Matalon Reuben, Surendran Sankar, Matalon Kimberlee Michals, Tyring Stephen, Quast Michael, Jinga Wei, Ezell Edward, Szucs Sylvia
Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA.
Pediatrics. 2003 Dec;112(6 Pt 2):1570-4.
The treatment of phenylketonuria (PKU) in children and adults has been difficult because of erosion of dietary adherence, leading to poor school performance, impairment of executive functioning, loss of IQ, and deterioration of white matter in the brain. Mutant PKU mice produced by exposure to N-ethyl-N'-nitrosourea (ENU) were used to examine the effect of large neutral amino acid (LNAA) supplementation on brain and blood phenylalanine (Phe).
Mice with PKU, genotype ENU 2/2 with features of classical PKU, were supplemented with LNAA while on a normal diet. Two dosages of LNAA were given 0.5 g/kg and 1.0 g/kg by gavage. Blood Phe was determined in the experimental, control, and sham-treated mice. Brain Phe was determined by magnetic resonance spectroscopy after perchloric acid extraction. Branched-chain amino acid transferase (BCAT) was determined in brain as a marker for energy metabolism.
Blood Phe was reduced in the LNAA-treated mice by an average of 15% (0.5 g/kg) and 50% (1.0 g/kg) in 48 hours. There was a sustained decrease in the blood Phe levels over a 6-week trial. The untreated mice and sham-treated mice maintained high blood Phe throughout the experiments. Brain Phe level determined by magnetic resonance spectroscopy showed a decline of 46% after the LNAA treatment. BCAT levels were lower (33%) in the ENU 2/2 mice compared with wild-type. The BCAT normalized in mice with PKU that were treated with LNAA.
The results suggest that giving LNAA lowered brain and blood Phe levels in mice with PKU. Energy metabolism generated from BCAT also improved in mice with PKU after treatment with LNAA. Data from the mice suggest that LNAA should be considered among the strategies to treat PKU in humans.
由于饮食依从性下降，儿童和成人苯丙酮尿症（PKU）的治疗一直很困难，这会导致学业成绩不佳、执行功能受损、智商下降以及脑白质退化。通过暴露于N-乙基-N'-亚硝基脲（ENU）产生的突变型PKU小鼠用于研究补充大中性氨基酸（LNAA）对脑和血苯丙氨酸（Phe）的影响。
具有PKU的小鼠，基因型为ENU 2/2，具有典型PKU的特征，在正常饮食的同时补充LNAA。通过灌胃给予两种剂量的LNAA，分别为0.5 g/kg和1.0 g/kg。测定实验小鼠、对照小鼠和假处理小鼠的血Phe。用高氯酸提取后，通过磁共振波谱法测定脑Phe。测定脑中的支链氨基酸转移酶（BCAT）作为能量代谢的标志物。
在48小时内，LNAA处理的小鼠血Phe平均降低了15%（0.5 g/kg）和50%（1.0 g/kg）。在为期6周的试验中，血Phe水平持续下降。未处理的小鼠和假处理的小鼠在整个实验过程中血Phe水平一直很高。通过磁共振波谱法测定的脑Phe水平在LNAA处理后下降了46%。与野生型相比，ENU 2/2小鼠的BCAT水平较低（33%）。用LNAA处理的PKU小鼠的BCAT水平恢复正常。
结果表明，给予LNAA可降低PKU小鼠的脑和血Phe水平。用LNAA处理后，PKU小鼠中由BCAT产生的能量代谢也得到改善。小鼠实验数据表明，在治疗人类PKU的策略中应考虑使用LNAA。
