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