Neurocognitive functioning in adults with phenylketonuria: Results of a long term study

doi:10.1016/j.ymgme.2013.08.013

Molecular Genetics and Metabolism

Volume 110, Supplement, 2013, Pages S44-S48

https://doi.org/10.1016/j.ymgme.2013.08.013 Get rights and content

Abstract

Objectives

A controlled long-term study was performed to assess the neurological and neuropsychological performance in adult patients with early-treated phenylketonuria (PKU).

Methods

We investigated 57 patients with early-treated classical PKU aged 19 to 41 years (mean age 31 years) and 46 matched healthy controls, matched for age and socioeconomic status. Patients and controls were assessed for their intelligence quotient (IQ), and 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-follow-up.

Results

In the five-year interval IQ, information processing and attention of patients and controls remained constant. At both assessment times the IQ scores were significantly lower in patients compared to controls. Older adult patients (> 32 years) showed poorer information processing and attention at both assessment times compared to young adult patients (< 32 years) and controls. IQ, information processing and attention showed no correlation to imaging results but were 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.

Conclusions

Cognitive performance in adult patients with early-treated PKU does not seem to be subject to deterioration observable in a five-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.

Introduction

In patients with classical phenylketonuria (PKU) blood phenylalanine (Phe) levels under free nutrition are above 1.2 mmol/L leading to concomitantly elevated brain Phe levels [1], [2], [3], [4], [5]. Untreated PKU leads to severe mental and psychomotor retardation [6].

If a diet is initiated shortly after birth that is strictly Phe-reduced and supplemented with a Phe-free amino acid mixture, mental and psychomotor retardation can be prevented. However, in spite of strict and early dietary treatment, outcome in patients with PKU is suboptimal [7]. Patients show mild reduction of intelligence [8], [9], neuropsychological deficits [10], and cerebral white matter abnormalities [11], [12], [13]. Studies described reduced attention abilities, slow information processing and motor reaction time as well as changes in the frequency distribution of brain electrical activity [14], [15], [16]. Single adult patients developed severe neurological deterioration years after ending dietary treatment [17]. Some improvement was noticed after reintroducing a Phe-restricted diet [18]. Up to now, studies in adolescence and adulthood are missing, a shortcoming that is yielding divergent national recommendations for treatment of adolescent and adult patients [19], [20].

The aims of our study were to examine the neurological status of adult early-treated patients with classical PKU in a long-term control-group design, and to assess cognitive, information-processing and attention abilities in order to detect possible consequences of long-term elevated blood Phe levels in adulthood.

Section snippets

Methods

We examined 57 early-treated adult patients (37 women, 20 men, mean 31.7 years, SD 5.9 years, range 19 to 41 years) with classical PKU who met the following criteria: start of diet within the first 10 weeks of life (mean: 7.8 weeks., SD: 2.1 weeks), ten blood-Phe-measurements per year up to the age of 10 years at a minimum, eight blood-Phe-measurements per year between the 11th and the 20th year of life at a minimum, and six blood-Phe-measurements per year at a minimum after the 20th year of life.

Magnetic resonance imaging

Magnetic resonance imaging studies were acquired on a 1.5-Tesla clinical imaging system (Gyroscan Intera, Philips, Best, The Netherlands). Axial PD- and T₂-weighted spin-echo images as well as coronal and sagittal T₁-weighted spin-echo images were acquired. The MRI scans were evaluated by a radiologist (JF) not involved in the clinical and psychological examination. In particular, they were graded according to severity and extent of white matter changes [12]. A normal scan was graded “0”;

Results

Patients reached a mean IQ that was within the normal range (100 ± 15) but significantly below the IQ of the healthy controls. As a group, patients did not need significantly more time to run through the trail making test (ZVT) and to complete the attention task (Test d2). Within the five year interval, the performance of patients and controls remained constant (Table 1).

Younger and older adult patients (age < 32 years vs. age > 32 years, according to the median of patient age at baseline) did not

Discussion

Well-controlled outcome studies are still missing in adult PKU. As the intellectual and physical development appeared to be quite normal under an early initiated Phe-restricted diet, neurological and neuropsychological evaluation in adulthood formerly was assumed not to be required. To date, neurological deterioration in several PKU adults years after ending the diet changed this assumption fundamentally. Studies on treated adult PKU patients revealed a high incidence of minor neurological

Acknowledgment

We would like to thank the SHS Company Heilbronn, Germany, for their generous support.

