Tyrosine supplementation for phenylketonuria

  • Review
  • Intervention

Authors


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. A deficiency of the amino acid tyrosine has been suggested as a cause of some of the neuropsychological problems exhibited in phenylketonuria. Therefore, this review aims to assess the efficacy of tyrosine supplementation for phenylketonuria.

Objectives

To assess the effects of tyrosine supplementation alongside or instead of a phenylalanine-restricted diet for people with phenylketonuria, who commenced on diet at diagnosis and either continued on the diet or relaxed the diet later in life. To assess the evidence that tyrosine supplementation alongside, or instead of a phenylalanine-restricted diet improves intelligence, neuropsychological performance, growth and nutritional status, mortality rate and quality of life.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register which is comprised of references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional studies were identified from handsearches of the Journal of Inherited Metabolic Disease (from inception in 1978 to 1998). The manufacturers of prescribable dietary products used in the treatment of phenylketonuria were also contacted for further references.

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

Selection criteria

All randomised or quasi-randomised trials investigating the use of tyrosine supplementation versus placebo in people with phenylketonuria in addition to, or instead of, a phenylalanine-restricted diet. People treated for maternal phenylketonuria were excluded.

Data collection and analysis

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

Main results

Six trials were found, of which three trials reporting the results of a total of 56 participants, were suitable for inclusion in the review. The blood tyrosine concentrations were significantly higher in the participants receiving tyrosine supplements than those in the placebo group, mean difference 23.46 (95% confidence interval 12.87 to 34.05). No significant differences were found between any of the other outcomes measured.

Authors' conclusions

From the available evidence no recommendations can be made about whether tyrosine supplementation should be introduced into routine clinical practice. Further randomised controlled studies are required to provide more evidence.

Résumé scientifique

Supplémentation en tyrosine pour la phénylcétonurie

Contexte

La phénylcétonurie est une maladie héréditaire pour laquelle le principal traitement est la restriction dans l'alimentation de phénylalanine amino-acide. Le régime alimentaire doit être initié au cours de la période néonatale pour prévenir ou réduire le handicap mental. Pour autant, le régime est extrêmement restrictif et peu ragoûtant, et il peut être difficile à suivre. On pense qu'une déficience en tyrosine amino-acide pourrait être la cause de certains problèmes neuropsychologiques qui apparaissent en cas de phénylcétonurie. Par conséquent, cette revue a pour objectif d'évaluer l'efficacité de la supplémentation en tyrosine pour traiter la phénylcétonurie.

Objectifs

Evaluer les effets de la supplémentation en tyrosine associée à ou à la place d'un régime alimentaire restreint en phénylalanine pour les personnes atteintes de phénylcétonurie, qui ont commencé un régime au moment du diagnostic et qui l'ont poursuivi ou qui l'ont assoupli au fil du temps. Evaluer les données qui indiquent que la supplémentation en tyrosine associée à, ou à la place d'un régime alimentaire restreint en phénylalanine améliore l'intelligence, les performances neuropsychologiques, la croissance et la statut nutritionnel, le taux de mortalité et la qualité de vie.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre d'essais du groupe Cochrane sur la mucoviscidose et les autres maladies génétiques qui est composé de références identifiées lors de recherches exhaustives dans des bases de données électroniques, ainsi que des recherches manuelles dans des journaux pertinents et des résumés d'actes de conférence. Des études supplémentaires ont été identifiées à partir de recherches manuelles dans le Journal of Inherited Metabolic Disease (des origines en 1978 à 1998). Les fabricants des produits diététiques pouvant être prescrits qui sont utilisés dans le traitement de la phénylcétonurie ont également été contactés pour obtenir des références complémentaires.

Date de la recherche les plus récente effectuée dans le registre d'essais sur les erreurs innées du métabolisme du Groupe Cochrane : le 28 juin 2012.

Critères de sélection

Tous les essais randomisés ou quasi-randomisés étudiant l'utilisation de la supplémentation en tyrosine par rapport à un placebo chez les personnes atteintes de phénylcétonurie, en association avec, ou à la place d'un régime alimentaire restreint en phénylalanine. Les personnes traitées pour une phénylcétonurie maternelle ont été exclues.

Recueil et analyse des données

Deux auteurs ont évalué de façon indépendante les essais en termes d'éligibilité et de qualité méthodologique, et ont extrait les données.

Résultats principaux

Six essais ont été trouvés, dont trois mentionnaient les résultats d'un total de 56 participants, ils étaient éligibles à l'inclusion dans la revue. Les concentrations de tyrosine dans le sang étaient bien plus élevées chez les participants recevant des suppléments en tyrosine que chez ceux du groupe avec placebo, avec une différence moyenne de 23,46 (intervalle de confiance à 95 % 12,87 à 34,05). Il n'a été découvert aucune différence significative entre les autres critères de jugement mesurés.

