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Sustitutos proteicos para niños y adultos con fenilcetonuria

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Referencias

Referencias de los estudios incluidos en esta revisión

Ir a:

MacDonald 2006b {published data only}

MacDonald A, Chakrapani A, Hendriksz C, Daly A, Davies P, Asplin D, et al. Protein substitute dosage in PKU: how much do young patients need?. Archives of Disease in Childhood 2006;91(7):588‐93. [MEDLINE: 16547085]
MacDonald A, Daly A, Chakrapani A, Rylance G, Asplin D, Hall SK, et al. What is the ideal dose of protein substitute in PKU?. SHS Inborn Error Review Series2003, issue 13:15.

Prince 1997 {published data only}

Buist NR, Prince AP, Huntington KL, Tuerck JM, Waggoner DD. A new amino acid mixture permits new approaches to the treatment of phenylketonuria. Acta Paediatrica 1994;407 Suppl:75‐7. [MEDLINE: 7766965]
Prince AP, McMurry MP, Buist NRM. Treatment products and approaches for phenylketonuria: improved palatability and flexibility demonstrate safety, efficacy and acceptance in US clinical trials. Journal of Inherited Metabolic Disease 1997;20(4):486‐98.

Schindeler 2007 {published data only}

Schindeler S, Ghosh‐Jerath S, Thompson S, Rocca A, Joy P, Kemp A, et al. The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Molecular Genetics and Metabolism 2007;91(1):48‐54. [MEDLINE: 17368065]
Thompson S. Large neutral amino acid therapy for phenylketonuria in Australia. Proceedings of the Second International Metabolic Nutrition Conference; 2008 April 24‐26; Atlanta. Atlanta, 2008.
Thompson S, Schindeler S, Ghosh‐Jerath S, Rocca A, Joy P, Kemp A, et al. Effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Journal of Inherited Metabolic Disease 2006;29(Suppl 1):52.

Referencias de los estudios excluidos de esta revisión

Ir a:

Acosta 1994 {published data only}

Acosta PB, Yannicelli S. Protein intake affects phenylalanine requirements and growth of infants with phenylketonuria. Acta Paediatrica 1994;407:66‐7.

Agostoni 2006 {published data only}

Agostoni C, Harvie A, McCulloch DL, Demellweek C, Cockburn F, Giovannini M, et al. A randomized trial of long‐chain polyunsaturated fatty acid supplementation in infants with phenylketonuria. Developmental Medicine and Child Neurology 2006;48(3):207‐12. [MEDLINE: 16483397]

Ahring 2010 {published data only}

Ahring KK, Mxller LB, Nielsen JB, Andersen JR. Phenylketonuria‐‐the effects on quality of life and plasma concentrations of phenylalanine and tyrosine of two different amino‐acid‐supplementations in different concentrations. Journal of Inherited Metabolic Diseases2010; Vol. 33, issue Suppl 1:S104.

Ahring 2012 {published data only}

Ahring KK, Mxller LB, Anderson JR. Phenylketonuria ‐ the effect of LNAA on amino acid profile [abstract]. Journal of Inherited Metabolic Diseases 2012;S38:Abstract no: P‐052.

Baumgartner 2004 {published data only}

Baumgartner C, Bohm C, Baumgartner D, Marini G, Weinberger K, Olgemoller B, et al. Supervised machine learning techniques for the classification of metabolic disorders in newborns. Bioinformatics 2004;20(17):2985‐96.

Cleary 2003 {published and unpublished data}

Cleary MA. Large neutral amino acids and phenylketonuria [abstract]. SHS Inborn Errors Review Series. 2003; Vol. Number 13.

Cleary 2006 {published data only}

Cleary MA, Feillet F, White FJ, Vidailhet M, Macdonald A, Grimsley A, et al. Randomised controlled trial of essential fatty acid supplementation in phenylketonuria. European Journal of Clinical Nutrition 2006;60(7):915‐20. [MEDLINE: 16523206]

Clemens 1991 {published data only}

Clemens PC, Heddrich‐Ellerbrok M, Wachtel V, Link RM. Plasma amino acids in adolescents and adults with phenylketonuria on three different levels of protein intake. Acta Paediatrica Scandinavica 1991;80(5):577‐80.

