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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

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Description of the condition

Phenylketonuria (PKU) is an inherited disease which affects 100 cases per million live births in Caucasian and Oriental populations (Scriver 1995). This disease is characterised by an absence or deficiency of the enzyme phenylalanine hydroxylase, a liver enzyme which is involved in the breakdown of the essential amino acid phenylalanine to tyrosine. In classical PKU there is a total, or almost total, deficiency of phenylalanine hydroxylase leading to high blood phenylalanine concentrations of 1200 μmol/L or more (Scriver 1995). In some cases blood phenylalanine concentrations are persistently raised above 400 μmol/L, but not to the levels seen in classical PKU, although some degree of phenylalanine hydroxylase activity remains present. These conditions are called the hyperphenylalaninaemias. However, for the purpose of this review the term PKU will be used to include both classical PKU and the hyperphenylalaninaemias.

In an infant with PKU, the blood phenylalanine concentration is within the normal range at birth, but becomes elevated usually within several hours to a few days of commencing a normal dietary protein intake. In severe cases this leads to neurological damage and mental retardation if left untreated (Paine 1957). In infants with less severe phenylalanine hydroxylase deficiency the occurrence of brain damage is more variable.

The results of a number of cohort studies have indicated that dietary treatment of PKU is effective in preventing, or reducing, mental handicap, if initiated within the first 20 days of life (MRC1 1993). The main principle of the diet is to reduce blood phenylalanine levels by avoiding foods with moderate to high levels of phenylalanine and to provide additional protein using a low phenylalanine or phenylalanine-free amino acid supplement (Dixon 1994). It is currently recommended that this diet is continued for life (MRC2 1993). The diet for PKU can be very complicated to follow and is often considered to be unpalatable. Therefore, it is sometimes difficult for people to adhere to the diet strictly, if at all. In view of this researchers have investigated other potential therapies which would facilitate compliance to treatment (Pietz 1995). Supplementation of the diet with tyrosine is one such therapy which has been studied in PKU.

 

Description of the intervention

Tyrosine, a neutral amino acid, is a precursor of two central neurotransmitters (chemicals which assist in the transmission of nerve impulses), dopamine and noradrenaline. High blood concentrations of phenylalanine have been found to impair uptake of tyrosine into the brain and result in lower than normal levels of tyrosine in both the blood and the brain (Oldendorf 1973). This deficiency of tyrosine has been suggested as one reason for the decreased neuropsychological performance seen in some people with PKU (Smith 1998). It has been suggested that tyrosine supplementation could have an important role in the treatment of PKU, although trials investigating this have achieved differing results and no specific recommendations have been made for its use (Lou 1985; Mazzocco 1992; Pietz 1995).

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

The aim of this review is to examine evidence that, in people with PKU (who commenced the diet at diagnosis and either continued on the diet or relaxed the diet later in life) tyrosine supplementation alongside, or instead of low phenylalanine diet, improves: intelligence; neuropsychological performance; growth and nutritional status; mortality rate; and quality of life.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials (RCTs), both published and unpublished. Trials where quasi-randomisation methods such as alternation are used will be included in future updates if there is sufficient evidence that the treatment and comparison groups are comparable in terms of clinical and nutritional status.

 

Types of participants

Individuals of any age with PKU and other forms of phenylalanine hydroxylase deficiency diagnosed by the Guthrie test or other recognised, validated screening test, in which dietary treatment was initiated early in infancy and continued or relaxed later in life. People treated for maternal PKU were not eligible for inclusion.

 

Types of interventions

Enteral supplementation of tyrosine compared with no tyrosine supplementation or placebo. This intervention may have been used either in combination with, or instead of, a low phenylalanine diet (and with or without the addition of the low phenylalanine or phenylalanine-free amino acid supplement).

 

Types of outcome measures

Outcome data were grouped into those measured at one, three, six, twelve months and annually thereafter. If outcome data were recorded at other time periods then consideration was given to examining these as well.

 

Primary outcomes

  1. Blood phenylalanine and tyrosine concentrations
  2. Weight gain and any other indices of nutritional status or growth
  3. Measures of intelligence and neuropsychological performance

 

Secondary outcomes

  1. Measures of quality of life
  2. Death

 

Search methods for identification of studies

 

Electronic searches

Relevant trials were identified from the Group's Inborn Errors of Metabolism Trials Register using the terms: tyrosine OR 4-hydroxyphenylalanine.

