Skip Navigation
  Print Page

Recommendations of the German Working Group for Metabolic Diseases for Control of Phenylalanine in Phenylketonuria

Skip sharing on social media links
Share this:

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).

Neuropsychological results

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).

Behavioral problems

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).

Non-PKU hyperphenylalaninemia

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).

References

  • Bick U, Ullrich K, Stöber U, Möller H, Schuierer G, Ludolph AC, et al. White matter abnormalities in patients with treated hyperphenylalaninemia: magnetic resonance relaxometry and proton spectroscopy findings. Eur J Pediatr 1993;152:1012-20.
  • Burgard P. Development of intelligence in early treated phenylketonuria. Eur J Pediatr (in press).
  • Burgard P, Armbruster M, Schmidt E, Rupp A. Psychopathology of patients treated early for phenylketonuria: results of the German collaborative study of phenylketonuria. Acta Paediatr Suppl 1994;407:108-10.
  • Burgard P, Bremer HJ, Bührdel P, Clemens PC, Mönch E, Przyrembel H, et al. Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997. Eur J Pediatr 1999;158:46-54.
  • Burgard P, Rey F, Rupp A, Abadie V, Rey J. Neuropsychologic functions of early treated patients with phenylketonuria on and off diet: results of a cross-national and cross-sectional study. Pediatr Res 1997;41:368-74.
  • Cleary MA, Walter JH, Jenkins JPR, Alani SM, Tyler K, Whittle D. Magnetic resonance imaging of the brain in phenylketonuria. Lancet 1994;344:87-90.
  • Diamond A. Phenylalanine levels of 6-10 mg/dl may not be as benign as once thought. Acta Pædiatr Suppl 1994;407:89-91.
  • Griffiths P, Paterson L, Harvie A. Neuropsychologic effects of subsequent exposure to phenylalanine in adolescents and young adults with early-treated phenylketonuria. J Intellect Disabil Res 1995;39:365-72.
  • Huttenlocher P. Synaptic density in human frontal cortex - developmental changes and effects of aging. Brain Res 1979;163:195-205.
  • Ludolph AC, Ullrich K, Nedjat S, Masur H, Bick U. Neurological outcome in 22 treated adolescents with hyperphenylalaninemia. Acta Neurol Scand 1992;85:243-8.
  • Ludolph AC, Vetter U, Ullrich K. Studies of multimodal evoked potentials in treated phenylketonuria: the pattern of vulnerability. Eur J Pediatr 1996;155(Suppl 1):S64-8.
  • Pietz J, Benninger Ch, Schmidt H, Scheffner D, Bickel H. Long-term development of intelligence IQ and EEG in 34 children with phenylketonuria treated early. Eur J Pediatr 1988;147:361-7.
  • Pietz J, Fätkenheuer B, Burgard P, Armbruster M, Esser G, Schmidt H. Psychiatric disorders in adult patients with early-treated phenylketonuria. Pediatrics 1997;99:345-50.
  • Pietz J, Kreis R, Schmidt H, Meyding-Lamade UK, Rupp A, Boesch C. Phenylketonuria: findings at MR imaging and localized in vivo H-1 MR spectroscopy of the brain in patients with early treatment. Radiology 1996;201:413-20.
  • Schmidt E, Rupp A, Burgard P, Pietz J, Weglage J, de Sonneville L. Sustained attention in adult phenylketonuria: the influence of the concurrent phenylalanine-blood-level. J Clin Exp Neuropsychol 1994;16:681-8.
  • Schmidt H, Burgard P, Pietz J, Rupp A. Intelligence and professional career in young adults treated early for phenylketonuria. Eur J Pediatr 1996;155(Suppl. 1):S97-100.
  • Scriver CR, Waters PJ. Monogenic traits are not simple: lessons from phenylketonuria. Trends Genet 1999;15:267-72.
  • Thompson AJ, Smith I, Brenton D, Youl BD, Rylance G, Davidson DC, et al. Neurological deterioration in young adults with phenylketonuria. Lancet 1990;336:602-5.
  • Waisbren SE, Brown MJ, de Sonneville LM, Levy HL. Review of neuropsychological functioning in treated phenylketonuria: an information processing approach. Acta Paediatr Suppl 1994;407:98-103.
  • Weglage J, Pietsch M, Fünders B, Koch HG, Ullrich K. Deficits in selective and sustained attention processes in early treated children with phenylketonuria - result of impaired frontal lobe functions? Eur J Pediatr 1996;155:200-4.
  • Weglage J, Schmidt E, Fünders B, Pietsch B, Ullrich K. Sustained attention in untreated non-PKU-hyperphenylalaninemia. J Clin Exp Neuropsychol 1996;18:343-8.
  • Weglage J, Ullrich K, Pietsch M, Fünders B, Zass R, Koch HG. Untreated non-phenylketonuric-hyperphenylalaninemia: intellectual and neurological outcome. Eur J Pediatr 1996;155(Suppl.1): S26-8.
  • Weglage J, Wiedermann D, Möller HE, Ullrich K. Pathogenesis of differential clinical outcomes in spite of identical genotypes and comparable phenylalanine concentrations in phenylketonurics. J Inherit Metab Dis 1998;21:181-2.
  • Welsh MC, Pennington BF, Oznoff S, Rouse B, McCabe ERB. Neuropsychology of early-treated phenylketonuria: specific executive function deficits. Child Dev 1990;61:1697-713.

Back to Abstracts

first | previous | next | last

Last Updated Date: 08/28/2006
Last Reviewed Date: 08/28/2006
Vision National Institutes of Health Home BOND National Institues of Health Home Home Storz Lab: Section on Environmental Gene Regulation Home Machner Lab: Unit on Microbial Pathogenesis Home Division of Intramural Population Health Research Home Bonifacino Lab: Section on Intracellular Protein Trafficking Home Lilly Lab: Section on Gamete Development Home Lippincott-Schwartz Lab: Section on Organelle Biology