MinireviewAdult phenylketonuria outcome and management
Highlights
► Adult PKU patients should have lifelong treatment. ► Dietary treatment is suboptimal. Continuation to adulthood is not well accepted. ► Pharmacologic treatment with sapropterin should be considered for responsive patients.
Introduction
The problem to evaluate treatment outcome in adult PKU (phenylketonuric) patients lies in the heterogeneity of the adult PKU population. This heterogeneity is not only based on the different treatment history of every individual patient but also on the different severity of the underlying defect of the enzyme phenylalanine hydroxylase (PAH). More than 600 mutations are described so far (http://www.pahdb.mcgill.ca/).
The other problem consists in the fact that there are no prospective studies available and that in later life other modulators as lifestyle and aging become more important when evaluating brain development and brain function. Long term dietary treatment also shows development of other problems like osteopenia or metabolic imbalances.
Having these problems in mind it is clear that up to now there are no evidence based treatment recommendations and only vague recommendations like “lifelong treatment” with very different suggestions for e.g. the blood phe targets as published in a European survey recently [1].
In this review we would like to describe outcome and management of adult PKU patients excluding maternal PKU but describing the different groups of adult PKU patients we see in our metabolic outpatient clinic.
1. PKU patients never treated, 2. PKU patients late treated (start 1–6 years of age) 3. Patients early treated but early or with poor compliance and 4. Patients early treated with good compliance until adulthood.
Data are based on literature review and personal clinical experiences.
Section snippets
Untreated adult PKU patients
Patients with untreated PKU are severely retarded in most cases and in addition may show challenging behavioral problems (Table 1). Treatment studies in untreated PKU's are difficult to perform. Besides ethical issues to conduct such studies measurement of improvement is difficult. The results are controversial, the study population always small. In some studies severity of behavioral disturbances may be reduced after introduction of a phe restricted diet [2], Table 1. In a recent placebo
Treatment in late diagnosed but treated PKU patients
Introduction of newborn screening and early dietary treatment resulted in the prevention of severe brain damage. However, due to screening failures and immigration of patients from countries where early detection and treatment of PKU is not yet established, there are a number of untreated PKU's in many European centers. In the last 20 years we saw in one center (Reutlingen, Germany) 10 patients missed by newborn screening due to various reasons (Table 2). After introduction of tandem mass
Outcome in early treated but early discontinued patients
For many years dietary treatment of PKU was terminated at 10 years of age, in some countries even at 6 years of age. Investigations in patients with early diet termination revealed that there was a loss of intellectual function [6]. Koch and coworkers [7] could demonstrate that patients continuing the diet until adulthood had a better outcome than those who stopped the diet earlier. In addition in this collaborative study Koch et al. could demonstrate that treatment quality also had an influence
Cognitive and neuropsychological outcome
In the following cognitive and neuropsychologic outcomes of adult early treated PKU patients are discussed.
A number of studies have demonstrated that cognitive outcome and neurosychologic tests are different from controls. In a meta analysis by Moyle et al. [9] including 5 studies there were reduced full scale IQ scores and reduced information processing speed and attention. In addition in 4 studies inhibitory abilities and motor control were reduced compared to controls. Except for working
Future management in adult PKU
Recent (partly double blind) studies in adult PKU patients further support recommendation for lifelong treatment. However, it has become evident that dietary treatment is suboptimal and continuation to adulthood often not accepted [34], [35]. Therefore other treatment options like pharmacologic treatment with sapropterin have to be considered [36], [37]. However, so far there are no long term controlled studies to prove that such a treatment is more successful than the diet. Further studies
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2024, Molecular Genetics and MetabolismMeta-analyses of cognitive functions in early-treated adults with phenylketonuria
2022, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Impairments are especially documented in IQ, speed of processing, and executive functions. Group performance is generally below average, but there is strong individual variability (for reviews see Burlina et al., 2019; Hofman, 2018; Trefz et al., 2011; van Spronsen et al., 2011; for adult results spanning a comprehensive set of functions see Brumm et al., 2004; Palermo et al., 2017). Most of these impairments and variability are attributable to poor metabolic control with many studies documenting strong correlations between blood Phe levels and performance in cognitive tasks (Jahja et al., 2017; Moyle et al., 2007a; Nardecchia et al., 2015; Ris et al., 1994; Romani et al., 2017, 2019; also for differences between groups with high vs low Phe see Bartus et al., 2018; Channon et al., 2007; Palermo et al., 2017).
Undiagnosed Phenylketonuria Can Exist Everywhere: Results From an International Survey
2021, Journal of PediatricsNeurocognitive functioning in adults with phenylketonuria: Report of a 10-year follow-up
2019, Molecular Genetics and Metabolism