The Inborn Errors of Metabolism Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE and the prospective handsearching of one journal - Journal of Inherited Metabolic Disease. Additional studies were identified from handsearches of the Journal of Inherited Metabolic Disease (from inception in 1978 to 1998). Unpublished work was identified by searching through the abstract books of the Society for the Study of Inborn Errors of Metabolism conference and the SHS Inborn Error Review Series. For full details of all searching activities for the register, please see the relevant section of the Cystic Fibrosis and Genetic Disorders Review Group Module.

Date of the most recent search of the Group's Inborn Errors of Metabolism Trials Register: 28 June 2012.

 

Searching other resources

Additional RCTs were identified from reference lists. Manufacturers of dietary products used in the treatment of PKU were contacted for any data from published and unpublished RCTs that they may have on file.

 

Data collection and analysis

 

Selection of studies

Two authors independently selected the trials to be included in the review.

 

Data extraction and management

The authors extracted data independently.

 

Assessment of risk of bias in included studies

Two authors independently assessed the methodological quality of the trials included in the review, according to the method described by Schulz (Schulz 1995). If the two authors disagreed about the quality of a trial, then the disagreement was resolved by discussion until a consensus was reached.

The method used to assess the quality of the trials focuses on four areas: allocation concealment; generation of the randomisation sequence; intention-to-treat analysis and blinding. We graded whether the allocation of participants to treatment groups was concealed to the investigators as being adequate, unclear or inadequate. We used the same three categories to assess the adequacy of the method used to generate the randomisation sequence. The third area by which we assessed the quality of the trials was whether an intention-to-treat analysis was employed. We assessed this using the following categories; adequate, unclear or with exclusions (i.e. participants were excluded from the final analysis).

 

Measures of treatment effect

For binary outcome measures, we planned to calculate a pooled estimate of the treatment effect for each outcome across studies, (the odds of an outcome among treatment allocated participants to the corresponding odds among controls). For continuous outcomes, we planned to record either mean change from baseline for each group or mean post-treatment/intervention values and standard deviation or standard error for each group. We planned to calculate a pooled estimate of treatment effect by calculating the mean difference.

 

Unit of analysis issues

We considered three methods of analysis for cross-over trials, depending on which data were available (Elbourne 2002). The ideal approach would have been to use the results of paired analysis, as this would have allowed a within-individual comparison of the treatment effect. If such data were not available, a second approach would have been to use data from the first arm of the trial only, and to ignore data from after the participants crossed-over into the second arm of the trial. A third, and unsatisfactory, approach would have been to ignore the cross-over design and use the combined results. This approach disregards the fact that the participants have appeared in both arms of the trial. The concern with this approach is the risk that any carry-over effect of the treatment could distort the results of the individual trials, and ultimately the meta-analysis.

 

Assessment of heterogeneity

We tested for heterogeneity between trial results using a standard chi squared test.

 

Data synthesis

In order to allow an intention-to-treat analysis, we sought data on the number of participants with each outcome event, by allocated treatment group, irrespective of compliance and whether or not the participant was later thought to be ineligible or otherwise excluded from treatment or follow up.

 

Subgroup analysis and investigation of heterogeneity

Subgroup analysis stratifying according to whether the participants continued to follow, or discontinued a low-phenylalanine diet prior and during the trial was performed.

 

Sensitivity analysis

We planned to perform a sensitivity analysis based on the methodological quality of the trials, including and excluding quasi-randomised trials.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Description of studies

 

Results of the search

Eight trials were identified by the searches (Kalkanoglu 2005; Lou 1987; Lykkelund 1988; MacDonald 2003; Mazzocco 1992; Pietz 1995; Smith 1998; Wasser 1992).

We are aware of one further trial which may be eligible for inclusion in the review, however, we have not yet been able to contact the authors to obtain information to assess whether this trial is eligible for inclusion in the review (Lines 1997).

 

Included studies

Three trials (56 participants) met the criteria for inclusion in the review (Mazzocco 1992; Pietz 1995; Smith 1998). All the trials investigated the effect of tyrosine supplementation in people with PKU who were diagnosed by neonatal screening and commenced on phenylalanine-restricted diet in early infancy. The trial by Pietz included people who had been on a relaxed diet for at least a year and investigated the effect of tyrosine supplementation alongside a relaxed diet (Pietz 1995). In the trials by Smith and Mazzocco, tyrosine supplementation in addition to the phenylalanine-restricted diet was investigated in a group of people who had remained on the diet from diagnosis (Mazzocco 1992; Smith 1998). All of the three trials were of cross-over design and both treatment and control arms of two of the trials were of four weeks duration (Pietz 1995; Smith 1998). The remaining trial entailed a double cross-over design with each arm lasting 10 to 14 days and no washout period in between (Mazzocco 1992). Therefore, for this trial we have only used the data from the first cross-over period (Mazzocco 1992).

