Higher blood PHE concentrations are associated with decreased performance on intelligence quotient (IQ) measures (F.2176, F.2627, F.2629, F.1197). In the AHRQ systematic review of 17 studies including 432 individuals with PKU, the association between high blood PHE concentration and decreased IQ was strongest when considering historical blood PHE (measured more than one year prior to testing) versus concurrent blood PHE (measured <6 weeks prior), and when looking at critical periods of development (< age 6 years). Increased PHE was associated with decreased IQ when blood PHE exceeded 400 μmol/L, supporting the frequently recommended blood PHE treatment range of 120-360 μmol/L (L.130). Blood PHE was also correlated with IQ beyond the critical period, lending support for continued intervention to maintain low blood PHE in older children and adults (F.2176). The ACMG recommends that blood PHE be maintained at 120-360 μmol/L for all ages (F.2626).

In both Delphi surveys and in the Nominal Group, there was consensus for the recommendation that blood PHE be maintained between 120-360 μmol/L; agreement was strongest for infants and children, including adolescents, and declined for adults and those returning to diet. Specifically:

In Delphi I, over 80% of all participants agreed that the recommended upper limit for blood PHE should be 360 μmol/l. For children ages 0-5 years there was 88% agreement and for children age 6-11 years there was 84% agreement. Agreement that 360 μmol/L should be the upper limit for blood PHE diminished for older children. For children age 12-18 years, 72% of participants agreed, and for individuals over age 18 years 63% of participants agreed. Comments noted the target goal of 360 μmol/L as desirable but not always achievable.

In Dephi 2, 100% of participants agreed that blood PHE concentration of 360 µmol/L is an appropriate upper limit for 0-2 years of age. The level of agreement declined for older age groups and for individuals who are late-treated or returning to diet. Specifically, agreement was: 90% for 12-18 years, 86% for 18 years and older, 67% for late-treated, 71% for returning to diet, and 76% during pregnancy. Comments suggested that adults, late-treated and those returning to diet, may be discouraged if they do not achieve these recommended goals. Comments also noted that during pregnancy the upper limit of treatment range should be lowered.

Although there was lack of consensus regarding a recommended treatment range for late- or untreated adults, or those returning to diet, 66% of respondents agreed on 360 μmol/L as an appropriate upper limit.

Nominal Group participants agreed on the following statements:

1. Maintain blood PHE between 120-360 μmol/l in all individuals with PKU during the critical period (0-12 yr) for optimal neurocognitive development (90% agreed).

2. Strive to achieve blood PHE between 120-360 μmol/l beyond the critical period for optimal neurocognitive functioning (57% agreed, 40% were neutral).  

High blood PHE concentration can inhibit uptake of TYR, a precursor of dopamine, into the frontal lobe of the brain, theoretically compromising executive function (EF). Definitions of EF and tools used to measure it vary, but EF domains generally include working memory, cognitive flexibility, inhibitory control, attention, and planning. EF deficits have been reported in individuals with PKU (F.2626).  However, an analysis of 19 studies found that while blood PHE concentration correlated with various measures of EF in some studies, the degree of correlation on individual measures was inconsistent (F.2176). Subsequent studies have shown that individuals with PKU performed less well on measures of EF, and in two studies performance did not correlate with concurrent blood PHE (F.677, F.1433). However, one study of 20 individuals with classic PKU who underwent tests of sustained attention, memory, and ability to perform complex operations showed improved performance when blood PHE was <360 μmol/L (F.1268).

Individuals with PKU may process information more slowly than controls (F.1244), but whether this is related to blood PHE has not been well documented (F.2629). Individuals with lower blood PHE concentrations have been reported to have improved processing speed in various aspects of memory while doing mental tasks (using WAIS-III, WMC-III, & TMT A & B testing) (F.677). In one study, adults with PKU who were off diet had lower reaction times than those on diet, but this was not a fixed deficit as women in one arm of the study  improved reaction times when blood PHE improved (F.2601). In another study of 11 individuals with PKU, the ratio of blood PHE:TYR showed a better association with EF performance than with blood PHE concentrations alone (F.1171). Children with a lifetime PHE:TYR ratio of <6 demonstrated normal EF, whereas those with a ratio above 6 had impaired EF. The ratio of blood PHE:TYR is 1.1 to 1 in individuals who do not have PKU.

