Executive Functioning of 4 Children With Hyperphenylalaninemia From Childhood to Adolescence

Case Report

Ethical approval for the study described was obtained from the Queensland University of Technology Human Research Ethics Committee and the Royal Children’s Hospital, Brisbane, Queensland, Ethics Committee. Written parental consent was obtained at both testing periods, as well as written child consent at the second testing period (adolescence). Two sibling pairs (3 boys, 1 girl) with hyperphenylalaninemia were assessed in 2001/2002 at a mean age of 4.66 years and again in 2009 at a mean age of 12.45 years on the EF measures reported below. The metabolic dietitian advised that all 4 children were adhering to a protein-restricted diet (but much less restricted than the classic PKU diet) and that they were cautiously treated and therefore prescribed enough PKU supplemental formula to ensure a minimum intake of 1 g protein/kg of body weight per day.

In 2001/2002, testing took place in the children’s home and was conducted by Dr Toni Jones. In 2009, testing took place on-site at the Royal Children’s Hospital Queensland and was conducted by Dr Rachael Sharman. Dr Sharman was blind to the adolescents’ biochemical levels and previous EF results at the time of testing. The children completed the following tests at a mean age of 4.66 years (age range: 3 years, 5 months, to 6 years, 11 months) and ∼8 years later at a mean age of 12.45 years:

1. Rey-Osterreith Complex Figure Test⁹: a commonly used test of visuospatial planning (standard scoring)

2. Wechsler Intelligence Scale for Children, Fourth Edition¹⁰, Digit Span: a working memory subtest

3. Neuropsychological Assessment II¹¹ Comprehension of Instructions: a comprehension task that involves a component of working memory (a series of instructions that need to be performed in a specific order and become increasingly lengthy and complex)

At the 2009 testing, the adolescents also completed the NEPSY-II Inhibition Task¹¹: this is a Stroop-type test highly similar to Diamond et al’s¹² original (day-night) Stroop task, which suggested that children with well-controlled PKU may still show subtle deficits. Children progress through 3 stages of the task, culminating in them holding and switching between 2 rules in mind, while inhibiting a prepotent response. Parents also completed the Behavior Rating Inventory of Executive Function¹³, an ecologically valid measure of EF recommended by the Waisbren and White¹⁴ review of the most appropriate instruments for assessment of EF in children with PKU.

Phenylalanine and tyrosine levels of these 4 children were available from infancy to the day of testing. Newborn screening phenylalanine values ranged from 320 to 550 μmol. Minimum monthly testing of phenylalanine was recorded across their lifetimes. Tyrosine levels were available on a sporadic basis before the year 2000 and at all phenylalanine testing points after the year 2000. Lifetime mean (SD) phenylalanine was 227 (20.7) μmol, lifetime mean tyrosine was 85 (17) μmol, lifetime mean phenylalanine:tyrosine ratio was 3.2 (0.79), concurrent mean phenylalanine was 295 (48) μmol, concurrent mean tyrosine was 80 (23.4) μmol, and concurrent mean phenylalanine:tyrosine ratio was 4 (1.9). Phenylalanine tolerance testing had also taken place for the participants at age 5 years and in early adolescence. Tolerance at age 5 years ranged from 40 to 66 mg/kg per day and in early adolescence from 55 to 63 mg/kg per day (note there were data for 3 of 4 participants only at adolescence). According to Campistol et al,² the combination of their mean phenylalanine levels and tolerance places these children in the mild hyperphenylalaninemia range.

Further analysis of the children’s phenylalanine levels showed they rarely exceeded 400 μmol at any 1 point during their lifetime. Their historical records indicated that 3 of the children demonstrated a phenylalanine level >400 μmol (1 child had a maximum of 420 μmol on 1 testing occasion, 1 child had a level of 470 μmol on 1 testing occasion, and 1 child had levels of 420 and 430 μmol on 2 testing occasions, respectively).

Table 1 presents means, SDs, and ranges for the EF tests. Rey-Osterreith Complex Figure Test performance was scored as either normal or impaired according to age-expected norms at both time points (early childhood and again at adolescence). The Wechsler Intelligence Scale for Children, Fourth Edition, Digit Span, and NEPSY II language comprehension task and inhibition (Stroop) tasks are represented as scaled scores (10 = average, 3 = 1 SD; higher scores represent better function). The Behavior Rating Inventory of Executive Function results are represented by t-scores (average = 50, 10 = 1 SD; higher t-scores represent higher levels of impairment). Clinically, EF impairment is suggested if any individual score is ≥1.5 SDs worse than the age-expected mean.

Table 1 shows that these 4 children with mild hyperphenylalaninemia performed within normal ranges on every task (ie, no individual child performed ≥1.5 SDs worse than the age-expected norm). No deterioration in performance was apparent from childhood to adolescence on the 3 tests available for longitudinal analysis.