Adult phenylketonuria outcome and management

doi:10.1016/j.ymgme.2011.08.025

Molecular Genetics and Metabolism

Volume 104, Supplement, 2011, Pages S26-S30

https://doi.org/10.1016/j.ymgme.2011.08.025 Get rights and content

Abstract

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. 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.

Late detected PKU patients (up to 4–6 years of age) benefit from strict dietary treatment and are able to catch up in intellectual performance. Untreated, severely retarded patients with behavioral changes may benefit from introduction of dietary treatment. However, individual decision is necessary and based on the personal situation of the patient.

In early and well treated patients a number of studies have demonstrated that cognitive and neurosychologic tests are different from controls. In addition there is evidence that patients with higher blood phenylalanine (phe) levels demonstrate more often psychiatric symptoms like depression and anxiety. Medical problems are more often observed: there are certain risks as impaired growth, decreased bone mineral density and nutrional deficits probably caused by dietary treatment with an artificial protein substitute and/or missing compliance with an unpleasant diet. The long term risk of a strict dietary treatment must be balanced with the risk of higher blood phe (mean blood phenylalanine > 600–900 μmol/L) on cognitive and neuropsychological functions and psychiatric symptoms. Further studies should consider the role of blood phe exposure for brain development in childhood and for brain function in all ages. Besides mean blood phe, fluctuation of blood phe over time is important. Fluctuation of blood phe is decreased by sapropterin treatment in responsive patients which would on the long term may have positive effects on cognitive outcome. Further studies also should include adult PKU patients.

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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Cited by (58)

Does hyperphenylalaninemia induce brain glucose hypometabolism? Cerebral spinal fluid findings in treated adult phenylketonuric patients
2024, Molecular Genetics and Metabolism
Despite numerous studies in human patients and animal models for phenylketonuria (PKU; OMIM#261600), the pathophysiology of PKU and the underlying causes of brain dysfunction and cognitive problems in PKU patients are not well understood. In this study, lumbar cerebral spinal fluid (CSF) was obtained immediately after blood sampling from early-treated adult PKU patients who had fasted overnight. Metabolite and amino acid concentrations in the CSF of PKU patients were compared with those of non-PKU controls. The CSF concentrations and CSF/plasma ratios for glucose and lactate were found to be below normal, similar to what has been reported for glucose transporter1 (GLUT1) deficiency patients who exhibit many of the same clinical symptoms as untreated PKU patients. CSF glucose and lactate levels were negatively correlated with CSF phenylalanine (Phe), while CSF glutamine and glutamate levels were positively correlated with CSF Phe levels. Plasma glucose levels were negatively correlated with plasma Phe concentrations in PKU subjects, which partly explains the reduced CSF glucose concentrations. Although brain glucose concentrations are unlikely to be low enough to impair brain glucose utilization, it is possible that the metabolism of Phe in the brain to produce phenyllactate, which can be transported across the blood-brain barrier to the blood, may consume glucose and/or lactate to generate the carbon backbone for glutamate. This glutamate is then converted to glutamine and carries the Phe-derived ammonia from the brain to the blood. While this mechanism remains to be tested, it may explain the correlations of CSF glutamine, glucose, and lactate concentrations with CSF Phe.
Meta-analyses of cognitive functions in early-treated adults with phenylketonuria
2022, Neuroscience and Biobehavioral Reviews
Citation 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).
Our study estimated size of impairment for different cognitive functions in early-treated adults with PKU (AwPKU) by combining literature results in a meta-analytic way. We analysed a large set of functions (N = 19), each probed by different measures (average = 12). Data were extracted from 26 PKU groups and matched controls, with 757 AwPKU contributing 220 measures. Effect sizes (ESs) were computed using Glass’ ∆ where differences in performance between clinical/PKU and control groups are standardized using the mean and standard deviation of the control groups. Significance was assessed using measures nested within independent PKU groups as a random factor. The weighted Glass’ ∆ was − 0.44 for all functions taken together, and − 0.60 for IQ, both highly significant. Separate, significant impairments were found for most functions, but with great variability (ESs from −1.02 to −0.18). The most severe impairments were in reasoning, visual-spatial attention speed, sustained attention, visuo-motor control, and flexibility. Effect sizes were larger with speed than accuracy measures, and with visuo-spatial than verbal stimuli. Results show a specific PKU profile that needs consideration when monitoring the disease.
Undiagnosed Phenylketonuria Can Exist Everywhere: Results From an International Survey
2021, Journal of Pediatrics
Neurocognitive functioning in adults with phenylketonuria: Report of a 10-year follow-up
2019, Molecular Genetics and Metabolism
The long-term prognosis of early treated phenylketonuria (PKU) is still under discussion. Aim of this controlled long-term study was to assess the neurological and neuropsychological outcome in adult patients with early-treated PKU.
We investigated 35 patients with early-treated classical PKU aged 29 to 51 years (mean age 41 years) and 18 healthy controls matched for age and socioeconomic status. Patients and controls were assessed for their intelligence quotient (IQ), attention and information-processing abilities. Magnetic resonance imaging (MRI) of the brain was performed in all patients. Neuropsychological assessments and MRI were repeated at a five-year and a ten-year follow-up.
In the entire interval IQ, information processing and attention of patients and controls remained constant. At both follow-up assessment times the IQ scores were significantly lower in patients compared to controls. Older adult patients (> 42 years) showed poorer information processing and attention at both assessment times compared to young adult patients (< 42 years) and controls. IQ, information processing and attention showed no correlation to imaging results. IQ, however, was significantly correlated to blood phenylalanine (Phe) levels in patients´ childhood and adolescence, and Phe levels had been higher in the adolescent years of older adult patients.
Cognitive performance in adult patients with early-treated PKU does not seem to deteriorate in a ten-year interval. Neuropsychological assessment in adults with PKU revealed neurocognitive impairment particularly in older adult patients. This seems to refer to an early relaxation of diet that was recommended when the older patients were adolescents. Results indicate a benefit of dietary control during adolescence in PKU.
Metabolomic disorders: confirmed presence of potentially treatable abnormalities in patients with treatment refractory depression and suicidal behavior
2023, Psychological Medicine
Does Hyperphenylalaninemia Induce Brain Glucose Hypometabolism? Cerebral Spinal Fluid (CSF) Findings in Treated Adult Phenylketonuric (PKU) Patients
2024, SSRN

