Large neutral amino acids in the treatment of PKU: from theory to practice

Notwithstanding the success of the traditional dietary phenylalanine restriction treatment in phenylketonuria (PKU), the use of large neutral amino acid (LNAA) supplementation rather than phenylalanine restriction has been suggested. This treatment modality deserves attention as it might improve cognitive outcome and quality of life in patients with PKU. Following various theories about the pathogenesis of cognitive dysfunction in PKU, LNAA supplementation may have multiple treatment targets: a specific reduction in brain phenylalanine concentrations, a reduction in blood (and consequently brain) phenylalanine concentrations, an increase in brain neurotransmitter concentrations, and an increase in brain essential amino acid concentrations. These treatment targets imply different treatment regimes. This review summarizes the treatment targets and the treatment regimens of LNAA supplementation and discusses the differences in LNAA intake between the classical dietary phenylalanine-restricted diet and several LNAA treatment forms.

• Publication year

  2010

• Venue

  Journal of Inherited Metabolic Disease

• Publication date

  2010-10-26

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1007/s10545-010-9216-1PMID 20976625PMCID 2992655
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Executive function in early-treated phenylketonuria: profile and underlying mechanisms.

  2010cited by this paper
• Phenylketonuria: High plasma phenylalanine decreases cerebral protein synthesis.

  2009cited by this paper
• Effect of l-dopa on visual evoked potentials and neuropsychological tests in adult phenylketonuria patients

  2009cited by this paper
• 5-Hydroxytryptophan rescues serotonin response to stress in prefrontal cortex of hyperphenylalaninaemic mice.

  2009cited by this paper
• Brain dysfunction in phenylketonuria: Is phenylalanine toxicity the only possible cause?

  2009cited by this paper
• Reduced availability of brain amines during critical phases of postnatal development in a genetic mouse model of cognitive delay.

  2008cited by this paper
• Double blind placebo control trial of large neutral amino acids in treatment of PKU: Effect on blood phenylalanine

  2007influential reference
• The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study.

  2007cited by this paper
• Large neutral amino acids in the treatment of phenylketonuria (PKU)

  2006influential reference
• Behavioural factors related to metabolic control in patients with phenylketonuria

  2005cited by this paper
• Future role of large neutral amino acids in transport of phenylalanine into the brain.

  2003cited by this paper
• Dietary Threonine Reduces Plasma Phenylalanine Levels in Patients With Hyperphenylalaninemia

  2003influential reference
• Brain phenylalanine concentrations in phenylketonuria: research and treatment of adults.

  2003influential reference
• Large neutral amino acid therapy and phenylketonuria: a promising approach to treatment.

  2003influential reference
• Deficits in brain serotonin synthesis in a genetic mouse model of phenylketonuria

  2002cited by this paper
• Cerebral protein synthesis in a genetic mouse model of phenylketonuria.

  2000cited by this paper
• Protein and Amino Acids

  2000cited by this paper
• Dramatic brain aminergic deficit in a genetic mouse model of phenylketonuria

  2000cited by this paper
• Measurement of neurotransmitter metabolites in the cerebrospinal fluid of phenylketonuric patients under dietary treatment

  2000influential reference
• Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria.

  1999influential reference
• Blood-Brain Barrier Carrier-Mediated Transport and Brain Metabolism of Amino Acids

  1998influential reference
• Randomised controlled trial of tyrosine supplementation on neuropsychological performance in phenylketonuria

  1998cited by this paper
• Factors affecting the variation in plasma phenylalanine in patients with phenylketonuria on diet.

  1996cited by this paper
• Effect of high-dose tyrosine supplementation on brain function in adults with phenylketonuria.

  1995cited by this paper
• An animal model of early-treated PKU

  1994cited by this paper
• Dopamine precursors and brain function in phenylalanine hydroxylase deficiency

  1994cited by this paper
• Cognition and tyrosine supplementation among school-aged children with phenylketonuria.

  1992cited by this paper
• Valine, isoleucine, and leucine. A new treatment for phenylketonuria.

  1990cited by this paper
• Increased neurotransmitter biosynthesis in phenylketonuria induced by phenylalanine restriction or by supplementation of unrestricted diet with large amounts of tyrosine

  1988influential reference
• Neutral amino acid transport at the human blood-brain barrier.

