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Tyrosine supplementation for phenylketonuria

  1. Diana Webster1,*,
  2. Joanne Wildgoose2

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 5 JUN 2013

Assessed as up-to-date: 1 MAY 2013

DOI: 10.1002/14651858.CD001507.pub3


How to Cite

Webster D, Wildgoose J. Tyrosine supplementation for phenylketonuria. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD001507. DOI: 10.1002/14651858.CD001507.pub3.

Author Information

  1. 1

    Bristol Royal Hospital for Children, Nutrition and Dietetic Department, Bristol, UK

  2. 2

    Bradford Royal Infirmary, Physio Corridor, Level 1, Bradford, UK

*Diana Webster, Nutrition and Dietetic Department, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol, BS2 8BJ, UK. Diana.Webster@ubht.nhs.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 5 JUN 2013

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Characteristics of included studies [ordered by study ID]
Mazzocco 1992

MethodsRandomised double-blind, double cross-over controlled trial.


Participants9 people with PKU (4 males, mean age 10.25 years, range 6.5 - 13.25 years). Phenylalanine restricted diet commenced in early infancy and continued at various levels throughout the trial.


InterventionsPhenylalanine restricted diet with a tyrosine supplement (2500 mg/day) in treatment arm (10 - 14 days), phenylalanine-restricted diet with placebo in control arm (10 - 14 days) of the trial.


OutcomesBlood phenylalanine and tyrosine concentrations, 6 tests of prefrontal functioning were carried out.


NotesA double cross-over design with all participants receiving both the placebo and tyrosine supplements on 2 separate occasions with no washout period in between.


Risk of bias

BiasAuthors' judgementSupport for judgement

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAn adequate intention-to-treat analysis was undertaken with no exclusions.

Pietz 1995

MethodsRandomised double-blind cross-over controlled trial. Duration 24 weeks.


Participants24 people with PKU (11 males, mean age 20.8 years, range 16 - 25 years). Low phenylalanine diet commenced early in infancy. Diet relaxed for approximately 1 year prior to study.


InterventionsAll participants continued on relaxed diet. Participants received 100 mg/kg/day tyrosine in treatment arm (4 weeks) or placebo in control arm (4 weeks).


OutcomesBlood phenylalanine and tyrosine concentrations. Blood chemistry and urinalysis was carried out as were visual evoked potentials and electroencephalographic spectral analysis. The following neuropsychological tests were carried out; Wechsler Intelligence Scale for Children, Sonneville Visual Attention Task, Finger Motor Speed Exercise, Dot Pattern Exercise.


Notes3 participants were excluded from the final analysis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe reason for the exclusion of two participants is not adequately described.

Smith 1998

MethodsRandomised double-blind cross-over controlled trial. Duration 12-16 weeks.


Participants23 people with PKU (11 males, mean age 11.3 years, range 6 - 28 years). Phenylalanine restricted diet commenced in early infancy and continued at various levels until the start of the trial.


InterventionsPhenylalanine-restricted diet with a tyrosine supplement (100 mg/kg/day) in treatment arm (4 weeks), phenylalanine-restricted diet with placebo in control arm (4 weeks) of the trial.


OutcomesBlood phenylalanine and tyrosine concentrations and phenylalanine: tyrosine ratio. A number of neuropsychological tests were carried out.


Notes2 participants were lost to follow up.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskTwo participants were excluded for either failing to take the allocated supplement or due to pharmacy errors.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Kalkanoglu 2005Study investigates intellectually disabled adults with untreated PKU.

Lou 1987Intervention was only administered for 3 days. Nine of 14 participants did not achieve dietary control in the neonatal period.

Lykkelund 1988Not a randomised controlled trial or not people with PKU.

MacDonald 2003Study investigated the use of phenylalanine-free protein substitutes, containing all amino acids other than phenylalanine, rather than just the effect of an additional tyrosine only supplement.

Wasser 1992Not a randomised controlled trial.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Lines 1997

MethodsDouble-blind cross-over trial. Placebo controlled.

ParticipantsInitially 9 participants (children and adults) who had a stable intake of phenylalanine according to diet diary. However, 3 patients compromised ;1 due to poor compliance associated with change in caretaker; 1 due to illness interfering with phenylalanine intake; 1 adult took half required dose for the first month.

Weight range: 37-87 kg

Interventions2 months in each intervention arm. Tyrosine supplement 40 mg/kg/day given in soft gelatine capsules in divided doses with the 3 main meals of the day.

OutcomesWeekly measures of blood phenylalanine levels.

Notes

 
Comparison 1. Tyrosine versus placebo (all participants)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Blood phenylalanine concentration (umol/l) (0-3 months)3mean difference (Fixed, 95% CI)21.78 [-75.69, 119.25]

 2 Blood tyrosine concentration(umol/l) (0-3 months)3mean difference (Fixed, 95% CI)23.46 [12.87, 34.05]

3 Weight gain (kg) (0-3 months)00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

4 Intelligence quotient (IQ) (0-3 months)00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

5 Neuropsychological performance (0-3 months)00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

6 Quality of life00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

7 Death00Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 2. Tyrosine versus placebo (continued on diet versus discontinued diet)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Blood phenylalanine concentration (umol/l) (0-3 months)3mean difference (Fixed, 95% CI)Subtotals only

    1.1 Participants with PKU continued on diet since diagnosis
2mean difference (Fixed, 95% CI)16.55 [-97.43, 130.53]

    1.2 Participants with PKU on diet from diagnosis who no longer follow diet
1mean difference (Fixed, 95% CI)36.0 [-152.01, 224.01]

 2 Blood tyrosine concentration (umol/l) (0-3 months)3mean difference (Fixed, 95% CI)Subtotals only

    2.1 Participants with PKU continued on diet since diagnosis
2mean difference (Fixed, 95% CI)14.83 [3.72, 25.94]

    2.2 Participants with PKU on diet from diagnosis who no longer follow diet
1mean difference (Fixed, 95% CI)109.0 [74.02, 143.98]

3 Weight gain (kg) (0-3 months)0Mean Difference (IV, Fixed, 95% CI)Subtotals only

   3.1 Participants with PKU continued on diet since diagnosis
00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

   3.2 Participants with PKU on diet from diagnosis who no longer follow the diet
00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

4 Intelligence quotient (IQ) (0-3 months)0Mean Difference (IV, Fixed, 95% CI)Subtotals only

   4.1 Participants with PKU continued on diet since diagnosis
00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

   4.2 Participants with PKU on diet from diagnosis who no longer follow the diet
00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Neuropsychological performance (0-3 months)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 Participants with PKU continued on diet since diagnosis
142Mean Difference (IV, Fixed, 95% CI)4.5 [-73.96, 82.96]

    5.2 Participants with PKU on diet from diagnosis who no longer follow the diet
142Mean Difference (IV, Fixed, 95% CI)-11.0 [-37.96, 15.96]

6 Quality of life00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

7 Death00Peto Odds Ratio (Peto, Fixed, 95% CI)0.0 [0.0, 0.0]