Can Care of Adult PKU Be Improved With Additional Dietary Large Neutral Amino Acids: An N-of-1 Study

  • End date
    Oct 31, 2023
  • participants needed
  • sponsor
    University of Southern California
Updated on 23 October 2022
amino acids
total protein
neutral amino acid


This research investigates the effects of combining a phenylalanine restricted diet (usual care) with LNAA supplementation (adjuvant LNAA) in well-controlled adults with classical PKU. The hypothesis is that symptoms are improved in well-controlled patients who receive adjuvant LNAA therapy compared with diet monotherapy. Six symptomatic classical PKU adults will be enrolled to test the hypothesis in a small series of N-of-1 randomized controlled trials over 18-weeks. All assessments will be collected in patient's homes. A 3-month follow-up period will assess the longer-term effects of adjuvant LNAA in patients who show clinical benefit at the end of the intervention period.


Clinical care of PKU confronts an increasing proportion of early-treated well-controlled adults, with a treatment goal that quality of life be as normal as possible. Even adults who have successfully managed their blood phenylalanine levels from birth can have symptoms which impact daily function. New therapies that target symptoms are needed, especially for symptomatic well-controlled classical adults with few treatment options. In Denmark and the LAC+USC U.S. clinic, adults are offered large neutral amino acid (LNAA) supplements when diet monotherapy becomes less effective for symptom management, or the patient wants a less restrictive diet. Many patients report improved symptoms. LNAA supplementation doesn't significantly reduce blood phenylalanine, suggesting a different mechanism for patient perceived benefits. Both LNAA supplementation and a phenylalanine restricted diet aim to improve brain neurotransmitter biochemistry to optimize outcomes through dietary intervention. The overall objective of this research is to evaluate additional dietary LNAAs on symptom management in adults with classical PKU at an individual level. N-of-1 randomized controlled trials will provide the highest level of evidence. The scientific premise is that manipulation of dietary LNAAs affects blood LNAA concentrations. LNAAs compete with phenylalanine for a shared transporter from blood to brain, dependent on blood concentrations and transporter affinities. Higher blood phenylalanine levels in adult PKU, with high transport affinity, produces excessive phenylalanine brain entry at the expense of other LNAAs. Insufficient LNAAs impairs synthesis of chemicals in the brain (neurotransmitters), a suggested mechanism of action for adult PKU symptoms. Additional dietary LNAAs may help to overcome this limitation of adult usual care. The study uses established PKU treatment products (medical foods) and biomarkers, (1) to determine effect of the adjuvant LNAA diet in symptom management; and (2) to evaluate correlations between changes in biomarkers and changes in symptoms during the intervention. Should findings show additive clinical value of LNAAs to the PKU diet, the strategy may become a useful adjunct. For participants, results will bring them closer to evidence-based individualized care. This work could advance the field closer toward personalized management.

Condition Phenylketonurias
Treatment PreKUnil® LNAA Medical Food for PKU
Clinical Study IdentifierNCT05174559
SponsorUniversity of Southern California
Last Modified on23 October 2022


Yes No Not Sure

Inclusion Criteria

age ≥ 18 years
diagnosis of classical PKU (blood phenylalanine ≥1200 µmol pre-treatment or off-treatment
≥ 2 PKU-related symptoms with clinically meaningful negative impact on daily life
is in regular clinical monitoring and is treated with a PKU diet with a natural protein restriction and medical foods
average blood phenylalanine levels between 360 and 900 µmol in past one year
able and willing to provide consent
demonstrates capacity to complete all requirements of the protocol
if on medications approved by the Principal Investigator agrees not to alter dose for duration of study
has stable daily access to phone, internet, and physical address

Exclusion Criteria

women who are breastfeeding, pregnant or planning to become pregnant in the next year
use of adjuvant PKU treatments (LNAAs, Kuvan®, Palinziq®) within past 3 months
use of psychotropic medications, melatonin, or any serotonin-reuptake inhibitors within past 3 months
demonstrates insufficient motivation or time required to complete full trial
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