  1988cited by this paper
• Increased Vigilance and Dopamine Synthesis by Large Doses of Tyrosine or Phenylalanine Restriction in Phenylketonuria

  1987influential reference
• Dietary problems of phenylketonuria: Effect on CNS transmitters and their possible role in behaviour and neuropsychological function

  1986influential reference
• Neutral amino acid transport at the human blood-brain barrier.

  1986cited by this paper
• PRELIMINARY SUPPORT FOR THE ORAL ADMINISTRATION OF VALINE, ISOLEUCINE AND LEUCINE FOR PHENYLKETONURIA

  1985cited by this paper
• Large doses of tryptophan and tyrosine as potential therapeutic alternative to dietary phenylalanine restriction in phenylketonuria.

  1985influential reference
• Reduction of Cerebrospinal Fluid Phenylalanine after Oral Administration of Valine, Isoleucine, and Leucine

  1982cited by this paper
• Neurotransmitter defects and treatment of disorders of hyperphenylalaninemia.

  1981influential reference
• Lowering brain phenylalanine levels by giving other large neutral amino acids. A new experimental therapeutic approach to phenylketonuria.

  1976cited by this paper
• Letter: One drug (phenytoin) in treatment of epilepsy.

  1976cited by this paper
• The effects of high phenylalanine concentrations on serotonin and catecholamine metabolism in the human brain.

  1972influential reference
• Effects of feeding individual amino acids upon the distribution of other amino acids between cells and extracellular fluid.

  1948cited by this paper

• Strategies for blood-brain barrier rejuvenation and repair.

  2026cites this paper
• Emerging insights into bioactivities of umami and umami-enhancing compounds: A review

  2026cites this paper
• Clinical assessment of growth patterns, weight, and dietary management in children and adults with phenylketonuria – a retrospective study

  2025cites this paper
• Untargeted Metabolomic Study for Urinary Characterization of Adult Patients with Phenylketonuria

  2025cites this paper
• Single Amino Acid Supplementation in Inherited Metabolic Disorders: An Evidence-Based Review of Interventions

  2025cites this paper
• Genotype–Phenotype Correlation in a Large Cohort of Eastern Sicilian Patients Affected by Phenylketonuria: Newborn Screening Program, Clinical Features, and Follow-Up

  2025cites this paper
• Methodological Considerations and Implications for Appetite and Feeding Behaviour Research in PKU; Current Knowledge, Practical Application and Future Perspectives

  2025cites this paper
• Phenylketonuria: modelling cerebral amino acid and neurotransmitter metabolism

  2025cites this paper
• New findings about neuropathological outcomes in the PKU mouse throughout lifespan.

  2024cites this paper
• Nutrition in Phenylketonuria.

  2024cites this paper
• The penetration of therapeutics across the blood-brain barrier: Classic case studies and clinical implications

  2024cites this paper
• The value of simultaneous determination of blood large neutral amino acids and tetrahydrobiopterin metabolites in the diagnosis of atypical hyperphenylalaninemia

  2024cites this paper
• Evaluation of Parents’ Knowledge about Nutritional Management of children with Phenylketonuria

  2023cites this paper
• Phenylalanine free infant formula in the dietary management of phenylketonuria

  2023cites this paper
• Possible role of tryptophan metabolism along the microbiota-gut-brain axis on cognitive & behavioral aspects in phenylketonuria.

  2023cites this paper
• A food pyramid for adult patients with phenylketonuria and a systematic review on the current evidences regarding the optimal dietary treatment of adult patients with PKU.

  2023cites this paper
• Engineering Organoids for in vitro Modeling of Phenylketonuria

  2022cites this paper
• Genetic etiology and clinical challenges of phenylketonuria

  2022cites this paper
• The increasing importance of LNAA supplementation in phenylketonuria at higher plasma phenylalanine concentrations.

  2021cites this paper
• Microencapsulation of drug with enteric polymer Eudragit L100 for controlled release using the particles from gas saturated solutions (PGSS) process

  2021cites this paper
• FENİLKETONÜRİ HASTALIĞI VE HASTALIĞA UYGUN GIDA ÜRETİMİ Phenylketonuria Disease and Appropriate Food Production for Patients

  2020influential citation
• Branched-chain alpha-ketoacid dehydrogenase deficiency (maple Branched-chain alpha-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes syrup urine disease): Treatment, biomarkers, and outcomes us how to this you.

  2020cites this paper
• Disorders of phenylalanine and tyrosine metabolism

  2020cites this paper
• Similarities and differences in key diagnosis, treatment, and management approaches for PAH deficiency in the United States and Europe

  2020cites this paper
• [Phenylketonuria, from diet to gene therapy].