View all citing articles on Scopus

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MinireviewAdult phenylketonuria outcome and management

Abstract

Highlights

Introduction

Section snippets

Untreated adult PKU patients

Treatment in late diagnosed but treated PKU patients

Outcome in early treated but early discontinued patients

Cognitive and neuropsychological outcome

Future management in adult PKU

Neurosci. Biobehav. Rev.

Mol. Genet. Metab.

Mol. Genet. Metab.

Mol. Genet. Metab.

Mol. Genet. Metab.

Mol. Genet. Metab.

Lancet

Lancet

Mol. Genet. Metab.

Challenges and pitfalls in the management of phenylketonuria

Pediatrics

Dietary treatment of destructive behavior associated with hyperphenylalaninemia

Clin. Neuropharmacol.

Adults with late diagnosed PKU and severe challenging behaviour: a randomised placebo-controlled trial of a phenylalanine-restricted diet

J. Neurol. Neurosurg. Psychiatry

Final intelligence in late treated patients with phenylketonuria

Eur. J. Pediatr.

Late-treated phenylketonuria and partial reversibility of intellectual impairment

Child Dev.

Loss of intellectual function in children with phenylketonuria after relaxation of dietary phenylalanine restriction

Pediatrics

Phenylketonuria in adulthood: a collaborative study

J. Inherit. Metab. Dis.

Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU

Neuropsychol. Rev.

Frontal lobe-dependent functions in treated phenylketonuria: blood phenylalanine concentrations and long-term deficits in adolescents and young adults

J. Inherit. Metab. Dis.

Minireview
Adult phenylketonuria outcome and management