Adult cognitive outcomes in phenylketonuria: explaining causes of variability beyond average Phe levels

Abstract

ObjectiveThe 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.MethodWe 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.ResultsPhe 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.ConclusionsOur 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 statementsWe 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.

Cognitive Outcomes and Relationships with Phenylalanine in Phenylketonuria: A Comparison between Italian and English Adult Samples

“…However, we do not know what effects prolonged high-levels of Phe may have on aging brains. Our results suggest that the effect of Phe on the brain is different in childhood to early adulthood [ 6 ], but further interactions may be seen later in life. Knowing which functions and relative tasks are most affected and most sensitive to Phe in young adults with PKU provides an important base-line to compare outcomes across the life-span and evaluate the effectiveness of treatment.…”

“…We used a χ 2 s to assess the significance of a positive/negative correlations ratio against a chance 50/50 ratio, which is expected if no true relation exists between cognitive performance and metabolic control. In addition, we used a one-sample t -test to assess whether the average correlation was significantly different from 0 (see Romani et al, [ 6 ] for a similar methodology). We carried out these analyses on both Italian and English PKU samples.…”

“…The objectives of the present study are twofold: 1. we aim to replicate results previously obtained with a relatively large sample of English AwPKU ( N = 37) [ 5 , 6 , 15 , 32 ] by administering a subset of tasks to a new sample of Italian patients; 2. we aim to demonstrate that the same tasks which are sensitive to blood Phe in English are also sensitive in Italian so that they also demonstrate impairments and relationships with blood Phe levels and Phe fluctuations throughout the lifespan. A comparison between English and Italian PKU samples is particularly relevant given differences in the approach to food and diet in the two countries.…”

“…The PKU diet is expensive, unpalatable, and unsociable. Thus, it is often self-relaxed in late childhood and abandoned during late adolescence [ 5 , 6 , 7 , 8 , 9 ]. Possibly because Phe levels remain suboptimal, on average, people with PKU do not reach their full cognitive potentials [ 7 ].…”

“…While Phe may be particularly toxic for developing brains, we need evidence of the safety of accumulating high Phe levels on aging brains. Finally, it is important to understand whether some individuals are less affected by high Phe since there is some evidence of individual variation [ 6 , 22 , 23 , 24 ]. For a few people with PKU, it may be less important to keep on a strict diet.…”