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Lacking direct neuropathological data, neuroimaging exploration has become the most powerful tool to give insight into pathophysiological alterations of early-treated PKU (ETPKU) patients. We conducted a systematic review of neuroimaging studies in ETPKU patients to explore 1) the occurrence of consistent neuroimaging alterations; 2) the relationship between them and neurological and cognitive disorders; 3) the contribution of neuroimaging in the insight of neuropathological background of ETPKU subjects; 4) whether brain neuroimaging may provide additional information in the monitoring of the disease course.
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Phenylketonuria (PKU, MIM #261600) is one of the most common inborn errors of metabolism (IEM) with an incidence of 1:10000 in the European population. PKU is caused by autosomal recessive mutations in phenylalanine hydroxylase (PAH) and manifests with elevation of phenylalanine (Phe) in plasma and urine. Untreated PKU manifests with intellectual disability including seizures, microcephaly and behavioral abnormalities. Early treatment and good compliance result in a normal intellectual outcome in many but not in all patients. This study examined plasma metabolites in patients with PKU (n = 27), hyperphenylalaninemia (HPA, n = 1) and healthy controls (n = 32) by LC- MS/MS. We hypothesized that PKU patients would exhibit a distinct “submetabolome” compared to that of healthy controls. We further hypothesized that the submetabolome of PKU patients with good metabolic control would resemble that of healthy controls. Results from this study show: (i) Distinct clustering of healthy controls and PKU patients based on polar metabolite profiling, (ii) Increased and decreased concentrations of metabolites within and afar from the Phe pathway in treated patients, and (iii) A specific PKU-submetabolome independently of metabolic control assessed by Phe in plasma. We examined the relationship between PKU metabolic control and extended metabolite profiles in plasma. The PKU submetabolome characterized in this study represents the combined effects of dietary adherence, adjustments in metabolic pathways to compensate for defective Phe processing, as well as metabolic derangements that could not be corrected with dietary management even in patients classified as having good metabolic control. New therapeutic targets may be uncovered to approximate the PKU submetabolome to that of healthy controls and prevent long-term organ damage.
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Citation Excerpt :
Only the measures taken at time 2 were included, since participants were adults at only this time; b) Weglage et al. (2013) assessed AwPKU at baseline and after five years. Only results at baseline were included, since all participants were already adults at this time and there were no differences between the two testing times.
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.
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Phenylketonuria (PKU) is a rare genetic condition caused by inborn error(s) in the gene for the enzyme phenylalanine hydroxylase. Resulting loss of phenylalanine (Phe) metabolism requires strict dietary therapy and/or medication to prevent toxic accumulation of Phe. Novel investigational therapies, including gene therapies that aim to address underlying causes of PKU, are now entering clinical trials. However, perceptions of this technology in the PKU community have not been assessed. We conducted a qualitative survey recruiting adult patients, caregivers, and patient advocates from the US and 3 EU countries to assess the impact of living with PKU and the perceptions of gene therapy. Telephone interviews were conducted for up to 60 min following a standardized discussion guide. Interviewers classified each participant by their level of knowledge regarding gene therapy as either: low (little or no prior awareness); moderate (awareness of gene therapy as a concept in PKU); or high (working knowledge of gene therapy, e.g., vectors). In total, 33 participants were recruited (patients, n = 24; caregivers, n = 5; advocates, n = 4). The patient sample was well balanced among age groups, sex, and US/EU geographies. The participants' experiences and burden of living with PKU were largely negative, characterized by frustrations with current management consistent with prior reports. Most participants (n = 18/33) were identified as displaying moderate gene-therapy knowledge, 10/33 as displaying high knowledge, and 5/33 as displaying low knowledge. Both positive and negative perceptions were observed; positive perceptions were often linked to “hope” that gene therapy may represent a cure, whereas negative perceptions were linked to the “uncertainty” of outcomes. High knowledge of gene therapy appeared to trend with negative perceptions; 7/10 participants from this group reported high levels of concern over gene therapy. In contrast, participants who displayed low knowledge reported low (n = 3/5) or moderate (n = 2/5) concern, with predominantly positive perceptions. These data highlight the need for education around the theoretical risk:benefit profile of gene therapy. Despite current unknowns around gene therapy, our study demonstrates the important role of healthcare providers as educators who can use available data to provide balanced information to patients and caregivers.

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Neurocognitive functioning in adults with phenylketonuria: Results of a long term study

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Magnetic resonance imaging

Results

Discussion

Acknowledgment

Brain Res.

Mol Genet Metab

Mol Genet Metab

Lancet

Mol. Genet. Metab.

Lancet

Mol. Genet. Metab.

Blood–brain barrier phenylalanine transport and individual vulnerability in phenylketonuria

J. Cereb. Blood Flow Metab.

Phenylketonuria and blood–brain barrier competition investigated by magnetic resonance spectroscopy

The dynamics of brain concentrations of phenylalanine and its clinical significance in patients with phenylketonuria determined by in vivo 1H magnetic resonance spectroscopy

Pediatr. Res.

Variability of blood–brain ratios of phenylalanine in typical patients with phenylketonuria

J. Cereb. Blood Flow Metab.

The hyperphenylalaninemias

Intellectual development of the patients of the German Collaborative Study of patients treated for phenylketonuria

Eur. J. Pediatr.

Review of neuropsychological functioning in treated phenylketonuria: an information processing approach

Acta Paediatr.

White matter abnormalities in patients with treated hyperphenylalaninemia: magnetic resonance relaxometry and proton spectroscopy findings

Eur. J. Pediatr.

White matter abnormalities in phenylketonuria: results of magnetic resonance measurements

Acta Paediatr.

Neurological findings in early treated phenylketonuria

Acta Paediatr.

The dynamics of brain concentrations of phenylalanine and its clinical significance in patients with phenylketonuria determined by in vivo ¹H magnetic resonance spectroscopy