Division of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, the Netherlands.
Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Mol Genet Metab. 2021 May;133(1):49-55. doi: 10.1016/j.ymgme.2021.02.008. Epub 2021 Mar 6.
In patients with phenylketonuria, stability of blood phenylalanine and tyrosine concentrations might influence brain chemistry and therefore patient outcome. This study prospectively investigated the effects of tetrahydrobiopterin (BH4), as a chaperone of phenylalanine hydroxylase on diurnal and day-to-day variations of blood phenylalanine and tyrosine concentrations.
Blood phenylalanine and tyrosine were measured in dried blood spots (DBS) four times daily for 2 days (fasting, before lunch, before dinner, evening) and once daily (fasting) for 6 days in a randomized cross-over design with a period with BH4 and a period without BH4. The sequence was randomized. Eleven proven BH4 responsive PKU patients participated, 5 of them used protein substitutes during BH4 treatment. Natural protein intake and protein substitute dosing was adjusted during the period without BH4 in order to keep DBS phenylalanine levels within target range. Patients filled out a 3-day food diary during both study periods. Variations of DBS phenylalanine and Tyr were expressed in standard deviations (SD) and coefficient of variation (CV).
BH4 treatment did not significantly influence day-to-day phenylalanine and tyrosine variations nor diurnal phenylalanine variations, but decreased diurnal tyrosine variations (median SD 17.6 μmol/l, median CV 21.3%, p = 0.01) compared to diet only (median SD 34.2 μmol/l, median CV 43.2%). Consequently, during BH4 treatment diurnal phenylalanine/tyrosine ratio variation was smaller, while fasting tyrosine levels tended to be higher.
BH4 did not impact phenylalanine variation but decreased diurnal tyrosine and phenylalanine/tyrosine ratio variations, possibly explained by less use of protein substitute and increased tyrosine synthesis.
在苯丙酮尿症（PKU）患者中，血液苯丙氨酸和酪氨酸浓度的稳定性可能会影响大脑化学物质，从而影响患者的预后。本研究前瞻性地研究了四氢生物蝶呤（BH4）作为苯丙氨酸羟化酶的伴侣对血液苯丙氨酸和酪氨酸浓度的日间和日常变化的影响。
采用随机交叉设计，在 BH4 治疗期和无 BH4 治疗期各进行 6 天，每天在空腹、午餐前、晚餐前、晚上 4 次测量干血斑（DBS）中的血液苯丙氨酸和酪氨酸浓度，每天 1 次测量空腹血样。序列是随机的。11 名确诊的 BH4 反应性 PKU 患者参与了研究，其中 5 名患者在 BH4 治疗期间使用了蛋白质替代物。在无 BH4 治疗期间，调整天然蛋白质摄入和蛋白质替代物的剂量，以使 DBS 苯丙氨酸水平保持在目标范围内。患者在两个研究期间都填写了 3 天的食物日记。DBS 苯丙氨酸和 Tyr 的变化以标准差（SD）和变异系数（CV）表示。
BH4 治疗并未显著影响日常苯丙氨酸和酪氨酸的变化，也未影响日间苯丙氨酸的变化，但与仅饮食治疗相比，降低了日间酪氨酸的变化（中位数 SD 17.6 μmol/L，中位数 CV 21.3%，p = 0.01）。因此，在 BH4 治疗期间，日间苯丙氨酸/酪氨酸比值的变化较小，而空腹时酪氨酸水平往往较高。
BH4 治疗并未影响苯丙氨酸的变化，但降低了日间酪氨酸和苯丙氨酸/酪氨酸比值的变化，这可能是由于减少了蛋白质替代物的使用和增加了酪氨酸的合成。