Gokmen‐Ozel 2011 {published data only}

Gokmen‐Ozel H, Ferguson C, Evans S, Daly A, MacDonald A. Does a lower carbohydrate protein substitute impact on blood phenylalanine control, growth and appetite in children with PKU?. Molecular Genetics and Metabolism 2011;104:S64‐7.

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.

Koletzko 2007 {published data only}

Koletzko B, Sauerwald T, Demmelmair H, Herzog M, von Schenck U, Bohles H, et al. Dietary long‐chain polyunsaturated fatty acid supplementation in infants with phenylketonuria: a randomized controlled trial. Journal of Inherited Metabolic Disease 2007;30(3):326‐32.

Levy 2007 {published data only}

Levy H, Milanowski A, Chakrapani A, Cleary M, Trefz F, Whitley C, et al. A phase 3 study of the efficacy of sapropterin in reducing phe levels in subjects with phenylketonuria. Journal of Inherited Metabolic Disease 2006;29(Suppl 1):13.
Levy HL, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz FK, et al. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R‐BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo‐controlled study. Lancet 2007;370(9586):504‐10.

MacDonald 2003a {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.

MacDonald 2005 {published data only}

MacDonald A, Lilburn M, Daly A, Hall SK, Hendriksz C, Chakrapani A, et al. Does ready to drink protein substitute improve compliance in PKU [abstract]. Society for the Study of Inborn Errors of Metabolism 42nd Annual Symposium; 2005 Sep 6‐9; Paris, France. 2005:41.

MacDonald 2006a {published data only}

MacDonald A, Lilburn M, Davies P, Evans S, Daly A, Hall SK, et al. 'Ready to drink' protein substitute is easier is for people with phenylketonuria. Journal of Inherited Metabolic Disease 2006;29(4):526‐31. [MEDLINE: 16736099]

MacDonald 2006c {published data only}

MacDonald A, Gokmen Ozel H, Daly A, Hendriksz C, Chakrapani A. Phenylalanine exchanges in PKU: should they be weighed?. Journal of Inherited Metabolic Disease 2006;29(Suppl 1):39.
MacDonald A, Gokmen Ozel H, Daly A, Hendriksz C, Chakrapani A. Phenylalanine exchanges in PKU: should they be weighed? [abstract]. Inborn Error Review Series (Dietary Management of Inborn Errors of Metabolism)2006; Vol. 16:12.

MacDonald 2008 {published data only}

MacDonald A, Ferguson C, Daly A, Hopkins V, Hall SK, Rylance G, Hendriksz C, et al. Ready to use protein substitute for children with PKU. Journal of Inherited Metabolic Diseases2008; Vol. 31, issue Suppl 1:142.

Marsden 2005 {published data only}

Marsden D, Mulkern R, Young‐Poussaint T, Rohr F, Waisbren S. Large neutral amino acid treatment in adult patients with PKU ‐ a pilot study [abstract]. Society for the Study of Inborn Errors of Metabolism 42nd Annual Symposium; 2005 Sep 6‐9; Paris, France. 2005:22.

Matalon 2006 {published data only}

Matalon R, Michals‐Matalon K, Burlina A, Giovannini M, Fiori L, Grechanina E, et al. Double blind placebo control trial in PKU with NeoPhe. Journal of Inherited Metabolic Disease 2006;29(Suppl 1):13.

Matalon 2007 {published data only}

Matalon R, Michals‐Matalon K, Bhatia G, Burlina AB, Burlina AP, Braga C, et al. Double blind placebo control trial of large neutral amino acids in treatment of PKU: effect on blood phenylalanine. Journal of Inherited Metabolic Disease 2007;30(2):153‐8. [MEDLINE: 17334706]

Rose 2005 {published data only}

Rose HJ, White F, Macdonald A, Rutherford PJ, Favre E. Fat intakes of children with PKU on low phenylalanine diets. Journal of Human Nutrition and Dietetics 2005;18(5):395‐400.

SHS 2001 {published data only}

SHS, Royal Hospital for Sick Children (Glasgow), Alder Hey Children's Hospital (Liverpool), Hospital for Sick Children Great Ormond Street (London), Royal Victoria Hospital (Belfast), The Children's Hospital (Sheffield). A multicentre study to evaluate and compare the nutritional adequacy of XP Analog and Lofenelac in the dietary management of infants with phenylketonuria (PKU). XP Analog and XP Analog LCP ‐ a compilation of abstracts2001.

