White matter abnormalities in phenylketonuria: results of magnetic resonance measurements.

In adolescents and adults with PKU, blood phenylalanine levels above 10 mg/dl are generally associated with white matter changes in MRI. The grade of these changes is correlated to most recent blood phenylalanine levels. Based on studies using T2 relaxometry the MRI changes seem to be the consequence of a reversible dysmyelination. The clinical relevance of these white matter changes remains unclear as the extent of MRI alterations did not correlate with IQ, neurological and electrophysiological deficits of the patients. The intracerebral phenylalanine concentration as measured by protonspectroscopy amounts to about 50% of blood phenylalanine concentrations. Preliminary data indicate that brain phenylalanine levels remain constant if blood concentrations exceed 20 mg/dl. This might be of clinical relevance for the treatment of adolescent and adult PKU patients.

[Phenylketonuria--change in therapeutic strategies. Study of intellectual development and dietary compliance of young phenylketonuria patients]. / Phenylketonurie--Wandel der therapeutischen Strategien. Studie zur Intelligenzentwicklung und Diättreue junger PKU-Patienten.

Recent results of research appear to show that over the past few years, clearly more restrictive dietary recommendations have become accepted in the treatment of phenylketonuria (PKU). A lifelong diet low in phenylalanine is the goal, since poor dietary discipline can lead to an appreciable decrease in the level of intelligence and, in rare cases, to severe neurological deficits. Furthermore, neuropsychological symptoms as sequelae of current high serum phenylalanine levels also occur. In the present study, the question as to the development of intelligence and compliance with diet was investigated. The results underscore the need for continuing adherence to a diet on the one hand, and for continuous psychosocial support on the other.

School performance and intellectual outcome in adolescents with phenylketonuria.

In a retrospective study, 34 treated adolescents with phenylketonuria and their relatives were tested with scale 2 of the Culture Fair Intelligence Test (CFT20) and self-developed questionnaire concerning their development in school. The patients also filled in the Anxiety Questionnaire for Children. With an IQ of 93.6, the patients reached a normal mean intellectual performance but this was significantly below the mean IQ of the general population (100, p < 0.01), the IQ of their mothers (98.2, p < 0.05), their fathers (105.4, p < 0.05) and their siblings (110.3, p < 0.05). The patients' IQs correlated significantly with the IQs of their mothers, the socio-economic status of their families, the quality of dietary control since birth and the serum phenylalanine concentration at the moment of testing. With respect to age at which the patients started school, type of school attended and number of school years which had to be repeated, there were no significant differences between the patients and their siblings. The patients did not display a markedly higher degree of general anxiety, nervousness at examination time or a greater reluctance to attend school.

[Treatment of phenylketonuria: wish and reality]. / Behandlung der Phenylketonurie: Wunsch und Wirklichkeit.

A diet strictly low in phenylalanine from soon after birth on can protect patients with phenylketonuria against intellectual and psychomotor retardation. Our study tries to answer the questions how the patients and their relations cope with the diet, and weather they reach the serum-phenylalanine-limits recommended by the German Association of Pediatric Metabolic Diseases in 1990.

[Phenylketonuria: illness experience and coping mechanisms]. / Phenylketonurie: Krankheitserleben und Krankheitsbewältigung.

If patients with PKU follow a strict diet low in phenylalanine from soon after birth their intellectual and psychomotor development will be within the normal range. Recent studies have shown that it is necessary to continue the burdensome diet throughout one's life. This is in contrast to past practice and puts additional emphasis on psychosocial aspects of PKU. In the present retrospective study we investigated how adolescent patients and their relatives' experience and cope with this chronic disease.

Neurological findings in early treated phenylketonuria.

Twenty early treated, normal intelligent patients (IQ: mean 101.4, SD 10.0; age: mean 10.11, SD 1.3 years) with classical phenylketonuria and 20 age-, sex- and IQ-matched healthy controls were investigated for neurological outcome, especially with regard to fine motor ability using the motor performance task ("Motorische Leistungsserie"). No pathological findings were seen on clinical neurological examination. The patient group had significantly poorer results in a concentration task (Test-d-2) as well as in some subtests of the motor performance task. Patients had difficulties in tasks which needed speed and precision of arm-hand-finger movements. High serum phenylalanine concentrations were significantly correlated with these deficiencies in fine motor ability. Our data demonstrated mild neurological impairment even in early and relatively strictly treated patients with phenylketonuria.

Intellectual, neurologic, and neuropsychologic outcome in untreated subjects with nonphenylketonuria hyperphenylalaninemia. German Collaborative Study on Phenylketonuria.

