V J Poustie1, P Rutherford. 1. Evidence Based Child Health Unit, Institute of Child Health, Royal Liverpool Children's Hospital NHS Trust, Alder Hey, Eaton Road, Liverpool, Merseyside, UK, L12 2AP. v.poustie@liv.ac.uk
Abstract
BACKGROUND: Phenylketonuria is an inherited disease for which the main treatment is the dietary restriction of the amino acid phenylalanine. The diet has to be initiated in the neonatal period to prevent or reduce mental handicap however the diet is very restrictive and unpalatable and can be difficult to follow. Whether the diet can be relaxed or discontinued during adolescence or should be continued for life remains a contraversial issue which we aim to address in this review. OBJECTIVES: To assess the effects of a phenylalanine restricted diet commenced early in life for patients with phenylketonuria. To assess the possible adverse effects of relaxation or termination of the diet on intelligence, neuropsychological outcomes and mortality, and to assess the effect on growth, nutritional status and eating behaviour and quality of life. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Trials Register which is a specialist trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Additional studies were identified from handsearching the Journal of Inherited Metabolic Disease (from inception, 1978 to 1998). The manufacturers of dietary products for phenylketonuria were also contacted. Date of the most recent search of the Group's specialised register: November 1999. SELECTION CRITERIA: All randomised or pseudorandomised controlled trials comparing a phenylalanine restricted diet to either relaxation or termination of dietary restrictions in patients with phenylketonuria. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the trial eligibility, methodological quality and extracted the data. MAIN RESULTS: Four studies were included in this review including a total of 251 patients. Few statistically significant differences were found between treatment and comparison groups for any of the outcomes apart from for blood phenylalanine level and intelligence quotient. Blood phenylalanine levels were significantly lower in those subjects with phenylketonuria following a phenylalanine restricted diet compared to those on a less restricted or relaxed diet (weighted mean difference at three months -672.203, 95% Confidence interval (CI) -813.799 to - 530.608). Intelligence quotient was significantly higher in subjects who continued on the phenylalanine restricted diet compared to those who terminated the diet (weighted mean difference after 12 months -5.00, 95% CI -9.595 to -0.405). However this is based on the results of only one study. REVIEWER'S CONCLUSIONS: The results of non-randomised studies have concluded that a phenylalanine restricted diet is effective in reducing blood phenylalanine levels and improving intelligence quotient and neuropsychological outcome. No randomised controlled trials have assessed the effect of a phenylalanine restricted diet versus no dietary restrictions from diagnosis. In view of evidence from non-randomised studies, such a trial would now be unethical and it is recommended that phenylalanine restricted diet should be commenced at the time of diagnosis. There is uncertainty about the precise level of phenylalanine restriction and when, if ever, the diet should be relaxed. These questions should be addressed by randomised controlled trials with careful consideration given to which patients to include.
BACKGROUND:Phenylketonuria is an inherited disease for which the main treatment is the dietary restriction of the amino acid phenylalanine. The diet has to be initiated in the neonatal period to prevent or reduce mental handicap however the diet is very restrictive and unpalatable and can be difficult to follow. Whether the diet can be relaxed or discontinued during adolescence or should be continued for life remains a contraversial issue which we aim to address in this review. OBJECTIVES: To assess the effects of a phenylalanine restricted diet commenced early in life for patients with phenylketonuria. To assess the possible adverse effects of relaxation or termination of the diet on intelligence, neuropsychological outcomes and mortality, and to assess the effect on growth, nutritional status and eating behaviour and quality of life. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Trials Register which is a specialist trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Additional studies were identified from handsearching the Journal of Inherited Metabolic Disease (from inception, 1978 to 1998). The manufacturers of dietary products for phenylketonuria were also contacted. Date of the most recent search of the Group's specialised register: November 1999. SELECTION CRITERIA: All randomised or pseudorandomised controlled trials comparing a phenylalanine restricted diet to either relaxation or termination of dietary restrictions in patients with phenylketonuria. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the trial eligibility, methodological quality and extracted the data. MAIN RESULTS: Four studies were included in this review including a total of 251 patients. Few statistically significant differences were found between treatment and comparison groups for any of the outcomes apart from for blood phenylalanine level and intelligence quotient. Blood phenylalanine levels were significantly lower in those subjects with phenylketonuria following a phenylalanine restricted diet compared to those on a less restricted or relaxed diet (weighted mean difference at three months -672.203, 95% Confidence interval (CI) -813.799 to - 530.608). Intelligence quotient was significantly higher in subjects who continued on the phenylalanine restricted diet compared to those who terminated the diet (weighted mean difference after 12 months -5.00, 95% CI -9.595 to -0.405). However this is based on the results of only one study. REVIEWER'S CONCLUSIONS: The results of non-randomised studies have concluded that a phenylalanine restricted diet is effective in reducing blood phenylalanine levels and improving intelligence quotient and neuropsychological outcome. No randomised controlled trials have assessed the effect of a phenylalanine restricted diet versus no dietary restrictions from diagnosis. In view of evidence from non-randomised studies, such a trial would now be unethical and it is recommended that phenylalanine restricted diet should be commenced at the time of diagnosis. There is uncertainty about the precise level of phenylalanine restriction and when, if ever, the diet should be relaxed. These questions should be addressed by randomised controlled trials with careful consideration given to which patients to include.