Phenylketonuria in adults: we know plenty, but there is much more to learn

Dear Editor:

We read with concern the article by Trepp et al. [1] describing a 4-wk randomized trial of high phenylalanine exposure in adults with phenylalanine hydroxylase (PAH) deficiency along with the accompanying editorial entitled “Phenylketonuria in adults: what do we know?” [2], which argues based upon this single study that it is not possible to detect any significant harm from large short-term fluctuations in Phe concentrations. In truth, the data did reveal decrements in attention and an increased incidence of adverse events when the participants were consuming increased dietary Phe, albeit no effects upon other cognitive outcomes were measured. The authors of the primary article appropriately recommended longer-term studies to better elucidate the effects of diet relaxation for adults with phenylketonuria (PKU).

In the editorial, Lachman and Langveld cite several articles, documenting impaired performance on neuropsychologic tests in adults with hyperphenylalaninemia, but appear to dismiss any clinical impact from these findings. We do not agree. A major literature review noted that, compared with control groups or standardized norms/reference values, suboptimal outcomes were reported for individuals with PKU in 58 of 60 neurocognitive/psychosocial studies, 4 of 6 quality of life studies, 30 of 32 brain pathology studies, 9 of 9 bone health studies, and 19 of 19 maternal PAH deficiency outcome studies [3]. In another systematic review and meta-analysis of the literature, a high prevalence of psychiatric symptoms, executive function impairments, and even neurologic deficits has been documented in adults with hyperphenylalaninemia [4]. Most recently, Thomas et al. [5] reviewed findings from 46 past publications examining within-participant effects associated with Phe decreases. Their meta-analysis revealed that significantly more studies have found benefits (compared with no benefits) of Phe lowering for both cognitive and well-being outcomes. Importantly, the effect size was significant both overall (0.55) and when adolescents and adults were considered separately (0.57). It is worth noting that Trepp et al have also published a companion but seemingly contradictory article in another journal describing a different outcome in the same experimental cohort, noting a reversible decrease in brain cortical thickness as measured by magnetic resonance imaging with increased ventricular and white matter volumes that correlated with decrements in cognition after 4 wk of high phenylalanine exposure [6].

The outcome of the study by Trepp et al. [1] in this issue contrasts with that of Clocksin et al. [7], who evaluated comprehensive neuropsychological functioning in 40 adults (age: 18–36 y) with concurrent blood Phe ranging from 79 to 1946 μM compared with age-matched controls without PAH deficiency. Mean intelligent quotient did not differ between study participants with PAH deficiency and controls; however, individuals with PAH deficiency did exhibit significant deficits in fluid cognition, visuospatial skills, executive function, motor skills, and processing speed. Critically, these measures exhibited strong negative correlations with blood Phe in the experimental cohort.

Although Lachman and Langeveld lament the lack of neuropsychological outcomes data supporting the licensing of novel pharmaceuticals such as sapropterin or pegvaliase in the treatment of PAH deficiency, positive outcome data during phase III clinical trial of pegvaliase do exist. Symptoms of inattention and poor mood improved significantly within the first year of open-label pegvaliase treatment in those individuals with PAH deficiency who exhibited these symptoms at baseline [8], with the greatest improvements occurring in those individuals with the largest decreases in blood Phe. Although the short 8-week placebo-controlled randomized discontinuation trial (RDT) did not identify a difference in attention or mood symptoms between the placebo group and those individuals that remained on active drug [9], the short duration of the RDT and the subjective nature of the self-reported scoring system may have obscured any meaningful benefits of treatment. However, in a small substudy within the RDT, several objective measures of cognition improved in individuals on pegvaliase in comparison with those on placebo [9]. Since commercialization of pegvaliase, further studies have continued to document the benefits of maintaining low blood Phe while liberalizing dietary Phe intake through pegvaliase treatment, including a recent report of 3 adults displaying marked improvement in both cognition and white matter integrity [10]. One of us (PM), as an adult with PAH deficiency and a practicing metabolic dietitian, has personally experienced the benefits of eliminating the PKU diet (previously restricted to 4–6 g natural protein per day) through pegvaliase treatment while effectively maintaining lower blood Phe concentrations (down to 45–120 μM from 480 μM when treated with diet). This transformative therapy has been associated with resolution of lifelong attention deficit-hyperactivity symptoms and cessation of pharmaceutical treatment of attention deficit-hyperactivity, leading to improved focus and success in both personal and professional life, including promotion into a management position. Although a single story, this anecdote is fully representative of the stories from many pegvaliase-treated adults in our clinical practices.

