at 33 ng/ml, 5-hydroxyindoleacetic acid (5-HIAA) was low at 4.2 ng/ml, and after a high dose of oral probenecid there was impaired accumulation of HVA to 128 ng/ml and 5-HIAA to 22.4 ng/ml. When the patient was 22 months of age, treatment with hydroxylated aromatic amino acid precursors was initiated, and after three months HVA and 5-HIAA levels were increased in CSF. The apparent restoration of biogenic amines in brain appears to have delayed the rate of neurological deterioration. DHPR activity in cultured skin fibroblasts of children with persistent hyperphenylalaninemia should permit early diagnosis and early treatment of this disorder.
在一名患有高苯丙氨酸血症和非典型苯丙酮尿症的儿童中，发现其肝脏、大脑和培养的皮肤成纤维细胞中严重缺乏二氢蝶啶还原酶（DHPR）。DHPR是辅助因子四氢生物蝶呤再生所必需的。该辅助因子在神经递质、血清素、多巴胺和去甲肾上腺素生物合成过程中芳香族氨基酸前体的羟基化过程中至关重要。在脑活检的灰质组织中，多巴胺含量低至每克组织3纳克，血清素几乎检测不到，而去甲肾上腺素含量高至每克1600纳克。脑脊液中，高香草酸（HVA）处于低正常水平，为33纳克/毫升，5-羟吲哚乙酸（5-HIAA）含量低，为4.2纳克/毫升，口服大剂量丙磺舒后，HVA积累受损，升至128纳克/毫升，5-HIAA升至22.4纳克/毫升。当患者22个月大时，开始用羟基化芳香族氨基酸前体进行治疗，三个月后脑脊液中HVA和5-HIAA水平升高。大脑中生物胺的明显恢复似乎延缓了神经功能恶化的速度。持续性高苯丙氨酸血症儿童培养的皮肤成纤维细胞中的DHPR活性应有助于对该疾病进行早期诊断和早期治疗。