Stroem 2011 {published data only}

Stroem P, Enggaard K, Nielsen JB. When will PKU infants blood phenylalanine reach the desired level? ‐A study of 207 PKU patients. Journal of Inherited Metabolic Diseases2011; Vol. 34, issue Suppl 3:S101.

ten Hoedt 2011 {published data only}

ten Hoedt AE, de Sonneville LM, Francois B, ter Horst NM, Janssen MC, Rubio‐Gozalbo ME, et al. High phenylalanine levels directly affect mood and sustained attention in adults with phenylketonuria: a randomised, double‐blind, placebo‐controlled, crossover trial. Journal of Inherited Metabolic Diseases 2011;34(1):165‐71.

Referencias de los estudios en espera de evaluación

Ir a:

Giovannini 2006 {published data only}

Giovannini M, Flori L, Casero D, Lammardo AM, Bertolotti D, Bonza M, et al. Effects of a six month‐supplementation of a new phe‐free powdered amino acid preparation on blood amino acid profile and levels of albumin, protein and transferrin in PKU patients. Journal of Inherited Metabolic Disease 2006;29(Suppl 1):52.

Lange 2004 {published data only}

Lange A, Starostecka E, Heleniak G, Lukamowicz J, Kudra A. Bone metabolism in relation to dietary treatment in phenylketonuric (PKU) children aged 6‐8 years. [abstract]. Journal of Inherited Metabolic Disease 2004;27(Suppl 1):18. [CENTRAL: 507906; CRS: 5500100000002702]

MacDonald 2003b {published data only}

MacDonald A, Rylance G, Davies P, Asplin D, Hall SK, Booth IW. Administration of protein substitute and quality of control in phenylketonuria: A randomized study. Journal of Inherited Metabolic Disease 2003;26(4):319‐26.

Acosta 2003

Acosta PB, Yannicelli S, Singh R, Mofidi S, Steiner R, DeVincentis E, et al. Nutrient intakes and physical growth of children with phenylketonuria undergoing nutrition therapy. Journal of the American Dietetic Association 2003;103(9):1167‐73. [MEDLINE: 12963945]

Arnold 2002

Arnold GL, Vladutiu CJ, Kirby RS, Blakely EM, Deluca JM. Protein insufficiency and linear growth restriction in phenylketonuria. Journal of Pediatrics 2002;141(2):243‐6.

Aung 1997

Aung TT, Klied A, McGinn J, McGinn T. Vitamin B12 deficiency in an adult phenylketonuric patient. Journal of Inherited Metabolic Disease 1997;20(4):603‐4.

Bickel 1953

Bickel H, Gerrard J, Hickmans EM. Influence of phenylalanine intake on phenylketonuria. Lancet 1953;265(6790):812‐3.

Dobbelaere 2003

Dobbelaere D, Michaud L, Debrabander A, Vanderbecken S, Gottrand F, Turck D, et al. Evaluation of nutritional status and pathophysiology of growth retardation in patients with phenylketonuria. Journal of Inherited Metabolic Disease 2003;26(1):1‐11.

DRIs 2002

Panel on Macronutrients, Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of Dietary Reference Intakes, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). Washington, D.C. National Academies Press2002.

Fehrenbach 1989

Fehrenbach AM, Peterson L. Parental problem‐solving skills, stress, and dietary compliance in phenylketonuria. Journal of Consulting and Clinical Psychology 1989;57(2):237‐41.

Griffiths 1995

Griffiths P, Paterson L, Harvie A. Neuropsychological effects of subsequent exposure to phenylalanine in adolescents and young adults with early‐treated phenylketonuria. Journal of Intellectual Disability Research 1995;39(5):365‐72.

Gropper 1988

Gropper SS, Acosta PB, Clarke‐Sheehan N, Wenz E, Cheng M, Koch R. Trace element status of children with PKU and normal children. Journal of the American Dietetic Association 1988;88(4):459‐65.

Guldberg 1998

Guldberg P, Rey F, Zschocke J, Romano V, Francois B, Michiels L, et al. A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype‐based prediction of metabolic phenotype. American Journal of Human Genetics 1998;63(1):71‐9.

Hanley 1970

Hanley WB, Linsao L, Davidson W, Moes CA. Malnutrition with early treatment of phenylketonuria. Pediatr Research 1970;4(4):318‐27.

Hanley 1993

Hanley WB, Feigenbaum A, Clarke JT, Schoonheyt W, Austin V. Vitamin B12 deficiency in adolescents and young adults with phenylketonuria. Lancet 1993;342(8877):997.