We agree with Lachman and Langeveld that there continues to be significant unmet treatment need in children with PAH deficiency and a desire for novel therapies in this age group that do not rely solely upon dietary Phe restriction. They correctly point out the difficulties of maintaining tight dietary protein restriction, which can have adverse nutritional, neuropsychological, and psychosocial consequences. Recent data from 73 generally well-treated individuals with PAH deficiency documented impaired executive function and fluid cognition [11] despite appropriate treatment suggesting that neurocognitive outcomes may yet be adversely impacted even with adequate metabolic control by current standards.

To conclude, we submit that although dietary Phe restriction itself may carry adverse chronic effects, adults with PAH deficiency experience significant burden of disease that can be only partially mitigated through lowering Phe levels using dietary Phe restriction. The chronic effects of disease and treatment are variable between individuals and are difficult to comprehensively describe with currently available assessment tools. Assessments over short periods, such as during short-term intervention trials, may not capture the full impact of either disease or treatment. Longitudinal study is necessary. We posit that unfolding evidence suggests significant benefits may accrue from novel Phe-lowering therapies that allow diet relaxation while maintaining low blood Phe concentrations. Further study is necessary to prove this hypothesis.

Author contributions

The authors’ responsibilities were as follows – COH, SEC, GA: responsible for the design, writing, and final content of the manuscript; PM: contributed to writing of the manuscript; GTB, DKG, EJ, HL, UL-K, NL, MM, SS, BS, JT, and EV have read the manuscript and suggested editorial alterations; and all authors: have read and approved the final manuscript.

Funding

The authors reported no funding received for this study.

Conflict of interest

COH reports financial support was provided by National Institutes of Health; consulting or advisory fees, funding grants, speaking and lecture fees, and travel reimbursement from BioMarin Pharmaceutical; consulting or advisory fees, funding grants, and travel reimbursement from Jnana Therapeutics; consulting or advisory fees from PTC Therapeutics, Tessera Therapeutics; and consulting or advisory fees and funding grants from Sanofi SA. GA reports consulting or advisory from PTC Therapeutics. DKG reports funding grants from BioMarin Pharmaceutical. SEC consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement from BioMarin Pharmaceutical and consulting or advisory fees from Jnana Therapeutics and PTC Therapeutics Inc. EJ reports consulting or advisory from Jnana Therapeutics, Arcturus Therapeutics Holdings, and Travere Therapeutics. HL reports consulting or advisory from BioMarin Pharmaceutical, Sanofi SA, Jnana Therapeutics, and PTC Therapeutics. NL reports consulting or advisory fees and funding grants from Amgen, Amicus, Audentes Therapeutics, BioMarin Pharmaceutical, Chiesi Pharmaceuticals, Sanofi SA, Jnana Therapeutics, Moderna, PTC Therapeutics, and Ultragenyx Pharmaceutical and consulting or advisory fees from Ipsen, Leadiant Biosciences, and Nestlé SA. MM reports consulting or advisory fees and funding grants from BioMarin Pharmaceutical, Jnana Therapeutics, PTC Therapeutics, and funding grants from NGGT. SS reports consulting or advisory fees and funding grants from BioMarin Pharmaceutical, Jnana Therapeutics, and PTC Therapeutics. BS reports speaking and lecture fees from Chiesi Pharmaceuticals and consulting or advisory fees from Amicus and Moderna. JT reports consulting or advisory and funding grants from BioMarin Pharmaceutical and funding grants from PTC Therapeutics and Sanofi SA. EV reports consulting or advisory fees, funding grants, speaking and lecture fees, and travel reimbursement from BioMarin Pharmaceutical and consulting or advisory fees from Amgen and PTC Therapeutics. The other authors report no conflict of interests.