Revision of treatments and guidelines for phenylketonuria: evidence from neurocognition

An inborn, inherited, error of metabolism, phenylketonuria (PKU) is a rare, highly treatable disease. In contrast to its relatively treatable nature, when left untreated, PKU can result in seizures, intellectual disability, and further medical issues. The most common method for prevention is the early introduction of a strict diet highlighting the restriction of phenylalanine (Phe). Despite its treatability, patients with PKU show an average 8-10 points lower than normal in addition to underperforming in neuropsychological tests.

Cognitive impairments have been associated with concurrent blood Phe levels, and even more so with lifetime blood Phe levels. The question being raised by the authors concerns whether or not the recommend Phe level for patients with PKU is too high. Currently, from the age of 0-10, this level varies between 240 and 360 micromolars/L. The drawback is that this range is not the result of studies comparing outcomes at Phe levels <240 micromolar/L, between 240 and 360 micromolar/L, and >360 micromolar/L.

Current treatment advises an absolute upper target level for Phe levels, not taking into account possible fluctuations of Phe values and the phenylalanine:tyrosine ratio (Phe:Tyr). This feeds into the second area of question the authors pose: what are the effects of lifetime Phe, concurrent Phe, variation in lifetime Phe levels, and lifetime and concurrent Phe:Tyr in predicting cognitive outcome in early and continuously treated children and adolescents with PKU

Methods

Participants consisted of 67 patients with PKU with a mean age of 10.8, and a control group of 73 participants with a mean age of 10.9 recruited from friends and families of patients and also local newspaper advertisements. Of the patients with PKU, 27 had pretreatment Phe levels of > 1200, 18 had pretreatment Phe levels between 600-1200, and 18 had pretreatment Phe levels <600, and 12 patients had pretreatment Phe levels <360. To test for concurrent Phe and Tyr levels, a blood sample was taken in the morning following an overnight fast. This was also used to test for lifetime Phe level. Through a series of computer based neuropsychological tests, executive functions inhibitory control and motor control were measured.

Results and discussion

Patients with Phe levels >360 differed in 2 of 3 inhibition tasks, motor control, and cognitive flexibility. Controls performed notably more accurately than patients with Phe levels between 240-360. A key finding was that patients with Phe levels <240 performed no different to the control group. Additionally, patients with Phe levels <240 outperformed those with Phe levels between 240-360.

It was found that Phe variation, lifetime and concurrent Phe, and lifetime and concurrent Phe:Tyr were significantly related to speed and accuracy on numerous cognitive tests and also to each other.

The two major findings of this study are:

1. Youths from the age of 6-15 with mean Phe levels of <240 since birth outperformed their peers with Phe levels between 240-360 on cognitive tests measuring motor control, inhibition, and cognitive flexibility.
2. Phe:Tyr and Phe variation may have predictive value in regards to motor control ad executive functioning.

The PKU-COBESO study

As mentioned in previous studies examined, phenylketonuria (PKU) is an inherited metabolic disorder. In the case of someone with the disease, there is a deficiency in the phenylalanine hydroxylase enzyme and as a result, phenylalanine (Phe) cannot be converted into tyrosine (Tyr). This excess of Phe, in combination with a lack of Tyr can lead to shortages of important neurotransmitters such as serotonin and dopamine. Serotonin is linked to cognitive functioning and a lack of it can result in decreased cognitive functioning. Dopamine is associated with the executive functioning primarily in the prefrontal cortex. There is a considerate lack of studies concerning behavioral problems and social skills for those with PKU. The aim of the study presented here is to explain a new Dutch multicenter study, namely the PKU-COBESO study. The primary goal of the PKU-COBESO study is to examine the behavioral problems, social functioning, cognitive functioning, and executive functioning in both continuous and early treatment patients principally in regards to their metabolic control.

Looking at the procedure for the PKU-COBESO study

The experiment sample for the study consisted of young adult patients with PKU who had beforehand participated in a neuropsychological study 10-15 years previous, and another group of patients who did not participate in the previous neuropsychological study. In the control group, participants were recruited from either the families and friends of the patients, or from non-family participants.