Herrmann 1994

Herrmann ME, Brosicke HG, Keller M, Monch E, Helge H. Dependence of the utilization of a phenylalanine‐free amino acid mixture on different amounts of single dose ingested. A case report. European Journal of Pediatrics 1994;153(7):501‐3.

Higgins 2003

Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327(7414):557‐60.

Hoeksma 2005

Hoeksma M, Van Rijn M, Verkerk PH, Bosch AM, Mulder MF, de Klerk JB, et al. The intake of total protein, natural protein and protein substitute and growth of height and head circumference in Dutch infants with phenylketonuria. Journal of Inherited Metabolic Disease 2005;28(6):845‐54.

Huemer 2007

Huemer M, Huemer C, Moslinger D, Huter D, Stockler‐Ipsiroglu S. Growth and body composition in children with classical phenylketonuria: results in 34 patients and review of the literature. Journal of Inherited Metabolic Disease 2007 Oct;30(5):694‐9.

Jones 1983

Jones BJ, Lees R, Andrews J, Frost P, Silk DB. Comparison of an elemental and polymeric enteral diet in patients with normal gastrointestinal function. Gut 1983;24(1):78‐84. [MEDLINE: 6401257]

Jüni 2001

Jüni P, Altman DG, Egger M. Systematic reviews in health care: Assessing the quality of controlled clinical trials. BMJ 2001;323(7303):42‐6.

Kindt 1985

Kindt E, Holm H, Halvorsen S, Lie SO. Net protein utilization determined by rat bioassay of a protein hydrolysate and a diet for children with phenylketonuria. British Journal of Nutrition 1985;54(2):349‐53.

Kindt 1988

Kindt E, Lunde HA, Gjessing LR, Halvorsen S, Lie SO. Fasting plasma amino acid concentrations in PKU children on two different levels of protein intake. Acta Paediatrica Scandinavica 1988;77(1):60‐6.

Krause 1986

Krause W, Epstein C, Averbook A, Dembure P, Elsas L. Phenylalanine alters the mean power frequency of electroencephalograms and plasma L‐dopa in treated patients with phenylketonuria. Pediatric Research 1986;20(11):1112‐6.

Legido 1993

Legido A, Tonyes L, Carter D, Schoemaker A, Di George A, Grover WD. Treatment variables and intellectual outcome in children with classic phenylketonuria. A single‐center‐based study. Clinical Pediatrics 1993;32(7):417‐25.

Levy 1996

Levy HL, Ghavami M. Maternal phenylketonuria: a metabolic teratogen. Teratology 1996;53(3):176‐84.

Lipson 1981

Lipson AH, Yu JS, O'Halloran MT, Williams R. Alcohol and phenylketonuria. Lancet 1981;317(8222):717‐8. [MEDLINE: 6110928]

MacDonald 1999

MacDonald A. Diet and Phenylketonuria, Birmingham University. PhD thesis1999.

MacDonald 2000

MacDonald A. Diet and compliance in phenylketonuria. European Journal Pediatrics 2000 Oct;159(Suppl 2):S136‐41.

Metges 2000

Metges CC, El‐Khoury AE, Selvaraj AB, Tsay RH, Atkinson A, Regan MM, et al. Kinetics of L‐[1‐(13)C]leucine when ingested with free amino acids, unlabeled or intrinsically labeled casein. American Journal of Physiology, Endocrinology and metabolism 2000;278(6):E1000‐9. [MEDLINE: 10827001]

MRC 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.

NIH 2000

National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16‐18, 2000. NIH Consensus Statement 2001;108(4):972‐82.

PAH database 2007

PAHdb Curatorial Team. Phenylalanine Hydroxylase Locus KnowledgeBase. www.pahdb.mcgill.ca (accessed October 3, 2007).

Paine 1957

Paine RS. The variability in manifestations of untreated patients with phenylketonuria (phenylpyruvic aciduria). Pediatrics 1957;20(2):290‐302. [MEDLINE: 13452670]

Pennington 1985

Pennington BF, van Doorninck WJ, McCabe LL, McCabe ER. Neuropsychological deficits in early treated phenylketonuric children. American Journal of Mental Deficiency 1985;89(5):467‐74.