In both Delphi surveys and in the Nominal Group, there was consensus that blood PHE should be maintained between 120-360 μmol/L. Agreement was strongest for infants and children, including adolescents, and declined for adults and those returning to diet.

Behavioral deficits, including attention deficit disorder, are seen more frequently in individuals with PKU (F.2626, F.2629). Because this is reported in both well-treated and poorly-treated PKU, the correlation to blood PHE is uncertain (F.2629). Results of electrophyisological testing (amplitudes and latencies of early and late event-related potential components elicited during a selective processing task) in 26 individuals with PKU compared to controls suggest that high blood PHE during sensitive periods for brain maturation may have long-lasting influences on selective attention (F.1196). Individuals with PKU experience more anxiety, depression and agoraphobia than the general population and symptoms are related to the degree of metabolic control (F.2626, F.2627, F.2629), although a specific blood PHE threshold has not been defined. High blood PHE had a negative effect on mood and attention in individuals with PKU given a PHE load mimicking a normal diet (F.2327).

In both Delphi surveys and in the Nominal Group, there was consensus for the recommendation that blood PHE be maintained between 120-360 μmol/L; agreement was strongest for infants and children, including adolescents, and declined for adults and those returning to diet.

White matter abnormalities are seen in magnetic resonance imaging (MRI) studies in individuals with PKU (F.2627, F.2629). High blood PHE is believed to interfere with myelination (F.2629). Brain changes seen on MRI are reversible when blood PHE is controlled. In one study, 5 subjects with PKU who were off diet and had white matter changes on MRI, had normal MRI findings 3-12 months after maintaining a strict diet resulting in blood PHE <400 μmol/L (F.2205).

In both Delphi surveys and in the Nominal Group, there was consensus for the recommendation that blood PHE be maintained between 120-360 μmol/L; agreement was strongest for infants and children, including adolescents, and declined for adults and those returning to diet.

A blood PHE concentration of 120 μmol/L is the typically recommended lower limit for the blood PHE treatment range in the US, although in Germany, for example, the acceptable lower limit for blood PHE is 40 μmol/L (L.130). Hypophenylalaninemia (blood PHE <30 μmol/L) was reported in the early days of PKU treatment, and a lower limit recommendation of 120 μmol/L was chosen because the usual method of monitoring at that time (the Guthrie test) was unreliable below 120 μmol/L. Currently tandem mass spectrometry or quantitative amino acid analysis is used for monitoring blood PHE and is accurate at low concentrations. The ACMG guideline states that blood PHE of 60–120 μmol/L should not be regarded as “too low,” particularly in the individual whose dietary PHE intake is not severely restricted. Adequate frequency of blood PHE monitoring in such individuals should eliminate any potential risk associated with prolonged low blood PHE (F.2626).

In both Delphi surveys, 100% of participants agreed that a blood PHE concentration of 120 µmol/L is an appropriate treatment range lower limit for all individuals with PKU.  In Delphi 2, 90% agreed a lower limit of 120 µmol/L is also appropriate for individuals who were late-treated, are returning to diet, or are pregnant.

Many treatment centers initiate treatment at a blood PHE of 360 μmol/L or higher. However, data is inconsistent regarding the impact of untreated blood PHE concentrations of 360-600 μmol/L on cognitive and executive function, and whether treatment is necessary. Some studies demonstrate normal outcomes and others show subtle neurocognitive deficits (L.160). A study of 31 individuals with hyperphenylalaninemia (HPA) who were never treated and whose blood PHE concentrations did not exceed 600 μmol/L had normal IQ, educational achievement and normal MRI studies; suggesting that some individuals with HPA may not need dietary treatment (F.2525). Blood PHE of >360 μmol/L may be considered suboptimal in an individual with treated PKU yet safe in a person with HPA because individuals with HPA: have less variability in blood PHE (which is associated with better neurocognitive outcomes) (F.905), have a lower PHE:TYR ratio (which may have a positive prognostic value) (F.1171), and may have lower brain concentrations of PHE. Blood PHE may not be the only determinant of the need for a PHE-restricted diet, since blood PHE can vary depending on state of health or dietary intake. Other factors such as genotype and dietary PHE tolerance should also be considered (F.2629).

In Delphi 1, 75% of participants agreed that a PHE restricted diet should be initiated in individuals with a blood PHE >360 µmol/L. There were no comments from those who disagreed.