All of the three included trials were of cross-over design (Mazzocco 1992; Pietz 1995; Smith 1998). One trial, which entailed a double cross-over design with each arm lasting 10 to 14 days and no washout period in between, published data which allowed the results of the first arm of the trial only to be used in the analysis (Mazzocco 1992). Similar first-arm data were not provided in the remaining two trials (where both treatment and control arms were of four weeks duration), therefore this method of analysis was not an option. For these, data from both arms of the trial had been combined, thus ignoring the cross-over design (Pietz 1995; Smith 1998).

 

Excluded studies

On closer inspection, two trials identified were not randomised controlled trials (Lykkelund 1988; Wasser 1992). One trial was identified which investigated the effect of tyrosine supplementation for PKU, however, we did not consider this eligible for inclusion (Lou 1987). The reason for this was that the intervention was only administered for three days, and most of the participants (9 of 14) did not achieve dietary control within the recommended time frame (before one month of age). In addition, this trial employed a cross-over design, but the trial publication does not provide the necessary data to allow the appropriate analysis of the results. A third trial investigated intellectually disabled adults with untreated PKU Kalkanoglu 2005. The final trial 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 (MacDonald 2003).

 

Risk of bias in included studies

 

Allocation

Allocation concealment was unclear in all three studies (Mazzocco 1992; Pietz 1995; Smith 1998). We considered the generation of randomisation sequence to be adequate in the trial by Smith (Smith 1998) but considered it unclear in the trials by Pietz and Mazzocco (Mazzocco 1992; Pietz 1995).

 

Blinding

All three studies were reported to be double-blinded (Mazzocco 1992; Pietz 1995; Smith 1998).

 

Incomplete outcome data

In two of the trials a number of participants were excluded from the final analysis. In one trial, two participants were excluded for either failing to take the allocated supplement or due to pharmacy errors (Smith 1998). In the other trial the reason for the exclusion of two participants is not adequately described (Pietz 1995). The third trial employed adequate intention-to-treat analysis, with no exclusions (Mazzocco 1992).

 

Effects of interventions

 

Primary outcomes

 

1. Blood phenylalanine concentration

This outcome was measured in all three trials. In two trials this measure was recorded after four weeks on tyrosine supplementation and after four weeks on placebo (Pietz 1995; Smith 1998); in the third study each arm of the trial lasted 10 to 14 days (Mazzocco 1992). There was no significant difference between the blood phenylalanine concentrations in the treatment and control arms of these trials.

 

2. Blood tyrosine concentration

Blood tyrosine concentrations were measured after four weeks on treatment and four weeks on placebo in two of the trials (Pietz 1995; Smith 1998) and after 10 to 14 days in each arm in the third trial (Mazzocco 1992). The blood tyrosine concentrations were significantly higher in the treatment arm than the control arm of two of the three trials and meta-analysis reflected this, weighted mean difference 23.46 (95% confidence interval 12.87 to 34.05).

 

3. Weight gain

This outcome was not measured in any of the trials.

 

4. Other measures of nutritional status

This outcome was not measured in any of the trials.

 

5. Intelligence quotient

This outcome was only measured in one trial but the results of all the participants were combined and compared with a group of non-PKU participants (Pietz 1995). Therefore, this outcome could not be assessed.

 

6. Neuropsychological performance

All three trials evaluated a number of measures of neuropsychological performance. Only one common measure, 'simple reaction time', was used in two trials although it was unclear whether the same method was used for both (Pietz 1995; Smith 1998). No significant difference was found between the treatment arm and the control arm in either trial or as the result of meta-analysis.

 

Secondary outcomes

 

1. Quality of life

This outcome was not measured in any of the trials.

 

2. Mortality

This outcome was not measured in any of the trials.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

The three trials considered in this review were of a good quality, but only included a small number of participants. The length of the treatment and control arms were short in all three trials and some of the outcomes considered important in this review were not measured. A significant difference was found between the blood tyrosine concentration in the treatment and control arm of all three trials, as would be expected when the treatment was tyrosine supplementation. No other significant differences were found in any of the other outcomes.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

 

Implications for practice

No conclusions can be reached on the effectiveness of tyrosine supplementation in PKU based on the evidence currently available. It is suggested that tyrosine supplementation is not introduced into widespread clinical practice until this intervention has been evaluated in a large multicentre RCT.