Pietz 1998

Pietz J, Dunckelmann R, Rupp A, Rating D, Meinck HM, Schmidt H, et al. Neurological outcome in adult patients with early‐treated phenylketonuria. Journal of Pediatrics 1998;157(10):824‐30. [MEDLINE: 9809823]

Przyrembel 2000

Przyrembel H, Bremer HJ. Nutrition, physical growth, and bone density in treated phenylketonuria. European Journal of Pediatrics 2000;159(Suppl 2):S129‐35.

Robinson 2000

Robinson M, White FJ, Cleary MA, Wraith E, Lam WK, Walter JH. Increased risk of vitamin B12 deficiency in patients with phenylketonuria on an unrestricted or relaxed diet. Journal of Pediatrics 2000;136(4):545‐7. [MEDLINE: 10753257]

Rouse 1990

Rouse B, Lockhart L, Matalon R, Azen C, Koch R, Hanley W, et al. Maternal phenylketonuria pregnancy outcome: a preliminary report of facial dysmorphology and major malformations. Journal of Inherited Metabolic Disease 1990;13(3):289‐91. [MEDLINE: 2122088]

Schoeffer 1994

Schoeffer A, Herrmann ME. Effect of dosage and timing of amino acid mixtures on nitrogen retention in patients with phenylketonuria. Journal of Nutritional Medicine 1994;4(4):415‐8.

Schulz 1995

Schulz B, Bremer HJ. Nutrient intake and food consumption of adolescents and young adults with phenylketonuria. Acta Paediatrica 1995;84(7):743‐8.

Scriver 2001

Scriver CR, Kaufman S. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D editor(s). The Metabolic & Molecular Bases of Inherited Disease. 8th Edition. New York: McGraw‐Hill, 2001:1667‐724.

Sibinga 1971

Sibinga MS, Friedman CJ, Steisel IM, Baker EC. The depressing effect of diet on physical growth in phenylketonuria. Developmental Medicine and Child Neurology 1971;13(1):63‐70.

van Rijn 2007

van Rijn M, Hoeksma M, Sauer P, Szczerbak B, Gross M, Reijngoud DJ, et al. Protein metabolism in adult patients with phenylketonuria. Nutrition 2007;23(6):445‐53.

Waisbren 2007

Waisbren SE, Noel K, Fahrbach K, Cella C, Frame D, Dorenbaum A, et al. Phenylalanine blood levels and clinical outcomes in phenylketonuria: A systematic literature review and meta‐analysis. Molecular Genetics and Metabolism 2007;92(1‐2):63‐70. [MEDLINE: 17591452]

Weetch 2006

Weetch E, Macdonald A. The determination of phenylalanine content of foods suitable for phenylketonuria. Journal of Human Nutrition and Dietetics 2006;19(3):229‐36.

Referencias de otras versiones publicadas de esta revisión

Ir a:

Rutherford 2005

Rutherford, Poustie. Protein substitute for children and adults with phenylketonuria. Cochrane Database of Systematic Reviews 2005, Issue 4. [DOI: 10.1002/14651858.CD004731.pub2]

Yi 2008

Yi SHL, Singh RH. Protein substitute for children and adults with phenylketonuria. Cochrane Database of Systematic Reviews 2008, Issue 4. [DOI: 10.1002/14651858.CD004731.pub3]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

MacDonald 2006b

Methods

Randomised controlled cross‐over trial.

Participants

Number of participants: 25 enrolled, ages 2 to 10 years.
Inclusion criteria: well controlled plasma phenylalanine concentrations over the past 6 months; ages 2 to 10 years; parents able to collect blood specimens.
Exclusion criteria: none indicated.

Interventions

Two doses of protein substitute for 14 days each with a 14‐day washout period.
1. 2 g/kg body weight/day
2. 1.2 g/kg body weight/day

Outcomes

1. Plasma phenylalanine concentrations
2. Intakes of total protein, protein from protein substitute, protein from food, and phenylalanine exchanges
3. Intakes of total energy and energy from protein substitute

Notes

Location: UK

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization process not described.

Allocation concealment (selection bias)

Low risk

Adequate.

Blinding (performance bias and detection bias)
All outcomes

High risk

Not used.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Inclusion of all randomized participants in the final analysis.
Prince 1997

Methods

Two‐phase trial (phase 1 trial length: 2 years; phase 2 study length: 3 years). Only phase 1 was an RCT.
Phase 1: Randomised controlled parallel trial.
Inclusion of all randomized participants in the final analysis: Phase I: unclear, data not shown;

Not included in this review: Phase 2: historic control trial. Only 25 of 28 randomized participants were included.