  2020cites this paper
• The Impact of a Slow-Release Large Neutral Amino Acids Supplement on Treatment Adherence in Adult Patients with Phenylketonuria

  2020cites this paper
• Design of amino acid-based self-assembled nano-drugs for therapeutic applications.

  2020cites this paper
• Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes.

  2020cites this paper
• Large neutral amino acid status in association with P:T ratio and diet in adult and pediatric patients with phenylketonuria

  2019cites this paper
• Nutritional management of phenylalanine hydroxylase (PAH) deficiency in pediatric patients in Canada: a survey of dietitians’ current practices

  2019cites this paper
• Glycomacropeptide: long-term use and impact on blood phenylalanine, growth and nutritional status in children with PKU

  2019cites this paper
• Studying the effect of large neutral amino acid supplements on oxidative stress in phenylketonuric patients

  2019cites this paper
• Propagation of Plasma L-Phenylalanine Concentration Fluctuations to the Neurovascular Unit in Phenylketonuria: An in silico Study

  2019cites this paper
• The blood–brain barrier as an endocrine tissue

  2019cites this paper
• DIAGNOSIS AND TREATMENT OF PHENYLKETONURIA: OPPORTUNITIES AND PROSPECTS

  2019cites this paper
• The Pharmabiotic for Phenylketonuria: Development of a Novel Therapeutic

  2019cites this paper
• The Benefit of Large Neutral Amino Acid Supplementation to a Liberalized Phenylalanine-Restricted Diet in Adult Phenylketonuria Patients: Evidence from Adult Pah-Enu2 Mice

  2019cites this paper
• Nutritional and Metabolic Characteristics of UK Adult Phenylketonuria Patients with Varying Dietary Adherence

  2019cites this paper
• Large Neutral Amino Acid Therapy Increases Tyrosine Levels in Adult Patients with Phenylketonuria: A Long-Term Study

  2019cites this paper
• PHENYLKETONURIA: A SUMMARY OF EXISTING AND PROSPECTIVE TREATMENTS

  2019influential citation
• Quantification of Amino Acid Transporter Interactions

  2019cites this paper
• Large neutral amino acid supplementation as an alternative to the phenylalanine-restricted diet in adults with phenylketonuria: evidence from adult Pah-enu2 mice.

  2018cites this paper
• Evidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria

  2018cites this paper
• The phenylketonuria patient: A recent dietetic therapeutic approach

  2018cites this paper
• Comparison of Glycomacropeptide with Phenylalanine Free-Synthetic Amino Acids in Test Meals to PKU Patients Ahring,

  2018cites this paper
• Diet therapies: bad communications and useless application in healthy individuals.

  2018cites this paper
• Amino Acids and Inherited Amino Acid-Related Disorders

  2018cites this paper
• Comparison of Glycomacropeptide with Phenylalanine Free-Synthetic Amino Acids in Test Meals to PKU Patients: No Significant Differences in Biomarkers, Including Plasma Phe Levels

  2018cites this paper
• Current strategies for the treatment of inborn errors of metabolism.

  2018cites this paper
• Combined large neutral amino acid supplementation for phenylketonuria (PKU)

  2017cites this paper
• Potential role of amino acids in pathogenesis of schizophrenia

  2017cites this paper
• Phenylketonuria in mice and men

  2017cites this paper
• Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria.

  2017cites this paper
• The Effect of Intact Protein from Foods and Phenylalanine Free Medical Foods on Large Neutral Amino Acids in Patients with Phenylketonuria.

  2017influential citation
• Phenylketonuria: A new look at an old topic, advances in laboratory diagnosis, and therapeutic strategies

  2017cites this paper
• A lifetime with Phenylketonuria: Towards a better understanding of therapeutic targets

  2017cites this paper
• Cerebral dopamine deficiency, plasma monoamine alterations and neurocognitive deficits in adults with phenylketonuria

  2017cites this paper
• The Effect of Large Neutral Amino Acids on Blood Phenylalanine Levels in Patients with Classical Phenylketonuria

  2017cites this paper
• Dietary intervention in the management of phenylketonuria: current perspectives

  2016cites this paper
• Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model.

  2016cites this paper
• Updated, web-based nutrition management guideline for PKU: An evidence and consensus based approach.

  2016cites this paper
• Impaired Neurotransmission in Early-treated Phenylketonuria Patients.