 
Implications for research

There are good theoretical reasons for believing that tyrosine supplementation may improve neuropsychological performance in PKU. There is thus a need for this intervention to be properly evaluated in RCTs over a long enough time period for any therapeutic effect to be demonstrated. Attention needs to be paid to including adequate numbers of participants, the dosage of tyrosine to be used and the length of time over which the intervention is taken. It would also be necessary to consider which are the appropriate outcomes to measure and consumer involvement in the design of the trial would be useful.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

We would like to thank the previous author team of Dr Vanessa Poustie and Mrs Patricia Rutherford for their work on developing this review.

Dr Vanessa Poustie and Mrs Patricia Rutherford thank the following experts in metabolic disease for commenting on the protocol.
Professor N Buist, Oregon, USA
Dr DC Davidson, Liverpool, UK
Dr B Wilcken, Sydney, Australia
Dr R Koch, Los Angeles, USA
Dr I Smith, London, UK
Dr J Collins, London, UK
Dr J Walter, Manchester, UK

Dr Vanessa Poustie and Mrs Patricia Rutherford also thank Dr D Isherwood, Liverpool, UK, for his assistance in the handsearching of the Journal of Metabolic Disease, and the British Dietetic Association for providing computer equipment used in the production of this review.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
Download statistical data

 
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]

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Last assessed as up-to-date: 1 May 2013.


DateEventDescription

1 May 2013New search has been performedA search of the Cochrane Cystic Fibrosis Group's Inborn Errors of Metabolism Trials Register identified one trial which was not eligible for inclusion in any section of the review.

1 May 2013New citation required but conclusions have not changedMinor changes were made throughout the review.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Protocol first published: Issue 2, 1999
Review first published: Issue 3, 1999


DateEventDescription

7 July 2010New search has been performedThe search of the Group's Inborn Errors of Metabolism Register identified two new references which have been added to the Excluded studies section of the review (Kalkanoglu 2005; MacDonald 2003).

7 July 2010New citation required but conclusions have not changedAs of Issue 8, 2010, Vanessa Posutie and Patricia Rutherford are no longer active authors on this review. Diana Webster and Joanne Wildgoose have undertaken this update.

12 September 2008AmendedConverted to new review format.

1 November 2005New search has been performedThe searches found no new trials eligible for inclusion in the review.

1 November 2004New search has been performedThe searches found no new trials eligible for inclusion in the review.

1 November 2003New search has been performedThe searches found no new trials eligible for inclusion in the review.

The new statistical method available in RevMan 4.2 (the generic inverse variance method) was used for four of the graphs included within MetaView. This has not significantly changed any of the Results as presented in earlier versions of this review.

The Group's medical statistician provided comments on this review which were addressed within this update. Minor changes have been made throughout many sections of the review.

1 November 2002New search has been performedOne further trial has been identified (Lou 1987) which appears to be eligible for inclusion in the review. However the reviewers have decided not to include the study as the intervention was only administered for three days, and most of the participants in the study (9 of 14) did not achieve dietary control in the neonatal period. This trial is therefore included in 'Excluded Studies'.

23 February 1999New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Review from Issue 8, 2010
Diana Webster:
- selection of eligible trials;
- production of the updates of the review;
- guarantor of the review.

Joanne Wildgoose:
- selection of eligible trials;
- comment on the updates of this review.

------------------------------------
Review up to Issue 8, 2010
Vanessa Poustie:
- identification of trials from Cochrane Cystic Fibrosis & Genetic Disorders Trials Register;
- handsearching of Journal of Inherited Metabolic Disease, 1978-1998;
- further identification of trials from publication reference lists;
- selection of eligible trials;
- assessment of trial methodology;
- extraction of relevant data from the trials;
- input of trial data;
- production of final review;
- production of the updates of the review;
- guarantor of the review.

Patricia Rutherford:
- selection of eligible trials;
- assessment of trial methodology;
- extraction of relevant data from the trials;
- comment on final draft of review;
- comment on the updates of the review.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Current authors: Diana Webster has received travel expenses to attend conferences from the manufacturers of dietary products used in the treatment of PKU.

