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Who Will Benefit from Which Diet: Can N-of-1 Studies Fill a Gap in the Care of Adult PKU?

Authors: Maria Depenweiller, Kathryn Moseley, Kirsten Ahring, Ash Morgan Chambers & Annie Prince

In phenylketonuria (PKU), a rare condition, deficient metabolism of phenylalanine to tyrosine disrupts blood-to brain transport of large neutral amino acids (LNAAs). LNAAs compete for brain influx, dependent on blood concentrations which can be manipulated by diet. Higher blood phenylalanine in PKU produces excessive brain entry at the expense of tyrosine and other LNAAs. Without intervention to restrict dietary phenylalanine during brain development, nearly all patients experience irreversible neurocognitive disability. The PKU diet lowers blood phenylalanine to a target (≤360 µmol/L; 6 times normal) by substituting a synthetic protein formula of LNAAs for regular protein foods. Strict adherence from age 0-12 years guarantees nearly normal neurocognitive outcomes.

Figure 1: What’s for dinner? For those with PKU, low phenylalanine formula with imitation low-protein pasta

One-size-fits-all diet presents challenges when applied to adults

Clinical care of PKU confronts an increasing proportion of adults with a treatment goal that quality of life be as normal as possible. Some adults experience neuropsychological symptoms which significantly impact quality of life. In theory, treatment effectiveness declines for nearly all adults (70-90%) who can’t get blood phenylalanine to target (≤360 µmol/L). In practice, research findings suggest that the blood target may not be clinically meaningful for adults (1). A relatively large sample of adults with representative blood levels (≤850 µmol/L) showed extreme variability in outcomes: completely normal neuropsychological test profile (25%), significant impairments in some functions (50%), or severe impairment (5%). Many patients reached performance indistinguishable from controls. It is well understood that the mature brain is less vulnerable to phenylalanine exposure. But we don’t know for whom the less severe diet is optimally effective, or if the PKU diet can be modified to improve effectiveness for certain adults. Research findings of deficient neurotransmitters, dopamine and serotonin, suggests a mechanism for adult symptoms (2). Adequate neurotransmitter synthesis requires sufficient precursor LNAAs.

An alternative approach

Dietary LNAA-adjuvant therapy for adult PKU is routine in Denmark and at least one U.S. clinic because patients feel and function better. The treatment aims to boost benefits of insufficient adult dietary phenylalanine restriction by increasing LNAAs relative to phenylalanine. However, clinical effects remain under-investigated.

N-of-1 trial opportunity

A single subject study was conducted to provide more rigorous evidence of our clinical experience. An adult volunteered with persistent symptoms, despite best diet efforts to reduce blood phenylalanine (500-600 µmol/L). The hypothesis was that LNAA-adjuvant therapy would reduce symptoms. The participant agreed to 3 blocked pairs (usual care and LNAA-adjuvant care), 6 treatment periods, at least 4 weeks each, in counterbalanced sequence (ABBAAB). During run-in, a standard dose of LNAAs was added to formula (LNAA 0.2 g/kg/day). The PKU-QOL Questionnaire (3) was chosen for its responsiveness to accurately detect symptom changes and was collected at the end of each period concurrent with blood samples at standardized times. The Global Rating Score Questionnaire (4) was administered at the trial’s end. Limited resources prevented blinding, placebos, and statistical analysis. These inadequacies restrict findings to cautious interpretation. Further N-of-1 studies complete with rigorous elements in additional participants are necessary before making conclusions.

Findings and Practice Implication

Visual analysis of clinical findings supports the hypothesis (figure). Moderate-major symptoms of usual care were absent with LNAA, and present with LNAA withdrawal. The trial was stopped early after 2 cycles. The patient-perceived a mean score difference of 0.66 per symptom item of PKU-QOL between treatments. A global rating score of 6 exceeded the minimal clinically important difference range of 1-3, the smallest difference in symptom changes which, from the patient’s perspective, would mandate a change in management. Other findings showed a reduced impact of food temptations on quality of life, from moderate to none-little with LNAA-adjuvant therapy. Blood phenylalanine: tyrosine ratio markedly declined, without clinically significant reduction in blood phenylalanine levels. The trial guided a change in management to LNAA-adjuvant therapy.

The results of this single patient trial (5) support doing N-of-1 studies to improve clinical decision-making in adults with PKU. We have applied for funding to conduct placebo-controlled, triple-blind, randomized, N-of-1 studies in six PKU adults. Specific aims are: 1. to determine individual treatment effect of additional diet LNAA to usual care in reducing symptoms; and 2. to evaluate variations in blood phenylalanine and phenylalanine: tyrosine ratio for correlation with symptom changes. For each individual patient, PKU-QOL scores, and scores for secondary measures (e.g. neuropsychological test performance) will be described in an individual patient report to guide diet therapy decisions.

About the Authors

Maria Depenweiller, BaSc, P.H.Ec

is a Canadian researcher, writer and cookbook author, with PKU.

Kathryn Moseley, M.S., R.D.

is on the faculty at the University of California Keck School of Medicine, USA. The PKU diagnosis of her daughter over 40 years ago led to a clinical and research career in helping those with PKU who find themselves where she first started, full of uncertainty.

Kirsten Ahring

is a metabolic Dietitian, working at the national clinic for PKU at the Copenhagen University Hospital in Copenhagen, Denmark. She is currently seeing PKU patients in clinic and working half time with PKU research. She completed her Ph.D. in PKU in 2019.

Ash Morgan Chambers, BSc psychology

is a medical writer in Portland OR.

Annie Prince, Ph.D., R.D.

is a third-year graduate student in the Human Investigations Program at Oregon Health & Science University, USA.


1. Palermo L, MacDonald A, Hall K, Geberhiwot T, Limback E, Romani C. Cognitive outcomes in early-treated adults with phenylketonuria (PKU): a comprehensive picture across domains. Neuropsychology 2017;31:255-267.

2. de Groot MJ, Hoesksma M, Reijngoud D-J, de Valk HW, Paans AMJ, Sauer PJJ, et al. Phenylketonuria: reduced brain influx reduced brain influx relates to reduced cerebral protein synthesis. Orphanet J of Rare Dis 2018; 8:133-141.

3. Regnault A, Burlina A, Cunningham A, Bettiol E, Moreau-Stucker F, Benmedjahed K, et al. Development and psychometric validation of measures to assess the impact of phenylketonuria and its dietary treatment on patients’ and parents’ quality of life: phenylketonuria-quality of life (PKU-QOL) questionnaires. Orphanet J Rare Dis 2015;10:59-77.

4. Jaeschke R, Guyatt GH, Keller J, Singer J. Interpreting changes in quality-of-life score in N-of-1 randomized trials. Controlled Clinical Trials 1991; 12: 2262S-235S.

5. Moseley K, Ahring KK, Kumru B, Depenweiller M, Chambers AM, Prince A. Adjuvant dietary therapy improves symptoms in a well-controlled adult with classical phenylketonuria (PKU): an N-of-1 randomized controlled trial (‘N-of-1 trial’). Poster session, Genetic Metabolic Dietitians Conference, April 2021, virtual.

March 2021 Conference Poster - Final
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