Based on the serum phenylalanine levels under free diet patients with hyperphenylalaninemia are classified as "classical" (>1200 micromol/L), "mild" (600-1200 micromol/L), or "non-phenylketonuria (PKU)-hyperphenylalaninemia" (<600 micromol/L). Recent studies revealed intellectual, neurologic, and neuropsychologic deficits as well as abnormalities of cerebral white matter (magnetic resonance imaging, MRI) in patients with early and adequately treated PKU. In addition deficits in IQ were reported for a group of 4-y-old patients with untreated mild PKU and non-PKU hyperphenylalaninemia (serum phenylalanine levels below 900 micromol/L). As a consequence, a lifelong diet with serum phenylalanine levels below 400 micromol/L was recommended even for those patients with serum phenylalanine levels remaining consistently between 400 and 600 micromol/L. Generally patients with non-PKU hyperphenylalaninemia were not treated, as a normal outcome was suspected, but the clinical development of patients with non-PKU hyperphenylalaninemia was not so far studied systematically. We assessed 28 untreated patients with non-PKU hyperphenylalaninemia (age: mean = 21.8, SD = 4.2 y) for IQ, school and job career, clinical-neurologic development, fine motor performances, selective and sustained attention, as well as for frontal lobe-dependent "executive functions." In addition, cranial MRI was obtained in 10 of these patients. Compared with healthy control subjects, matched for age, sex, and socioeconomic status, the patients reached normal results in all clinical and psychometric tests. Cranial MRI revealed no abnormalities. Additionally, no significant correlations between serum phenylalanine levels and test results were obtained. In the absence of any demonstrative effect, treatment is unlikely to be of significant effect in patients with non-PKU hyperphenylalaninemia.

Untreated non-phenylketonuric-hyperphenylalaninaemia: intellectual and neurological outcome.

The intellectual, neurological, and neuropsychological outcome of patients with non-phenylketonuric-hyperphenylalaninaemia (PKU-HPA) (serum phenylalanine levels under free diet < 600 mumol/l) has not been systematically studied so far. We therefore tested 28 patients (mean age = 21.8, SD = 4.2 years) for IQ (WAIS-R/WISC-R), school performance, job career, clinical neurological examination, fine motor performance (motor performance task), and selective and sustained attention (stroop task, Dot Pattern Exercise from the Sonneville visual attention task). In addition, cranial MRI (1.5 T unit) was obtained in 10 of these patients. Clinical-neurological examination revealed no significant abnormalities in the non-PKU-HPA patients. They also had a normal IQ (mean = 101.9, SD = 13.6). Compared to their healthy siblings, they attended a normal school and had a normal job career. The motor performance task revealed no deficits in fine motor abilities. The patients performed normally in the stroop task and the dot pattern exercise. Their MRIs were normal. Our results indicate that patients with non-PKU-HPA are not at risk for developing intellectual, neurological, and neuropsychological impairment, as described for patients with treated mild or classical phenylketonuria. From this point of view a dietary treatment is not necessary in patients with hyperphenylalaninaemia.

Psychosocial aspects in phenylketonuria.

Psychosocial aspects in phenylketonuric (PKU) patients are reported. In two separate studies patients with PKU differing in age (children versus adolescents), were assessed. The main message of the first prospective study on 58 10-year-old patients is that normally intelligent PKU patients who were treated early and strictly did not show a higher risk for severe emotional and behavioural maladjustment compared with healthy controls at the age of 10 years. The data were obtained in the course of the German PKU Collaborative Study by the "Personality Questionnaire for Children (PFK 9-14)". All patients received nutritional, medical, and psychological counselling every 6 months. In the second retrospective study, 34 early treated, normally intelligent adolescents with PKU (age: mean = 14.6, SD = 2.0, range = 11-18 years) and their mothers were assessed with several psychometric personality inventories and self-developed questionnaires concerning their psychosocial situation and their disease- and diet-specific knowledge. Using the Mannheimer Biographic Inventory (MBI), the Personality Questionnaire for Children (PFK 9-14), and the Freiburger Personality Inventory (FPI) the adolescent patients described their social life and their emotional development as being distinctly restricted. Their knowledge concerning disease and diet was alarmingly poor and the majority had great difficulties in satisfactory dietetic management without parental help. In addition to the burdensome diet, developmental crises like puberty may cause more frequently emotional and behavioural problems in PKU patients.

German Maternal Phenylketonuria Study.