Conclusions des auteurs

A partir des données disponibles, aucune recommandation ne peut être établie quant à l'introduction systématique de la supplémentation en tyrosine dans la pratique clinique. Il est nécessaire de réaliser des essais contrôlés randomisés complémentaires pour fournir plus de données.

アブストラクト

フェニルケトン尿症に対するチロシン補充

背景

フェニルケトン尿症は、アミノ酸であるフェニルアラニンの摂取制限を主な治療とする遺伝性疾患である。知的障害を予防または緩和するには、新生児期に制限食を始める必要がある。しかし、食事は制限が厳しく、味も悪く、制限食の継続が困難となりかねない。フェニルケトン尿症で示される神経心理学的な異常の一部の原因として、アミノ酸であるチロシンの欠乏が示唆されている。したがって、本レビューは、フェニルケトン尿症に対するチロシン補充の有効性を評価することを目的とする。

目的

フェニルケトン尿症患者を対象としてフェニルアラニン制限食と並行またはその代わりにチロシン補充することの効果を評価すること。食事療法は診断時に開始し、継続または後年になって緩和した。フェニルアラニン制限食と並行またはその代わりにチロシンを補充することにより、知能、神経心理学的パフォーマンス、成長・栄養状態、死亡率およびQOLが改善するというエビデンスを評価すること。

検索戦略

Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Registerを検索し、包括的なデータベース検索ならびに関連性のある雑誌および会議会報の抄録集のハンドサーチから同定した参考文献も含めた。Journal of Inherited Metabolic Diseaseのハンドサーチから、さらに研究を同定した(1978~1998年)。 フェニルケトン尿症の治療に使用する処方可能な栄養剤の製造業者にも連絡を取って、さらに参考文献を求めた。

Group’s Inborn Errors of Metabolism Trials Registerの最新のデータ検索:2012年6月28日

選択基準

フェニルケトン尿症患者を対象にフェニルアラニン制限食と並行またはその代わりにチロシンを補充する群とプラセボ群を全ランダム化または準ランダム化比較試験で調査した。母性フェニルケトン尿症の治療を受ける患者は除外した。

データ収集と分析

2名の著者が独立して試験の適格性、方法論的な質を評価し、データを抽出した。

主な結果

6件の試験を確認したが、そのうち総計56例の参加者の結果を報告している3件の試験がレビュー対象として適切であった。血中チロシン濃度はプラセボ群と比較してチロシン補充を受けた参加者の方が有意に高く、平均差は23.46であった(95%信頼区間12.87~34.05)。その他の測定アウトカムに有意差は確認されなかった。

著者の結論

日常臨床にチロシン補充を導入すべきかどうかについて、現在入手可能なエビデンスからは推奨はできない。別のエビデンスを示すには、さらにランダム化比較試験が必要となる。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2015.12.26]《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Plain language summary

Adding the amino acid tyrosine to the diet of people with phenylketonuria

Phenylketonuria is an inherited disease. People with phenylketonuria can either not process phenylalanine from their diet at all or only in part. High blood levels of phenylalanine can cause brain or nerve damage. A diet avoiding foods high in phenylalanine can be hard to follow. People with phenylketonuria can have low levels of the amino acid tyrosine in their blood. We searched for trials which compared adding tyrosine to diet along with or instead of a phenylalanine-restricted diet. We were able to include three trials with 56 people in the review. Although the amount of tyrosine measured in the blood of those taking the supplement was higher, there were no differences noted in any other outcome measures. There is no evidence to suggest that tyrosine should be routinely added to the diet of people with phenylketonuria. Further randomised controlled trials are needed to provide more evidence.

Résumé simplifié

Ajout de tyrosine amino-acide au régime alimentaire des personnes atteintes de phénylcétonurie

La phénylcétonurie est une maladie héréditaire. Les personnes atteintes de phénylcétonurie ne peuvent pas transformer la phénylalanine issue de leur alimentation, en totalité ou seulement en partie. Des taux élevés de phénylalanine dans le sang peuvent entraîner des dommages cérébraux ou nerveux. Il peut être difficile de suivre un régime alimentaire qui évite les aliments riches en phénylalanine. Les personnes atteintes de phénylcétonurie peuvent avoir des taux bas de tyrosine amino-acide dans leur sang. Nous avons recherché les essais qui comparaient l'ajout de tyrosine à un régime alimentaire en association avec ou à la place d'un régime restreint en phénylalanine. Nous avons pu inclure trois essais, impliquant 56 participants, dans la revue. Bien que la quantité de tyrosine mesurée dans le sang des personnes prenant le supplément était plus élevée, il n'a été constaté aucune différence dans les autres critères de jugement. Il n'existe pas de données permettant de suggérer que la tyrosine pourrait être ajoutée systématiquement au régime alimentaire des personnes atteintes de phénylcétonurie. Il est nécessaire de réaliser d'autres essais contrôlés randomisés pour fournir plus de données.

