Biopterin synthesis defect. Treatment with L-dopa and 5-hydroxytryptophan compared with therapy with a tetrahydropterin.
Biopterin synthesis defect. Treatment with L-dopa and 5-hydroxytryptophan compared with therapy with a tetrahydropterin.
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生物蝶呤合成缺陷。
DOI：
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发表时间：
1984
影响因子：
15.9
通讯作者：
W. Hanley
中科院分区：
文献类型：
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作者：
R. Mcinnes;S. Kaufman;J. Warsh;G. van Loon;S. Milstien;G. Kapatos;S. Soldin;P. Walsh;D. Macgregor;W. Hanley
我们已经确定了一个普遍缺乏单胺类神经递质的患者与生物蝶呤合成缺陷。研究了神经递质前体（L-3，4-二羟基苯丙氨酸[L-多巴]、5-羟基色氨酸[5-HTP]和四氢蝶呤[6-甲基四氢蝶呤（6 MPH 4）]使单胺神经递质代谢正常化的能力。治疗前，血浆、脑脊液或尿液中多巴胺（DA）、去甲肾上腺素、肾上腺素和六种单胺代谢物的浓度非常低或检测不到。L-Dopa和5-HTP替代治疗开始于7月龄。这种疗法通常纠正单胺及其代谢产物的缺乏，并改善神经发育，直到25个月。尽管有这些益处，但间歇给予L-多巴不能稳定改善急性神经功能或DA代谢。左旋多巴给药后3 h内，患者血浆DA水平与运动活动和警觉性呈平行上升和下降趋势。临床最佳剂量的左旋多巴产生正常的血浆去甲肾上腺素和肾上腺素水平，但过量的DA及其代谢产物浓度。此外，L-多巴的临床和生化作用分别被苯丙氨酸和5-HTP抑制，表明这些氨基酸具有拮抗药理作用。在35月龄时，尝试使用高剂量（8-38 mg/kg/d）的6 MPH 4对这种疾病的单胺缺乏和高苯丙氨酸血症进行生理纠正。合成的四氢生物蝶呤类似物6 MPH 4控制高苯丙氨酸血症。在脑脊液中获得显著浓度的6 MPH 4;未检测到神经系统改善或中枢神经系统单胺合成刺激。这些研究结果表明，L-多巴和5-HTP的替代治疗的复杂性，但表明，这种治疗可能是部分有效的生物喋呤缺乏的患者谁是高剂量的四氢蝶呤无反应。
We have identified a generalized deficiency of monoamine neurotransmitters in a patient with a defect in biopterin synthesis. Neurotransmitter precursors (L-3,4-dihydroxyphenylalanine [L-dopa]; 5-hydroxytryptophan [5-HTP] and a tetrahydropterin [6-methyltetrahydropterin (6MPH4)] were investigated for their ability to normalize monoamine neurotransmitter metabolism. Before treatment, the concentrations of dopamine (DA), norepinephrine, epinephrine, and six monoamine metabolites were very low or undetectable in plasma, cerebrospinal fluid, or urine. L-Dopa and 5-HTP replacement was begun at age 7 mo. This therapy generally corrected the deficiency of monoamines and their metabolites, and improved neurological development until the age of 25 mo. Despite these benefits, the intermittent administration of L-dopa could not produce a stable improvement of acute neurological function or DA metabolism. In the 3 h after L-dopa administration, plasma DA and the motor activity and alertness of the patient rose and fell in parallel. Doses of L-dopa that were clinically optimal produced normal plasma levels of norepinephrine and epinephrine, but excessive concentrations of DA and its metabolites. Furthermore, the clinical and biochemical effects of L-dopa were inhibited by phenylalanine and 5-HTP, respectively, demonstrating that these amino acids have antagonistic pharmacological effects. Physiological correction of the monoamine deficit and the hyperphenylalaninemia of this disorder was attempted at age 35 mo using high doses (8-38 mg/kg per d) of 6MPH4. 6MPH4, a synthetic analogue of tetrahydrobiopterin, controlled the hyperphenylalaninemia. Significant concentrations of 6MPH4 were obtained in the cerebrospinal fluid; no neurological improvement or stimulation of monoamine synthesis in the central nervous system was detected. These findings indicate the complexity in replacement therapy with L-dopa and 5-HTP, but suggest that this treatment may be partially effective in biopterin-deficient patients who are unresponsive to high doses of tetrahydropterins.