Participants

Phase 1:
Number of participants: 28 enrolled, ages 4 to 10 years.
Inclusion criteria: diagnosed with moderate to severe PKU; ages 4 to 10 years; currently treated by a protein‐restricted diet supplemented with protein substitute.
Exclusion criteria: none indicated.

Not included in this review: Phase 2: historic control trial.

Interventions

Phase 1:
1. Novel protein substitute: 100% US RDA for protein (1989) for 2 years. The novel protein substitute contained 10 g protein equivalent for 400 kcal (100 g dry powder) and included a reduction in methionine and cystine, and eliminated aspartic acid and glutamic acid.
2. Control protein substitute (PhenylFree, Mead‐Johnson Co., Evansville, IN, USA): 100% US RDA for protein (1989) for two years.

Not included in this review: Phase 2: historic control trial.

Outcomes

Phase 1:
1. Growth
2. Serum protein (prealbumin and transferrin) concentrations
3. Serum phenylalanine concentrations
4. Serum essential amino acid concentrations
5. Protein substitute intake assessed by 4‐day diet records
6. Protein substitute intake assessed by product acquisition records

Not included in this review:
7. Compliance rating
Phase 2: historic control trial.

Notes

Location: USA

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomization process not described.

Allocation concealment (selection bias)

Unclear risk

Unclear if allocation concealment was used.

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Unclear if blinding was used.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Unclear as data not shown whether all randomized participants were included in the final analysis.

Schindeler 2007

Methods

Randomised controlled cross‐over trial.

Participants

Number of participants: 16 enrolled, ages 11 to 45 years.
Inclusion criteria: diagnosed with classical PKU; early initiation of treatment; currently treated by a protein‐restricted diet supplemented with protein substitute.
Exclusion criteria: none indicated.

Interventions

4‐arm trial; each arm lasted 14 days separated with washout periods of at least 4 weeks. Participants were instructed to remain on a low‐phenylalanine diet through the entirety of the trial.

1. Placebo without protein substitute
2. Placebo plus protein substitute

Not included in this review:
3. LNAAs plus protein substitute
4. LNAAs without protein substitute

Outcomes

1. Neuropsychological performance (attention, reaction time, response inhibition, generativity, self‐monitoring, cognitive flexibility, planning, immediate span, and working memory)
2. Plasma phenylalanine concentrations
3. Plasma phenylalanine: tyrosine ratio
4. Intakes of total protein, protein from protein substitute, protein from food, and phenylalanine
5. Brain phenylalanine concentrations

Not included in this review:
6. Self‐reported ratings of mood
7. LNAA intake

Notes

Location: Australia

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Generation of allocation sequence: randomization process not described.

Allocation concealment (selection bias)

Low risk

Adequate.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Participants, investigators, and outcome assessor were blinded to treatment allocation.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomized participants are included in the final analysis of neuropsychological performance, plasma phenylalanine and tyrosine concentrations, and brain phenylalanine concentrations. Two participants were excluded from diet analyses due to failure to submit diet records in at least one of the trial arms.

LNAA: large neutral amino acid
PKU: phenylketonuria
RCT: randomised controlled trial
RDA: recommended daily allowance

Characteristics of excluded studies [ordered by study ID]

Ir a:

Study

Reason for exclusion

Acosta 1994

Not a CCT or RCT. Ascertained by communication with current head of metabolic products who contacted the author (her predecessor in post). Infants fed Analog XP were studied first, and Phenex study began after this.

Agostoni 2006

Intervention not eligible for inclusion.

Ahring 2010

Intervention not eligible for inclusion.

Ahring 2012

Intervention not eligible for inclusion.

Baumgartner 2004

Intervention not eligible for inclusion.

Cleary 2003

Participants and intervention not eligible for inclusion.

Cleary 2006

Intervention not eligible for inclusion.

Clemens 1991

Not a CCT or RCT.

Gokmen‐Ozel 2011

Intervention not eligible for inclusion.

Kalkanoglu 2005

Group of participants not eligible for inclusion.

Koletzko 2007

Intervention not eligible for inclusion.

Levy 2007

Intervention not eligible for inclusion.