  2016cites this paper
• Neurotransmitter Imbalance in Early-Treated Phenylketonuria

  2016cites this paper
• Protein substitutes for phenylketonuria in Europe: access and nutritional composition

  2016cites this paper
• INFLUEN Ţ A DIETEI F Ă R Ă FENILALANIN Ă ASUPRA DEZVOLT Ă RII NEUROPSIHICE ÎN FENILCETONURIE

  2016cites this paper
• Phenylketonuria: Phenylalanine Neurotoxicity

  2015cites this paper
• Diagnostik og behandling af fenylketonuri

  2015cites this paper
• Understanding Large Neutral Amino Acids and the Blood-Brain Barrier

  2015cites this paper
• Development of an innovative strategy based on engineered autologous erythrocytes as “enzyme replacement therapy” for the treatment of Phenylketonuria

  2015cites this paper
• Alternative therapies to address the unmet medical needs of patients with phenylketonuria

  2015cites this paper
• Dépistage et suivi au long terme, d’une cohorte de phénylcétonurie et hyperphénylalaninémie modérée permanente en Normandie

  2015cites this paper
• Large Neutral Amino Acid Supplementation Exerts Its Effect through Three Synergistic Mechanisms: Proof of Principle in Phenylketonuria Mice

  2015cites this paper
• Reduction of l-phenylalanine in protein hydrolysates using l-phenylalanine ammonia-lyase from Rhodosporidium toruloides

  2015cites this paper
• Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands--A review.

  2015cites this paper
• The Amino Acid Specificity for Activation of Phenylalanine Hydroxylase Matches the Specificity for Stabilization of Regulatory Domain Dimers

  2015cites this paper
• Practices in prescribing protein substitutes for PKU in Europe: No uniformity of approach.

  2015cites this paper
• Phenylalanine sensitive K562-D cells for the analysis of the biochemical impact of excess amino acid

  2014cites this paper
• Single amino acid supplementation in aminoacidopathies: a systematic review

  2014cites this paper
• Nutritional Management of Aminoacidopathies in Saudi Arabia

  2014cites this paper
• The effects of an acute bout of moderate-intensity exercise on plasma amino acid concentrations in adolescent boys with phenylketonuria

  2014cites this paper
• Single amino acid supplementation in aminoacidopathies

  2014cites this paper
• Efeitos da hiperfenilalaninemia materna em ratas Wistar sobre alguns parâmetros de metabolismo energético na prole e efeito protetor da associação de piruvato com creatina

  2014cites this paper
• Therapeutic implication of L-phenylalanine aggregation mechanism and its modulation by D-phenylalanine in phenylketonuria

  2014cites this paper
• Association of common variants in PAH and LAT1 with non-syndromic cleft lip with or without cleft palate (NSCL/P) in the Polish population.

  2014cites this paper
• Phenylketonuria Scientific Review Conference: state of the science and future research needs.

  2014influential citation
• Systematic review of large neutral amino acids for treatment of phenylketonuria

  2013cites this paper
• Non-physiological amino acid (NPAA) therapy targeting brain phenylalanine reduction: pilot studies in PAHENU2 mice

  2013cites this paper
• Sapropterin dihydrochloride for the treatment of hyperphenylalaninemias

  2013cites this paper
• Caring for children with phenylketonuria.

  2013cites this paper
• Advances in the nutritional and pharmacological management of phenylketonuria

  2013cites this paper
• Nutritional Support in Inborn Errors of Metabolism

  2013cites this paper
• Successful Live Birth following Preimplantation Genetic Diagnosis for Phenylketonuria in Day 3 Embryos by Specific Mutation Analysis and Elective Single Embryo Transfer.

  2013cites this paper
• PHENYLKETONURIA - YESTERDAY, TODAY.....TOMORROW

  2013cites this paper
• INFLUENŢA DIETEI FĂRĂ FENILALANINĂ ASUPRA DEZVOLTĂRII NEUROPSIHICE ÎN FENILCETONURIE

  2013cites this paper
• Inhibition of L-type amino acid transport with non-physiological amino acids in the Pahenu2 mouse model of phenylketonuria

  2012cites this paper
• el paciente adulto con fenilcetonuria: un nuevo reto para el médico

  2012cites this paper
• Psychosocial aspects of PKU: Hidden disabilities-A review

  2012cites this paper
• Clinical therapeutics for phenylketonuria

  2012cites this paper
• Phenylketonuria: nutritional advances and challenges

  2012cites this paper
• Actualidades en el tratamiento nutricional de la fenilcetonuria

  2011cites this paper