Previous authors: Vanessa Poustie and Tricia Rutherford have previously received travel expenses to attend conferences from the manufacturers of dietary products used in the treatment of PKU. Mrs Tricia Rutherford has been employed by Vitaflo, a manufacturer of protein substitutes, since September 2005; however, the protocol and the original review were completed prior to her commencing employment at this company.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • North West NHS Executive Research & Development Directorate Training Fellowship Scheme, UK.
  • British Dietetic Association General Education Trust, UK.

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. Additional references
  21. References to other published versions of this review
Mazzocco 1992 {published data only}
  • Mazzocco MM, Yannicelli S, Nord AM, Van Doorninck W, Davidson-Mundt AJ, Greene CL. Cognition and tyrosine supplementation among school-aged children with phenylketonuria. American Journal of Diseases of Children 1992;146(11):1261-4.
Pietz 1995 {published data only}
  • Pietz J, Landwehr R, Kutscha A, Schmidt H, de Sonneville L, Trefz FK. Effect of high-dose tyrosine supplementation on brain function in adults with phenylketonuria. Journal of Pediatrics 1995;127(6):936-43.
Smith 1998 {published data only}
  • Smith ML, Hanley WB, Clarke JTR, Klim P, Schoonheyt W, Austin V, et al. Randomised controlled trial of tyrosine supplementation on neuropsychological performance in phenylketonuria. Archives of Disease in Childhood 1998;78(2):116-21.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. Additional references
  21. References to other published versions of this review
Kalkanoglu 2005 {published data only}
  • Kalkanoglu HS, Ahring KK, Sertkaya D, Moller LB, Romstad A, Mikkelsen I, et al. Behavioural effects of phenylalanine-free amino acid tablet supplementation in intellectually disabled adults with untreated phenylketonuria. Acta Paediatrica 2005;94(9):1218-22.
Lou 1987 {published data only}
Lykkelund 1988 {published data only}
  • Lykkelund C, Nielsen JB, Lou HC, Rasmussen V, Gerdes AM, Christensen E, et al. Increased neurotransmitter biosynthesis in phenylketonuria induced by phenylalanine restriction or by supplementation of unrestricted diet with large amounts of tyrosine. European Journal of Pediatrics 1988;148(3):238-45.
MacDonald 2003 {published data only}
  • MacDonald A, Ferguson C, Rylance G, Morris AA, Asplin D, Hall SK, et al. Are tablets a practical source of protein substitute in phenylketonuria?. Archives of Disease in Childhood 2003;88(4):327-9.
Wasser 1992 {published data only}
  • Wasser S, Ettrich KU, Schmidt KD, Selle D, Theile H. Case studies of the effect of tyrosine administration in children with phenylketonuria on cognitive processes [Fallstudien zum einfluss von tyrosingaben bei phenylketonurischen kindern auf kognitive prozesse]. Klinische Padiatrie 1992;204(6):417-21.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. Additional references
  21. References to other published versions of this review
Dixon 1994
  • Dixon M. Disorders of amino acid metabolism, organic acidaemias and uria cycle defects. In: Shaw V, Lawson M editor(s). Clinical Paediatric Dietetics. Oxford: Blackwell Science, 1994:177-209.
Elbourne 2002
  • Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta-analysis involving cross-over trials: methodological issues. International Journal of Epidemiology 2002;31(1):140-9.
Lou 1985
  • Lou HC, Guttler F, Lykkelund C, Bruhn P, Niederwieser A. Decreased vigilance and neurotransmitter synthesis after discontinuation of dietary treatment for phenylketonuria in adolescents. European Journal of Pediatrics 1985;144(1):17-20.
MRC1 1993
  • Medical Research Council Working Party on Phenylketonuria. Phenylketonuria due to phenylalanine hydroxylase deficiency: an unfolding story. British Medical Journal 1993;306(6870):115-9.
MRC2 1993
  • Medical Research Council Working Party on Phenylketonuria. Recommendations on the dietary management of phenylketonuria. Archives of Disease in Childhood 1993;68(3):426-7.
Oldendorf 1973
  • Oldendorf WH. Saturation of blood brain barrier transport of amino acids in phenylketonuria. Archives of Neurology 1973;28(1):45-8.
Paine 1957
Schulz 1995
  • Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Journal of the American Medical Association 1995;273(5):408-12.
Scriver 1995
  • Scriver CR, Kaufman S, Woo SLC. The hyperphenylalaninaemias. In: Scriver CR, Beaudet AL, Sly WS, Valle D editor(s). The Metabolic and Molecular Bases of Inherited Disease. 7th Edition. New York: McGraw-Hill, 1995:1015-76.