Using diet to manage phenylketonuria

Review question

We reviewed the evidence about the effects of a low-phenylalanine diet started early in life in people with phenylketonuria. We also aimed to assess the possible effects of relaxing or stopping the diet on intelligence, quality of life and other outcomes. This is an updated version of a previously published review.

Background

Phenylketonuria is an inherited disease treated with dietary restriction of the amino acid phenylalanine. The diet is started in newborns to prevent learning disability; however, it is restrictive and can be difficult to follow. Whether the diet can be relaxed or stopped during adolescence or should be continued for life remains a controversial issue, which we aim to address in this review.

Search date

The evidence is current to: 30 April 2020.

Study characteristics

The review included four studies with 251 people with phenylketonuria. One study looked at the effects of stopping a low-phenylalanine diet at four years of age, a second study looked at the effect of returning to low-phenylalanine diets in children who had previously relaxed their diet, a third study looked at the effect of increasing phenylalanine intake in children who had continued on a low-phenylalanine diet since diagnosis and the fourth (a large, multicentre study) investigated the use of a strict low-phenylalanine diet compared to a moderately strict low-phenylalanine diet in newly diagnosed children.

Key results

Given the differences between the studies, we were unable to combine many results across the four studies. We found few major differences between treatment and comparison groups for the outcomes of interest. Blood phenylalanine levels were significantly lower in participants with phenylketonuria following a low-phenylalanine diet compared to those on a less restricted diet, mean difference (MD) at three months -698.67 (95% confidence interval (CI) -869.44 to -527.89). Intelligence quotient was significantly higher in participants who continued the diet than in those who stopped the diet, MD after 12 months 5.00 (95% CI 0.40 to 9.60). However, these results came from a single study. More research is needed to show if it is safe to relax this diet later on; however, no new studies are expected in this area so we do not plan to update the review.

Quality of the evidence

The overall quality of the evidence varied across studies.

Authors' conclusions: 

The results of non-randomised studies have concluded that a low-phenylalanine diet is effective in reducing blood phenylalanine levels and improving intelligence quotient and neuropsychological outcomes. We were unable to find any randomised controlled studies that have assessed the effect of a low-phenylalanine diet versus no diet from diagnosis. In view of evidence from non-randomised studies, such a study would be unethical and it is recommended that low-phenylalanine 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. This should be addressed by randomised controlled studies; however, no new studies are expected in this area so we do not plan to update this review.

Read the full abstract...
Background: 

Phenylketonuria is an inherited disease treated with dietary restriction of the amino acid phenylalanine. The diet is initiated in the neonatal period to prevent learning disability; however, it is restrictive and can be difficult to follow. Whether the diet can be relaxed or discontinued during adolescence or should be continued for life remains a controversial issue, which we aim to address in this review. This is an updated version of a previously published review.

Objectives: 

To assess the effects of a low-phenylalanine diet commenced early in life for people with phenylketonuria. To assess the possible effects of relaxation or termination of the diet on intelligence, neuropsychological outcomes and mortality, growth, nutritional status, eating behaviour and quality of life.

Search strategy: 

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings.

Most recent search of the Inborn Errors of Metabolism Trials Register: 30 April 2020.

Selection criteria: 

All randomised or quasi-randomised controlled trials comparing a low-phenylalanine diet to relaxation or termination of dietary restrictions in people with phenylketonuria.

Data collection and analysis: 

Two authors independently assessed study eligibility and methodological quality, and subsequently extracted the data.

Main results: 

We included four studies in this review (251 participants), and found few significant differences between treatment and comparison groups for the outcomes of interest. Blood phenylalanine levels were significantly lower in participants with phenylketonuria following a low-phenylalanine diet compared to those on a less restricted diet, mean difference (MD) at three months -698.67 (95% confidence interval (CI) -869.44 to -527.89). Intelligence quotient was significantly higher in participants who continued the diet than in those who stopped the diet, MD after 12 months 5.00 (95% CI 0.40 to 9.60). However, these results came from a single study.

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