OBJECTIVE The objective was to deepen the understanding of the causes of individual variability in phenylketonuria (PKU) by investigating which metabolic variables are most important for predicting cognitive outcomes (Phe average vs Phe variation) and by assessing the risk of cognitive impairment associated with adopting a more relaxed approach to the diet than is currently recommended. METHOD We analysed associations between metabolic and cognitive measures in a mixed sample of English and Italian early-treated adults with PKU (N = 56). Metabolic measures were collected through childhood, adolescence and adulthood; cognitive measures were collected in adulthood. Metabolic measures included average Phe levels (average of median values for each year in a given period) and average Phe variations (average yearly standard deviations). Cognition was measured with IQ and a battery of cognitive tasks. RESULTS Phe variation was as important, if not more important, than Phe average in predicting adult outcomes and contributed independently. Phe variation was particularly detrimental in childhood. Together, childhood Phe variation and adult Phe average predicted around 40% of the variation in cognitive scores. Poor cognitive scores (> 1 SD from controls) occurred almost exclusively in individuals with poor metabolic control and the risk of poor scores was about 30% higher in individuals with Phe values exceeding recommended thresholds. CONCLUSIONS Our results provide support for current European guidelines (average Phe value = < 360 μmol/l in childhood; = < 600 μmo/l from 12 years onwards), but they suggest an additional recommendation to maintain stable levels (possibly Phe SD = < 180 μmol/l throughout life). PUBLIC SIGNIFICANCE STATEMENTS We investigated the relationship between how well people with phenylketonuria control blood Phe throughout their life and their ability to carry out cognitive tasks in adulthood. We found that avoiding blood Phe peaks was as important if not more important that maintaining average low Phe levels. This was particularly essential in childhood. We also found that blood Phe levels above recommended European guidelines was associated with around 30% increase in the risk of poor cognitive outcomes.

中文翻译：

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苯丙酮尿症的成人认知结局：解释超出平均Phe水平的变异原因。

目的目的是通过研究哪些代谢变量对于预测认知结果最重要（Phe平均值与Phe变异）并评估与采用苯丙酮尿症有关的认知障碍的风险，从而加深对苯丙酮尿症（PKU）个体变异原因的理解。比目前建议的饮食更轻松的饮食方法。方法我们分析了英国和意大利的PKU早期治疗成年人（N = 56）的混合样本中新陈代谢和认知指标之间的关联。通过儿童，青春期和成年期收集代谢指标；成年后收集了认知指标。代谢测量包括平均Phe水平（给定时间段内每年平均值的平均值）和平均Phe变化（平均每年标准偏差）。认知是通过智商和一系列认知任务来衡量的。结果Phe变异在预测成人结局方面与Phe平均值一样重要，甚至更为重要，并且独立发挥作用。苯丙氨酸的变异对儿童尤其有害。儿童Phe变异和成人Phe平均值共同预测了认知分数变异的约40％。不良的认知评分（对照组的> 1 SD）几乎仅发生在代谢控制较差的个体中，Phe值超过建议阈值的个体的不良评分风险大约高30％。结论我们的研究结果为当前的欧洲指南提供了支持（儿童平均Phe值= <360μmol/ l，从12岁开始= = 600μmo/ l），但他们提出了另一项建议，以保持稳定水平（可能在整个生命周期中Phe SD = <180μmol/ l）。公开意义声明我们研究了苯丙酮尿症患者一生中对血液苯丙氨酸的控制状况与成年后执行认知任务的能力之间的关系。我们发现，避免血液中Phe峰与保持平均低Phe水平同等重要，甚至更为重要。这在童年时期尤其重要。我们还发现，高于建议的欧洲指南的血液苯丙氨酸水平与不良认知结果风险增加约30％有关。公开意义声明我们研究了苯丙酮尿症患者一生中对血液苯丙氨酸的控制状况与成年后执行认知任务的能力之间的关系。我们发现，避免血液中Phe峰与保持平均低Phe水平同等重要，甚至更为重要。这在童年时期尤其重要。我们还发现，高于建议的欧洲指南的血液苯丙氨酸水平与不良认知结果风险增加约30％有关。公开意义声明我们研究了苯丙酮尿症患者一生中对血液苯丙氨酸的控制状况与成年后执行认知任务的能力之间的关系。我们发现，避免血液中Phe峰与保持平均低Phe水平同等重要，甚至更为重要。这在童年时期尤其重要。我们还发现，高于建议的欧洲指南的血液苯丙氨酸水平与不良认知结果风险增加约30％有关。