Phe Response

It is well known that deleterious effects on neurocognition, intelligence, and executive functioning are associated with high blood and brain concentrations of Phe in patients diagnosed with phenylketonuria (PKU).²² The purpose of dietary Phe restrictions is to lower blood and brain Phe levels, thereby reducing the risk of damage to the brain.

There is speculation that fluctuations in Phe levels are of potential significance in their relation to intelligence and neurocognition; however, there remains no current definition regarding Phe fluctuations and these have been measured in many different ways (e.g., standard deviation [SD], regression analysis of Phe concentrations, standard error of the estimate [SEE], and mean and its accompanying SD of index dietary control [IDC] measured by six-month mean Phe values).²² In the review by Cleary et al.,²² it was noted that a number of studies have reported that the highest concentrations of Phe were seen in the morning in patients with PKU when observing diurnal variation of blood Phe levels. Other studies identified in this review have also reported that there may be up to 400% variation in day-to-day blood Phe levels in adults with well-controlled PKU, that blood Phe levels fluctuate to a larger extent in patients with PKU when compared with healthy patients, that blood Phe concentrations increase with age while there is uncertainty regarding whether fluctuations decrease with age, and that fluctuations may be influenced by genotype, rates of growth, dietary adherence, diet, and illness.²²

With regard to the impact of blood Phe fluctuations on the brain, Cleary et al.²² reported that healthy controls have approximately equal concentrations of blood and brain Phe concentrations, while increases in Phe concentrations in the blood are higher than increases in the brain in patients with PKU. In addition, they noted that peaks of Phe levels last longer, are not as steep, and occur later in the brain when compared with blood in these patients.²² There is contradicting evidence regarding the effects on neurocognition, measures of brain activity, and Phe fluctuations in patients with PKU, with some studies showing correlations between Phe fluctuations and deficits in executive functioning, cognition, and intelligence while others finding no associations.²² Hood et al.²³ reported that Phe variability was a better predictor of cognitive performance when compared with the various other aforementioned indices of Phe control, along with being a better predictor of executive functioning in children aged five years and older when compared with patients younger than five years of age. Hood et al.²⁴ retrospectively analyzed the microstructural white matter integrity using mean diffusivity from diffusion tensor imaging and various Phe indices to measure blood Phe concentrations in early and continuously treated patients with PKU in order to determine if prolonged exposure to both high and variable levels of blood Phe correlated with white matter compromise. The authors reported that microstructural white matter integrity compromise was correlated with mean Phe, the IDC, mean exposure, and the SD of exposure, indicating that high and variable blood Phe concentrations were predictors of white matter compromise in this population.²⁴ Viau et al.³⁰ suggested that there was an association between measures of intelligence and the quality of metabolic blood Phe control during certain developmental periods. Perceptual reasoning appeared to be strongly associated with proper blood Phe control during their zero-to-six and seven-to-12 years of age periods, with specific areas of verbal comprehension being affected by increases of blood Phe levels in children aged zero to six years.³⁰ However, the evidence obtained by Viau et al.³⁰ was not supportive that blood Phe level variability was good indicator of intelligence. That being said, all of these results indicate that continual blood Phe concentrations should be monitored and controlled in childhood and that this should continue throughout the life of the patient with PKU.^22-24

ADHD-RS-IV and ASRS

The ADHD-RS-IV scale is based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria used to assess ADHD symptoms in children and is completed by a parent or guardian.²⁵ The full scale comprises 18 items that are separated into two subscales: an Inattention subscale and a Hyperactivity-Impulsivity subscale. Each of the subscales is composed of nine items that assess the frequency of ADHD symptoms, with each item rated on a four-point Likert frequency scale (0 = never or rarely; 1 = sometimes; 2 = often; and 3 = very often).²⁵ The recall period is one month. A higher score corresponds with worse severity of ADHD. This scale has been observed to be reliable and valid in children with ADHD.²⁵ In the Inattention subscale, scores range from 0 to 27, with greater inattentive severity measured with higher scores.²⁵

The full ASRS scale is also an 18-item instrument that was developed to assess ADHD symptom and behaviour frequency in adults.²⁵ It is a self-rated instrument with five response options for each of the 18 items (0 = never; 1 = rarely; 2 = sometimes; 3 = often; and 4 = very often), which are subdivided into two subsections: Part A, which measures inattention symptoms, and Part B, which measures hyperactivity and impulsivity symptoms.²⁵ It has a recall period of one month. Scores range from 0 to 36 in the ASRS Inattention score, with higher scores indicating a greater amount of inattentive severity.²⁵

Wyrwich et al.²⁵ used only the summed nine-item Inattention subscale in both of these scales in order to ascertain its validity, reliability, and responsiveness in patients with PKU from PKU-016 who were undergoing treatment with SAP. The Inattention subscales of both the ADHD-RS-IV and ASRS were observed to be valid, reliable, responsive, and robust measures of inattention in children with PKU aged eight years or older.²⁵ No MCIDs for children with PKU were available for either of the subscale scores.

Brief

The BRIEF was developed to systematically and quantitatively assess everyday behaviour, by recording common descriptors of executive function-related behaviours. The BRIEF—Adult Version (BRIEF-A) is a self-reported questionnaire for patients aged 18 years or older, whereas the Parent Form of the BRIEF (BRIEF-Parent) is a parent- or legal guardian—reported questionnaire for patients younger than 18 years. The BRIEF-Parent contains 86 items within eight clinical scales that measure different aspects in three index scales including Behavioral Regulation Index (BRI), Metacognition Index (MI), and Global Executive Composite (GEC). The BRIEF includes three-point Likert scale items that indicate the extent to which the child’s behaviour never occurred (1), sometimes occurred (2), or occurred often (3). The raw total score is calculated by totalling the scores of 72 items constituting eight subscales. The BRIEF-A is composed of 75 items within nine clinical scales and three index scales. The raw total score is calculated by totalling the scores of 70 items constituting nine subscales.

No relevant information on the validity or reliability of the BRIEF instrument could be located following a focused medical literature search.