The study itself consisted of a neuropsychological assessment, questionnaires, and an analysis of the PKU patients’ metabolic control. The neurological assessment comprised of a combination of either the WISCIII or WAISCIII (depending on the participants age) and the ANT (Amsterdam Neuropsychological Tasks), and numerous paper and pencil tasks. The aim of the neuropsychological component was to measure:

1. Executive functions

2. Social cognitive skills

3. Motor control

The questionnaires aimed to ascertain:

1. General demographic information

2. Executive functioning throughout daily life

3. Social functioning

4. Mental health/behavioral problems

Blood samples were taken from the PKU patients in order to determine concurrent Phe and Tyr levels, and the levels of other metabolic features.

Examining the findings in the preliminary results

In the preliminary analysis, results showed that adult PKU patients differed on ‘internalizing problems’, reported more ‘avoidant personality problems’, scored worse on ‘relationships’ and also ‘self care’. Additionally, the concurrent Phe levels of adults with PKU were not significantly related to social skills and behavioral problems. Childhood Phe levels were shown to be significantly related to ‘thinking problems’ and ‘somatic problems’.

For discussion

The PKU-COBESO study has two main questions it seeks to answer:

1. How does leniency of diet in early stages of PKU go on to influence cognitive and behavioral functioning, and the potential for an adult to thrive in life.

2. To what extent do Phe influenced cognitive problems manifest in the daily living of PKU patients.

The results of the study should be considered preliminary. Having said that, the results are complimentary to the expected findings and provide evidence for the importance of further study focusing on the mental health and social functioning in early treated PKU.

Investigating the usefulness of BRIEF in day to day care of patients with phenylketonuria

The origins, effects, and treatment of PKU have been discussed previously. The following article focuses on the effects PKU has on executive functioning specifically. To ascertain these effects the implementation of the Behavior Rating Inventory of Executive Functioning (BRIEF) is proposed. This is an easily applied standardized questionnaire which can also be employed by non-psychologists. However, the accuracy of the BRIEF has been called in to question. To address this, the authors also use the Amsterdam Neuropsychological Tasks (ANT) measure, which has been used several times in the past to ascertain the neurocognitive functioning of PKU patients of various ages and early and continued treatment. Using the two tests, the authors attempt to investigate whether the BRIEF-A (adult version) is a useful instrument in the screening of patients with PKU during their daily living.

Procedure

The sample for this study consisted of 55 Dutch adult patients with PKU. Additionally, this study was a part of the PKU-COBESO mentioned in the previous article. The BRIEF-A test consisted of 75 questions 9 subdomains related to executive functioning, 4 subdomains which determine the Behavioral Regulation Index (BRI). The overall executive functioning in daily life score is denoted as the Global Executive Composite (GEC).

For the ANT, three tests were used to measure executive functioning: Shifting Attentional Set Visual (SSV), Sustained Attention Dots (SAD), and Feature Identification (FI).

Looking at results

Of the 55 patients, 23 scored within the borderline/clinical range of the BRIEF-A. Patients showed problems in the domains of cognitive flexibility and inhibitory control when compared to the healthy population. Subsequently, two groups were formed on the basis of BRIEF-A GEC scores using a cutoff T-score of >= 60 (>1 SD above the mean). No significant differences were found between the groups on the basis of gender, age, and IQ. Additionally, no significant differences were found between the two groups on concurrent and historical Phe concentration levels. There was found to be some agreement between the BRIEF and the ANT indicating that the null hypothesis could not be rejected.

For discussion

The fact that patients with PKU still face problems in attention and learning was the driving factor for this investigation into the efficacy of the BRIEF as a tool for monitoring patients. The results show that 42% of patients scored in the borderline/clinical range. Despite this, only 11% of patients showed scores greater than 1 SD. From the results of the ANT, we see that PKU patients had problems with inhibitory control and cognitive flexibility. The BRIEF-A appears to identify executive dysfunction across studies.