Management of phenylketonuria for optimal outcome: a review of guidelines for phenylketonuria management and a report of surveys of parents, patients, and clinic directors.

OBJECTIVE: The development of guidelines for phenylketonuria (PKU) management in the United Kingdom has resulted in much discussion in the community of parents and PKU clinics and parents have asked why the United States does not have such guidelines. The objective of this report is to discuss PKU management in the United States, the British guidelines on PKU management, and the feasibility, suitability, and mechanism of developing PKU management guidelines in the United States. METHODS: Members of the American Academy of Pediatrics (AAP) Committee on Genetics (COG) reviewed the literature and conducted surveys of parents of children with PKU, young adults with PKU, and directors of PKU clinics in the United States. A meeting was held at the National Institute of Child Health and Human Development to review the AAP/COG efforts at reviewing the status of PKU management and guideline development in the United States. RESULTS: The British guidelines are more stringent than the PKU management practices in many parts of the United States. Evidence exists that stricter management improves developmental outcome. The parents who responded to the surveys indicated willingness to comply with more stringent dietary management if that would improve outcome. They also identified problems that make such management difficult. The clinic directors supported the timeliness of the review. Some had begun a trend toward more stringent control of blood phenylalanine concentrations, at least in the first 4 years of life. CONCLUSION: The AAP Committee on Genetics will complete its subject review of the management of PKU. Guidelines for care of PKU in the United States probably would look quite similar to the existing guidelines in other countries. The parents surveyed supported more stringent PKU management, but information from a broader distribution of parents would provide a more representative view. The status of the US health care system creates problems for improved PKU management in the United States that do not exist in the countries already following stricter guidelines.

Physical growth of children treated for phenylketonuria.

The growth of 133 children participating in the Collaborative Study of Children Treated for Phenylketonuria (PKU) was compared to growth data from the National Center for Health Statistics (NCHS) to determine whether the growth patterns of the children with PKU were the same as those of unaffected children. Height and weight by age, and weight by height, were analysed for ages 2-10 years. Head circumference by age was analysed for ages 2-7 years. Median height by age of the PKU children was consistently near the 50th percentile of the NCHS growth curves for males and females. However, for both sexes, median weight by height and by age was between the 50th and 75th percentiles for children over 3 years old. Two-sample t-tests showed mean weight was significantly different (p less than 0.05) between the PKU and NCHS groups at most ages for both sexes. Median head circumference for the PKU children tended to be smaller than NCHS standards; however, the maximum difference at any age was less than 0.5 cm. Polynomial growth curves fitted to the PKU and NCHS growth data showed that, on average, the PKU males and females weighed more than their unaffected counterparts, while height and head circumference for both groups were very close. Including median serum phenylalanine (phe) level (mg/dl) in the growth curves suggested that the weight differences between the PKU and NCHS groups are related to degree of diet adherence. Higher phe levels in the PKU group were associated with higher weight levels, more so for girls (p less than 0.001) than for boys (p = 0.08). No relationship was found between phe level and height or head circumference. We conclude that growth in children treated for PKU differs from national standards for weight by age and weight by height, but not for height by age. We speculate that diet adherence may be an important factor in determining which children have a tendency to become overweight.

Reinstitution of diet therapy in PKU patients from twenty-two US clinics.

In a nationwide survey we found 72 PKU (phenylketonuria) patients who had terminated diet but later returned to diet. Sixty-one patients resumed diet due to clinical problems. Age at initial diet discontinuation ranged from three to 20 years. The most prevalent problems reported were poor school performance, and mood and/or behavior changes. Following diet reinstitution, only positive changes were noted for 42 patients, no changes for 19 patients, and 11 had one or more negative changes. Improvements and blood phenylalanine levels were not significantly correlated, but only 11 patients maintained levels less than 10 mg/dl. The number of improvements was significantly correlated with length of time on diet (p less than 0.001). After a median of 10 months on diet, 22 patients had again discontinued due to poor diet control, lack of motivation, poor formula tolerance, lack of apparent benefits and/or changes for the worse. Median time on diet for the 50 second-time continuers was two years nine months.

Biopterin synthesis defects: problems in diagnosis.

Hyperphenylalaninemia due to a biopterin synthesis defect was detected in an infant with decreased biopterin and increased neopterin levels in plasma and urine. Tetrahydrobiopterin (BH4) administration normalized plasma phenylalanine levels. CSF biopterin and neurotransmitter metabolite levels were normal and with the infant's normal growth and development suggest that the defect in biopterin synthesis did not affect CNS biopterin metabolism. Comparison of plasma and urine pterin levels from this patient with levels reported in patients who have neurologic complications fails to reveal differences that would distinguish patients at risk for neurologic problems. CSF pterin and neurotransmitter levels may correlate with neurologic function in these patients. CSF pterin and neurotransmitter determinations should be performed prior to initiation of neurotransmitter precursor and BH4 replacement therapies in patients who were determined to have biopterin synthesis defect(s).

Diet policies of PKU clinics in the United States.

About two-thirds of 90 clinics treating phenylketonuria (PKU) now recommend indefinite continuation of a low phenylalanine diet as compared to 1978 when fewer than one-fourth had this policy. The percentage of children maintained on diet has increased markedly for six to eight year-olds. Greater conservatism in clinic diet recommendations likely reflects reports of adverse consequences following diet discontinuation and negative individual clinic experiences.

EEG in phenylketonuria. Attempt to establish clinical importance of EEG changes.

To determine the importance of an abnormal EEG in phenylketonuria (PKU), we reviewed 137 EEGs from 48 patients with PKU. Patients were divided into three groups: group 1 (n = 14) had only normal EEGs, group 2 (n = 20) had only abnormal EEGs, and group 3 (n = 14) initially had normal EEGs that later became abnormal. The most common EEG abnormality was focal paroxysmal discharge. Patients in group 2 started treatment at a later age an had a greater frequency of seizures and mental retardation. Phenylalanine levels greater than 20 mg/dL were more often associated with abnormal EEGs. Older patients were more likely to have abnormal EEGs; 78% of the 41 patients who had EEGs at age 6 or older had abnormal records, whereas only 15% of the 26 patients who had EEGs before the age of 6 had abnormal records. Conventionally treated patients with classic PKU and normal EEGs in infancy may have abnormal EEGs when retested later even though they remain on a restricted diet. Although not usually associated with clinical deterioration, abnormal EEGs may unveil the presence of CNS dysfunction even when a child is in satisfactory clinical condition.

Diet discontinuation policies and practices of PKU clinics in the United States.

Marked diversity in policies and practices for discontinuation of the PKU diet in the U.S. was found in a nationwide survey. Seventy-two of the 78 identified clinical centers treating PKU provided data. No clinicians are currently considering diet discontinuation at ages earlier than their present policy or practice. A definite trend toward later discontinuation of diet was identified. A few clinicians have always recommended indefinite diet continuation while many clinics have experience with children ages 9--12 who have discontinued the diet. Clinics with seven or more children off diet in this age range are significantly more likely than smaller clinics to be considering a later age for diet discontinuation. There were 151 children approximately age 10 or older, who remain on a low phenylalanine diet. These children are followed by 29 clinics, but over one-half of them are followed by five clinics which have had long-standing policies of indefinite diet continuation. Factors associated with success in long-term management are a firm clinic policy supporting continued diet treatment; frequent, supportive contacts with the family; open discussion by staff with families and establishment of a trusting relationship; teaching children to accept responsibility for diet management from an early age.