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By Peter Burgard, Ph.D
A working party of the German Working Group for Metabolic Diseases has evaluated patients with phenylketonuria (PKU) in terms of their intelligence quotient (IQ), education, neuropsychology, electroencephalography (EEG) results, magnetic resonance imaging (MRI) results, neurology, and behavior. All members of the working party were experienced in research on PKU and treatment of patients with PKU (Burgard, Bremer, Bührdel, et al., 1999).
Level of blood phenylalanine (Phe)
Patients with Phe blood levels >=600 µmol/L (10 mg/dL) on a normal diet must be treated with a low Phe diet, including a Phe-free protein or amino acid supplement. Phe blood levels should remain between 40 and 240 µmol/L (0.7–4 mg/dL) until the age of 10, not exceed 900 µmol/L (15 mg/dL) between ages 10 and 15, and not exceed 1200 µmol/L (20 mg/dL) after age 15.
Age at dietary relaxation
Patients ages 15 years and older with Phe levels <=1200 µmol/L (20 mg/dL) may be allowed to discontinue a restricted diet. Patients who show overt impairments or symptoms related to PKU should continue to follow a strict dietary regimen. Diet should be monitored by regular examination at least once a year.
Psychometric intelligence and educational progress
Longitudinal data from the German and U.S. collaborative studies of PKU (CSPKU) and the British PKU Register reveal that high levels of Phe adversely influence IQ until age 10, but not later (Burgard, in press). The mean IQ of German patients with average levels of 270 µmol/L during the first 5 years of life and of 300 µmol/L (5 mg/dL) between ages 5 and 9 was no different from the mean IQ of a healthy control group matched for age, sex, and socioeconomic status. Patients with higher levels during their first 5 years showed lower IQ scores in their first IQ test at the age of 5, but showed no further deterioration. At the age of 12, type of schooling and number of repeated classes were normal for both groups. In a sample of 51 young adult patients with mean annual Phe levels of 250 µmol/L (4.1 mg/dL) up to the age of 10, IQ remained stable between adolescence and adulthood as levels increased to an average of 900 µmol (15 mg/dL) at the age of 20. School grades of patients were higher than those of their fathers (secular trend), and grade distribution was not significantly different from that of the entire German population (Schmidt, Burgard, Pietz, et al., 1996).
Impaired choice reaction-time appeared to be the only consistent result in a review of 21 neuropsychologic studies (Waisbren, Brown, de Sonneville, et al., 1994). Reanalysis of studies with repeated measurements of low and high Phe levels revealed a mean change in reaction time of 111 milliseconds (ms) for mean level change of 966 µmol/L (Schmidt, Rupp, Burgard, et al., 1994). Phe level effects were reversible regardless of patient’s age and amount of time without dietary treatment, and could be observed 1 week after changing Phe blood levels. Compared with the reaction times of healthy controls, mean reaction times increased by 194 ms for children ages 10 years and younger (mean concurrent Phe level 558 µmol/L [9.2 mg/dL]), 82 ms for adolescents between ages 11 and 18 (mean concurrent Phe level 942 µmol/L [15.6 mg/dL]), and 159 ms for young adults between ages 17 and 25 (mean concurrent Phe level 1146 µmol/L [18.9 mg/dL]). After 5 to 10 years of strict treatment to maintain Phe levels below 400 µmol/L, diet relaxation does not result in long-term deterioration of reaction times (Burgard, Rey, Rupp, et al., 1997; Griffiths, Paterson, Harvie, 1995). The hypothesis of impaired executive functions presumably due to dopamine deficiency in the frontal lobes was investigated with children younger than age 6, adolescents, and young adults. Results for children were in line with IQ data and confirm the recommendation of therapeutic Phe levels below 360 µmol/L (6 mg/dL) during the first 5 years (Diamond, 1994; Welsh, Pennington, Oznoff, et al., 1990). Results for adolescents and adults were patchy (Griffiths, Paterson, Harvie, 1995; Weglage, Pietsch, Fünders, et al., 1996). A policy of minimizing risks may be justified by the fact that synaptic density in the frontal cortex reaches maturity at approximately age 16 (Huttenlocher, 1979).
Results of EEG, visually evoked potentials (VEPs), MRI, MR spectroscopy, and neurological tests
Abnormal EEG findings (general slowing, generalized paroxysmal activity with and without spikes) increase with age but were not regarded as crucial for decisions about treatment (Pietz, Benninger, Schmidt, et al., 1988). VEPs, significantly prolonged in about 30 percent of patients, did not correlate with age at start of treatment, parameters of biochemical control (Bick, Ullrich, Stöber, et al., 1993; Ludolph, Vetter, Ullrich, 1996; Pietz, Kreis, Schmidt, 1996), MRI results, or clinical abnormalities. Auditory-evoked potentials in early-treated patients were normal (Ludolph, Ullrich, Nedjat, et al., 1992). Abnormal MRI scans show partial reversibility after 2 to 3 months of continuous reduction of Phe below 360 to 900 µmol/L (6–15 mg/dL), regardless of the amount of time without treatment preceding the scan (Bick, Ullrich, Stöber, et al., 1993; Cleary, Walter, Jenkins, et al., 1994). MRI changes were not correlated with age at diet initiation or results of MR examination, nor with electrophysiological results, neurological deficits, psychiatric problems, or IQ. These changes probably reflect a reversible structural defect of myelin, rather than permanent demyelination. Overt neuropathology (para- and quadriparesis, tremor, ataxia, epilepsy) was found in a few young adults (Thompson, Smith, Brenton, et al., 1990). Most of these patients were treated late or lacked dietary control in infancy. Clinical examinations of 51 early and strictly treated adolescents and young adults showed no neurological abnormalities except for discrete resting tremor and slightly brisk tendon reflexes of the lower limbs, not associated with MRI grading or biochemical control (Pietz, Kreis, Schmidt, et al., 1996).
Psychiatric interviews of 60 patients in the German CSPKU at the age of 13 (mean Phe level from infancy to 13 years is 500 µmol/L [8.3 mg/dL]) showed an increase of mild behavioral or emotional disturbances (without need for psychiatric treatment) by a factor of 1.5 compared with the normative sample (Burgard, Armbruster, Schmidt, et al., 1994). Symptoms were not correlated with Phe levels, and no PKU-specific behavioral pattern could be delineated. Similar results were found in a study of adult PKU patients (Pietz, Fätkenheuer, Burgard, et al., 1997).
Untreated patients with Phe levels <600 µmol/L (10 mg/dL) were no different from their unaffected siblings with regard to MRI and IQ results, educational and professional progress, fine motor performance, and neuropsychological variables (Weglage, Schmidt, Fünders, et al., 1996; Weglage, Ullrich, Pietsch, et al., 1996).
Need for further research
Our present knowledge suggests that infancy and early childhood are the most vulnerable periods for most patients with PKU and therefore the most important periods for strict treatment to reduce abnormal Phe levels. However, the developmental sciences also regard old age as a stage of human development relying heavily on biological variables. It is not possible to know whether adverse effects in late adulthood and old age can be successfully prevented by treatment in childhood. Nor do we know whether statistically significant neuropsychological data on children are of clinical relevance—for example, as markers of late effects. Therefore, careful longitudinal followup is necessary to evaluate current as well as future treatment policies. Not all patients with the same genotype or Phe level have the same vulnerability to PKU and need the same kind of treatment (Weglage, Wiedermann, Möller, et al., 1998). The pathogenesis of PKU is still not very well understood, and a three-step model from genotype to Phe blood level to outcome is too simple (Pietz, Kreis, Schmidt, et al., 1996; Scriver, Waters, 1999).
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