MacDonald 2003a

Intervention not eligible for inclusion. The trial did not set out to compare two different doses of protein substitute intake, but examined a group of 20 participants with PKU and studied the effects of giving participants at least 40% of their daily protein substitute requirements as tablets for at least 12 weeks. There was better compliance with protein substitute as tablets, therefore, in this trial, different intakes of protein substitute were only measured as outcomes.

MacDonald 2005

Intervention not eligible for inclusion.

MacDonald 2006a

Intervention not eligible for inclusion.

MacDonald 2006c

Participants, intervention, and outcomes not eligible for inclusion.

MacDonald 2008

Intervention not eligible for inclusion.

Marsden 2005

Participants and intervention not eligible for inclusion.

Matalon 2006

Intervention not eligible for inclusion.

Matalon 2007

Intervention not eligible for inclusion.

Rose 2005

Intervention not eligible for inclusion.

SHS 2001

Not a CCT or RCT (ascertained by communication with co‐ordinator of original study at SHS).

Stroem 2011

Intervention not eligible for inclusion.

ten Hoedt 2011

Intervention not eligible for inclusion.

CCT: controlled clinical trial
PKU: phenylketonuria
RCT: randomized controlled trial

Characteristics of studies awaiting assessment [ordered by study ID]

Ir a:

Giovannini 2006

Methods

Randomised parallel trial.
Generation of allocation sequence: randomization process not described.
Allocation concealment: unclear.
Blinding: unclear.
Inclusion of all randomized participants in the final analysis: unclear.

Participants

Number of participants: 13 enrolled, ages 5 to 26 years.
Inclusion criteria: none indicated; title and text indicate diagnosis with phenylketonuria as a criterion.
Exclusion criteria: none indicated.

Interventions

1. 100% of total nitrogen needs from slow‐release protein substitute (6 months)
2. 80% of total nitrogen needs from slow‐release protein substitute (6 months)

Outcomes

1. Plasma phenylalanine concentrations
2. Plasma amino acid concentrations
3. Plasma protein concentrations (albumin, total protein, and transferrin)

Notes

Location: Italy.
The lead investigator will be contacted for further information needed to complete the assessment of trial eligibility.

Lange 2004

Methods

Open, parallel trial.

Method of allocation not described.
Inclusion of all participants in the final analysis: unclear.

Participants

Number of participants: 20, ages 6 to 8 years

Inclusion criteria: none indicated; title and text indicate diagnosis with PKU as a criterion.
Exclusion criteria: none indicated.

Interventions

1. Treatment with both Milupa PKU 2 and PKU 2 mix for 6 months

2. Treatment with both Milupa PKU 2 only for 6 months

Outcomes

1. Anthropometric parameters (not otherwise described)
2. Diet intake of chosen nutrients (not otherwise described)

Notes

Location: Poland.

The lead investigator will be contacted for further information needed to complete the assessment of trial eligibility.

MacDonald 2003b

Methods

Randomised controlled cross‐over trial.
Generation of allocation sequence: randomization process not described.
Allocation concealment: adequate.
Blinding: not used.
Inclusion of all randomized participants in the final analysis: No.

Participants

Number of participants: 16 enrolled, 15 included in analysis, ages 1 to 10 years.
Inclusion criteria: well controlled plasma phe concentrations over the past 6 months; parents able to collect blood specimens.
Exclusion criteria: none indicated.

Interventions

1. Protocol A: protein substitute administered in 3 equal doses over a 10‐hour period (7 days)
2. Protocol B: protein substitute administered in 3 equal doses over a 14‐hour period (7 days)
3. Protocol C: protein substitute administered in 4 equal doses over a 14‐hour period (7 days)
4. Protocol D: protein substitute administered in 6 equal doses over a 24‐hour period (3 days)

Outcomes

1. 24‐hour plasma phenylalanine variation
2. 24‐hour dietary phenylalanine distribution
3. Energy intake (% EAR)

Outcomes not reported in manuscript:
4. Other nutrient intakes (carbohydrates, fat)

Notes

Location: UK.

Initially only 13 participants were randomised into protocols A, B, and C. A further 3 participants were randomized into protocols A, B, and D. Since the 3 participants were introduced after the initial randomisation phase, their results may not be included in the review. At the present time only information from protocol C can be used as the extra participants did not enter this group. Individual patient data must be sought from the author. This would enable the 3 extra participants to be identified within groups A and B and D and excluded from the analysis.

EAR: estimated average requirements
Phe: phenylalanine
PKU: phenylketonuria
RCT: randomised controlled trial