Notes de traduction

Traduit par: French Cochrane Centre 16th July, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Laički sažetak

Dodavanje amino kiseline tirozina u prehranu ljudi oboljelih od fenilketonurije

Fenilketonurija je nasljedna bolest. Osobe s fenilketonurijom ne mogu metabolizirati fenilalanin iz hrane ili to mogu samo djelomično. Visoka razina fenilalanina u krvi može izazvati oštećenje mozga ili živaca. Prehrana siromašna fenilalaninom teško se provodi. Osobe s fenilketonurijom mogu imati nisku razinu aminokiseline tirozina u krvi. U ovom Cochrane sustavnom pregledu pretražena je literatura kako bi se pronašli pokusi koji uspoređuju dodatak tirozina u prehranu uz prehranu siromašnu fenilalaninom ili umjesto nje. U pregled su uključena tri pokusa s 56 ljudi. Iako je količina tirozina izmjerena u krvi onih koji su uzimali dodatak tirozina bila veća, nije bilo razlike u bilo kojoj drugoj mjeri ishoda. Nema dokaza da se tirozin treba rutinski dodavati u prehranu osoba s fenilketonurijom. Potrebni su randomizirani kontrolirani klinički pokusi da bi pribavilo više dokaza.

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Bartłomiej Kisiel
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

平易な要約

フェニルケトン尿症患者の食事へのアミノ酸であるチロシンの補充

フェニルケトン尿症は遺伝性疾患である。フェニルケトン尿症患者は、食事から摂取されるフェニルアラニンを全く分解できないか、できても一部のみである。血中フェニルアラニン値の上昇は、脳または神経損傷の原因となる。フェニルアラニンが豊富な食品を避けた食事を続けることは難しい。フェニルケトン尿症患者は、アミノ酸であるチロシンの血中濃度が低くなる可能性がある。フェニルアラニン制限食と並行またはその代わりにチロシン補充をする比較試験を検索した。レビューに56例を含む3件の試験を選択できた。チロシン補充を受けた人の血中チロシン濃度は高く測定されたが、アウトカム指標に差は認められなかった。フェニルケトン尿症患者の食事にチロシンをルーチンに補充すべきと示唆するエビデンスはない。ほかにエビデンスを得るには、さらにランダム化比較試験(RCT)が必要である。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2015.12.26]《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Background

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

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

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

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

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

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

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

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)3 mean difference (Fixed, 95% CI)21.78 [-75.69, 119.25]
2 Blood tyrosine concentration(umol/l) (0-3 months)3 mean 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]
Analysis 1.1.

Comparison 1 Tyrosine versus placebo (all participants), Outcome 1 Blood phenylalanine concentration (umol/l) (0-3 months).

Analysis 1.2.

Comparison 1 Tyrosine versus placebo (all participants), Outcome 2 Blood tyrosine concentration(umol/l) (0-3 months).

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)3 mean difference (Fixed, 95% CI)Subtotals only
1.1 Participants with PKU continued on diet since diagnosis2 mean difference (Fixed, 95% CI)16.55 [-97.43, 130.53]
1.2 Participants with PKU on diet from diagnosis who no longer follow diet1 mean difference (Fixed, 95% CI)36.0 [-152.01, 224.01]
2 Blood tyrosine concentration (umol/l) (0-3 months)3 mean difference (Fixed, 95% CI)Subtotals only
2.1 Participants with PKU continued on diet since diagnosis2 mean difference (Fixed, 95% CI)14.83 [3.72, 25.94]
2.2 Participants with PKU on diet from diagnosis who no longer follow diet1 mean difference (Fixed, 95% CI)109.0 [74.02, 143.98]
3 Weight gain (kg) (0-3 months)0 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3.1 Participants with PKU continued on diet since diagnosis00Mean 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 diet00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Intelligence quotient (IQ) (0-3 months)0 Mean Difference (IV, Fixed, 95% CI)Subtotals only
4.1 Participants with PKU continued on diet since diagnosis00Mean 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 diet00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Neuropsychological performance (0-3 months)2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
5.1 Participants with PKU continued on diet since diagnosis142Mean 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 diet142Mean 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]
Analysis 2.1.

Comparison 2 Tyrosine versus placebo (continued on diet versus discontinued diet), Outcome 1 Blood phenylalanine concentration (umol/l) (0-3 months).

Analysis 2.2.

Comparison 2 Tyrosine versus placebo (continued on diet versus discontinued diet), Outcome 2 Blood tyrosine concentration (umol/l) (0-3 months).

Analysis 2.5.

Comparison 2 Tyrosine versus placebo (continued on diet versus discontinued diet), Outcome 5 Neuropsychological performance (0-3 months).

What's new

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

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 performed

The 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

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

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

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.

Characteristics of studies

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

  1. a

    PKU: phenylketonuria

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
  1. a

    PKU: phenylketonuria

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.
Participants

Initially 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