Cognitive and Psychological Risks for Diet-Managed Patients

Outcomes of diet-managed patients are not optimal

Even those PKU patients who follow the Phe-restricted diet are not immune to the effects of PKU. For those who are diet-managed and keep blood Phe in range, the subtle changes may occur in the following areas: executive functioning, processing speed, attention, inhibition, and motor control. PKU patients who are diet-managed but who do not consistently keep their blood Phe in the range specified by their doctors may exhibit changes in the following areas: verbal/IQ scales, memory, attention, cognitive, social, and behavioral/moods.^56-58

Diet-managed patients are still at risk for psychological and social problems

Early-treated PKU patients have been shown to be at risk of depression, anxiety, phobic tendencies, isolation from their peers, and features of Attention Deficit Hyperactivity Disorder (ADHD).⁵⁹ A systematic review of treated PKU patients suggests that both stressful dietary intervention and neurological impairment may play a part in behavior problems.⁵⁹ Several studies that were reviewed documented an association between behavior problems and both a lower IQ and poor Phe control.⁵⁹

Diet-managed PKU patients aged 5–20 years were found to report the use of stimulant medication significantly more (P<0.006) than an age- and sex-matched control group with chronic illness who saw medical personnel often and who also had to deal with a nontypical diet and lifestyle (type I diabetes mellitus patients).⁶⁰ Of the 10 continuously treated classic PKU patients who reported using stimulant medication, the mean blood Phe levels were significantly different than the 28 continuously treated classic PKU patients who did not use stimulant medication: 792 µmol/L vs 486 µmol/L, respectively (P<0.02).

Each parent of a stimulant drug–using child believed that the stimulant was efficacious in treating their child’s behavioral symptoms with no discontinuations.⁶⁰ The stimulant-drug effect did not appear to be achieved through lowering the Phe concentrations; mean plasma Phe concentration for the years before and after starting stimulant medications were not significantly different

Stimulant Medication Use in PKU Children Compared with Diabetic Children ⁶⁰

Case studies on patients with agoraphobia motivated a larger study in which 50 women with PKU were compared with 47 women without PKU and also 49 women with diabetes. All patients were administered a test of agoraphobic and avoidant behavior. The women with PKU had a 20% incidence of agoraphobic scores compared with 9% and 6% in the women without PKU and the women with diabetes, respectively. These results were also shown to correlate with blood Phe levels. In fact, reduced agoraphobic behavior correlated with lowered Phe levels.²

Additionally, early-treated adult PKU patients have shown an increase in psychiatric symptoms despite management with a Phe-restricted diet. In a cross-sectional study of 35 PKU patients aged 17–33 years and 181 controls, significant differences were observed for the following symptoms: depressed mood, phobias, generalized anxiety, hypochondriac worries, and anxiety involving the work place. Overall, patients in the study showed a pattern of predominantly emotional and functional symptoms in comparison with controls.¹

Cognitive problems still occur in early-treated patients

Even when managed with a restricted diet, PKU patients may develop cognitive problems. In a study comparing PKU patients and a diabetic control group, the children with PKU showed a reduced cognitive performance speed relative to the control group initially and at the 3-year follow-up. This result was observed in spite of the fact that blood Phe levels did not increase during the 3-year period. The deficit was due to performance speed only, for instance, a decrease in the speed of reading, naming, and in the interference task, and not due to specific frontal lobe–dependent functions. The mean IQ function of the PKU patients was 100 and did not differ from the general population.⁶¹

One observational clinical study compared children with PKU (n=46), children exposed to high levels of Phe prenatally due to maternal PKU (n=15), and a control group of the unaffected siblings of the PKU children (n=18). Antshel and Waisbren found that higher levels of Phe were toxic and detrimental to the neurological system in a dose-dependent fashion where executive function and cognitive tempo were concerned. Furthermore, the children exposed to Phe in utero had executive function difficulties consistent with ADHD.⁴

A retrospective study of 26 early and continuously treated PKU patients found school performance to also be significantly impaired compared with an age- and sex-matched control group (n=21). The mean age was 12.3 years. Fifty percent of the PKU patients presented with school problems. Of these, 10 (38.5%) required special tutoring and 3 others (11.5%) repeated classes. These numbers were significantly higher than the control group, in which 5 (23.8%) had school problems (4[19%] needed tutoring and 1[4.8%]repeated classes). Furthermore, the index of dietary control (IDC) in the PKU patients over the previous 6 months depicted a close, but not significant, relationship with school performance: the IDC over the previous 6 months in PKU patients without school problems was 449 µmol/L compared with 529 µmol/L in the PKU patients who experienced school problems.⁵⁸

Moyle et al looked at the cognitive deficits of 12 PKU patients who were early and continuously diet-managed patients until adolescence and compared them with an age- and sex-matched control group. The mean age of participants was 29 years. Their results showed a reduced speed of processing in 2 independent tests of the PKU group.⁵⁶ These data were consistent with previous research showing that adults with PKU display a reduced speed of processing, whether or not they are maintained on a low-Phe diet.⁶²

Working memory issues exist in diet-managed patients

In a recent study, children aged 6–17 with PKU, despite being managed with restricted diet, had significantly poorer working memory scores than controls. Younger children had a mean Phe of 7.0 mg/dL (420 µmol/L), while older children had a mean Phe level of 9.3 mg/dL (558 µmol/L). Working memory abilities appeared to decline with advancing age, even when Phe levels were managed within target range (mean blood Phe=8.3 mg/dL or 498 µmol/L). Effects tended to emerge over time.⁴³

Longitudinal tests were performed in a group of 148 early and continuously treated PKU subjects aged 6 months to 7 years who were divided into 3 age groups for appropriate cognitive testing measures, and were also performed in multiple control groups. Results showed that when both working memory and inhibitor control were required, children with Phe levels of 360–600 µmol/L performed worse than subjects with Phe levels below 360 µmol/L, unaffected siblings, and age- and sex-matched controls. In addition, the concurrent Phe levels were strongly and consistently related to performance on the tasks not only within the PKU group but within the same child over time. No evidence was shown that the difference in test results between PKU children with higher Phe levels and their matched controls changed over time when the ages of 6 months to 6 years were analyzed.⁴²