The German maternal phenylketonuria (MPKU) Study began in 1989 and since 1992 works together with the American-Canadian MPKU Study. Main goals of the study are: (1) to find women with phenylketonuria (PKU) and mild untreated hyperphenylalaninaemia (HPA); (2) to inform them about the risks of an untreated pregnancy with PKU and HPA; (3) to evaluate the efficacy of the phenylalanine (Phe) restricted dietary treatment prior to and during pregnancy by following the physical and cognitive development of offspring from treated pregnancies. An interim report of the study is presented. Until now, 43 pregnancies have been followed. They resulted in 34 live births, 24 from women with PKU and 10 form women with HPA. There are significant negative correlations between the gestational age in which the dietary control (blood Phe level < 360 mumol/l) was reached and pregnancy outcome as measured by growth parameters and early cognitive and motor developmental quotients at the age of 2 years. For minimizing risks of MPKU, preconceptional dietary control is strongly recommended. Tracking and timely information of young women about risks of MPKU is of outmost importance.

Deficits in selective and sustained attention processes in early treated children with phenylketonuria--result of impaired frontal lobe functions?

UNLABELLED: Twenty normally intelligent children with early treated phenylketonuria (PKU) (IQ: mean = 101.4, SD = 10.0; age: mean = 10 years 11 months, SD = 1.3 years) and 20 healthy controls, matched for age, sex and IQ, were assessed for their selective (Stroop Task) and sustained attention (Test-d-2). Using positron emission tomography an activation of the frontal lobe during the Stroop task had previously been demonstrated. In addition to the Stroop Task and the Test-d-2, a short-term memory test as a "non-frontal-lobe-function-task" was administered to all subjects. Group comparisons demonstrated that PKU children had specific deficits in selective and sustained attention, which were significantly correlated with the concurrent serum phenylalanine concentration. CONCLUSION: The results give evidence that even dietary treated children with PKU were suffering from impaired attentional control mechanisms in spite of a normal IQ. The deficits might be the result of impaired frontal lobe functions.

Sustained attention in untreated non-PKU-hyperphenylalaninemia.

Twenty-four untreated adolescent and adult patients with non-PKU hyperphenylalaninemia (HPA) (serum Phe levels < 600 mumol/L) and 24 healthy controls matched for age, sex, and IQ were investigated for simple motor reaction time and sustained attention, which are prolonged in patients with mild or classical phenylketonuria (PKU). Patients with HPA were of normal intelligence and did not differ significantly from healthy controls in their test results. For HPA patients, reaction times and sustained attention were not significantly influenced by serum phenylalanine concentrations. We conclude that dietary treatment is not necessary in patients with non-PKU HPA.

No fine motor deficits in patients with untreated non-phenylketonuria hyperphenylalaninaemia.

Twenty-four untreated adolescent and adult patients with non-phenylketonuria (PKU) hyperphenylalaninaemia (HPA) (serum phenylalanine levels < 600 mumol l-1) and 24 healthy controls matched for age, sex and IQ were investigated for their neurological outcome, especially for fine motor abilities by the Motor Performance Task. No pathological findings could be revealed by clinical neurological examination. Patients with HPA and healthy controls did not significantly differ in their fine motor performances. These performances were not significantly influenced by serum phenylalanine concentrations. Our results indicate that untreated patients with non-PKU HPA are not at clinically significant risk for developing fine motor deficits and severe neurological impairment. From this point of view a dietary treatment is not necessary in patients with HPA, as recommended most recently.

Psychological and social findings in adolescents with phenylketonuria.

In a retrospective study, 34 early treated, normally intelligent adolescents with phenylketonuria (PKU) and their parents were tested with several psychometric personality inventories and self-developed questionaires concerning their psychosocial situation and their disease- and diet-specific knowledge. Results show that the patients are characterized by less autonomy, a more negative evaluation of their scholastic ability, less achievement motivation, low frustration tolerance, more negative self description, less extraversion and impulsiveness, a feeling of not being quite healthy, more grave and a higher level of dependency from their families. The patients saw their whole social situation as being distinctly restricted. Their knowledge concerning disease and diet was alarmingly poor and the majority had great difficulties in managing the diet satisfactorily without parental help. Up to the age of 15 years the serum phenylalanine levels were persistently above the desired range.

Cranial MRI in PKU: evaluation of a critical threshold for blood phenylalanine.

A group of 15 adolescent patients with PKU and good life time blood phenylalanine control was tested for white matter abnormalities on MRI. Five of the patients presented mild to moderate abnormalities in association with blood phenylalanine levels above 5.0 mg/dl. Patients with and without MRI changes could statistically not be discriminated by blood phenylalanine concentrations at the time of investigation as well as by phenylalanine levels of different time periods prior to MRI examination.

Effect of L-dopa on visual evoked potentials and neuropsychological tests in adult phenylketonuria patients.

Eight adult, untreated patients with classical phenylketonuria received L-dopa and a decarboxylase inhibitor for 2 weeks. No effect of L-dopa therapy on choice reaction time tasks, sustained attention, frontal lobal function as well as latencies of visual evoked potentials was found. The results raise the question if adult patients with phenylketonuria really suffer from functional dopamine deficiency.