University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, the Netherlands.
University of Groningen, Groningen Institute for Evolutionary Life Sciences, Department of Molecular Neurobiology, Groningen, the Netherlands.
Mol Genet Metab. 2022 Jan;135(1):27-34. doi: 10.1016/j.ymgme.2021.11.003. Epub 2021 Dec 14.
Large neutral amino acid (LNAA) treatment has been suggested as alternative to the burdensome severe phenylalanine-restricted diet. While its working mechanisms and optimal composition have recently been further elucidated, the question whether LNAA treatment requires the natural protein-restricted diet, has still remained.
Firstly, to determine whether an additional liberalized natural protein-restricted diet could further improve brain amino acid and monoamine concentrations in phenylketonuria mice on LNAA treatment. Secondly, to compare the effect between LNAA treatment (without natural protein) restriction and different levels of a phenylalanine-restricted diet (without LNAA treatment) on brain amino acid and monoamine concentrations in phenylketonuria mice.
BTBR Pah-enu2 mice were divided into two experimental groups that received LNAA treatment with either an unrestricted or semi phenylalanine-restricted diet. Control groups included Pah-enu2 mice on the AIN-93 M diet, a severe or semi phenylalanine-restricted diet without LNAA treatment, and wild-type mice receiving the AIN-93 M diet. After ten weeks, brain and plasma samples were collected to measure amino acid profiles and brain monoaminergic neurotransmitter concentrations.
Adding a semi phenylalanine-restricted diet to LNAA treatment resulted in lower plasma phenylalanine but comparable brain amino acid and monoamine concentrations as compared to LNAA treatment (without phenylalanine restriction). LNAA treatment (without phenylalanine restriction) resulted in comparable brain monoamine but higher brain phenylalanine concentrations compared to the severe phenylalanine-restricted diet, and significantly higher brain monoamine but comparable phenylalanine concentrations as compared to the semi phenylalanine-restricted diet.
Present results in PKU mice suggest that LNAA treatment in PKU patients does not need the phenylalanine-restricted diet. In PKU mice, LNAA treatment (without phenylalanine restriction) was comparable to a severe phenylalanine-restricted diet with respect to brain monoamine concentrations, notwithstanding the higher plasma and brain phenylalanine concentrations, and resulted in comparable brain phenylalanine concentrations as on a semi phenylalanine-restricted diet.
大中性氨基酸（LNAA）治疗已被提议作为替代繁琐的严格苯丙氨酸限制饮食的方法。虽然其作用机制和最佳组成最近得到了进一步阐明，但 LNAA 治疗是否需要天然蛋白质限制饮食的问题仍然存在。
首先，确定在 LNAA 治疗的苯丙酮尿症小鼠中，额外的自由限制天然蛋白质限制饮食是否可以进一步提高大脑氨基酸和单胺浓度。其次，比较 LNAA 治疗（无天然蛋白质限制）和不同水平的苯丙氨酸限制饮食（无 LNAA 治疗）对苯丙酮尿症小鼠大脑氨基酸和单胺浓度的影响。
BTBR Pah-enu2 小鼠分为两组，分别接受 LNAA 治疗和限制或半限制苯丙氨酸的饮食。对照组包括接受 AIN-93 M 饮食的 Pah-enu2 小鼠、无 LNAA 治疗的严格或半限制苯丙氨酸饮食、以及接受 AIN-93 M 饮食的野生型小鼠。十周后，收集脑和血浆样本以测量氨基酸谱和脑单胺能神经递质浓度。
与 LNAA 治疗（无苯丙氨酸限制）相比，在 LNAA 治疗中添加半限制苯丙氨酸饮食可降低血浆苯丙氨酸水平，但大脑氨基酸和单胺浓度相似。LNAA 治疗（无苯丙氨酸限制）与严格苯丙氨酸限制饮食相比，大脑单胺浓度相似，但大脑苯丙氨酸浓度较高，与半限制苯丙氨酸限制饮食相比，大脑单胺浓度显著较高，但苯丙氨酸浓度相似。
本研究结果表明，PKU 患者的 LNAA 治疗不需要限制苯丙氨酸饮食。在 PKU 小鼠中，LNAA 治疗（无苯丙氨酸限制）在大脑单胺浓度方面与严格的苯丙氨酸限制饮食相当，尽管血浆和大脑苯丙氨酸浓度较高，但与半限制苯丙氨酸限制饮食的大脑苯丙氨酸浓度相当。
