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Objectivegram (EEG) is an easy and non invasive evaluation method for diagnosis and early prognosis in children. Our aim was to assess the association between EEG and the patients’ Developmental Quotient (DQ) level in phenylketonuria. Materials & Methods In this study, 94 PKU patients (45 boys, 49 girls; mean age: 8.5 6.2 years) who were diagnosed through newborn screening tests or later were followed. PKU was confirmed with a serum phenylalanine concentration above 6 mg/ dl in untreated newborns. The patients were matched in gender, age and phenylalanine level. The ASQ (Age and Stage Questionnaire) was used for evaluation of the developmental stage of the case (abnormal EEG) and control (normal EEG) groups and the Wechsler Intelligence Scale was used to assess cognitive and intellectual abilities. Finally, one way ANOVA and chi square tests were used for analysis and P< 0.05 was considered significant. Results case group consisted of 63 patients (67%) with abnormal EEGs and the control group consisted of 31 patients (33%) with normal EEGs. In patients with abnormal EEGs, 34 (53%) had mild, nine (14%) had moderate and 20 (33%) had severe EEG changes. Distribution of high and low DQ levels in these three groups show significant difference (p=0.001). Distribution of DQ level in the abnormal and normal EEG patients showed a significant difference (p=0.001). Conclusionwas no significant difference between phenylalanine level in case and

Background: Due to late onset neurological symptoms, MRI abnormalities, and neuropsychological deficits the long-term outcome of treated PKU is still unclear.

FACTORS AFFECTING COGNITIVE, MOTOR, EXECUTIVE AND BEHAVIORAL FUNCTIONING IN CHILDREN WITH PHENYLKETONURIA (PKU). 835

In an animal model of hyperphenylalaninemia PHE was measurable by MRS in the brain in vivo. Blood and brain concentrations were not correlated (Avison et al 1990, Pediatr Res). We measured brain PHE in 4 early treated adult PKU patients (type I) during an oral load with l-PHE using localized MRS (1.5 T, standard head or surface coil, double echo localisation sequence, TE 20 ms). The PHE peak was identified at 7.4 ppm. in all patients calculating difference spectra (baseline spectra of 8 healthy subjects). PHE quantification was accomplished using the unsuppressed water signal as internal standard (Kreis et al 1993, J Magn Reson B). Blood PHE steaply increased from 981 (696 -1158) uMol/l preload to maximum within 2 h after load. After 5 h (1713 (1423-1913) uMol/l) PHE was stable, after 20 h (1581 (1440 - 1653) uMol/l PHE levels slowly decreased. Increase of brain PHE (preload 230 (80 - 340 uMol/l) was much slower and less steap and continued from 5 h (290 (260 - 330) uMol/l) to 20 h (340 (240 - 490 uMol) postload. Individual blood/brain ratios varied from 2.73 - 5.43. Using MRS to measure PHE in the brain (and thus in the affected compartment) and its dynamics of influx through the blood-brain barrier it should become possible to determine the interindividually different risk in developing brain damage on a more valid basis.(Grant DFG PH96/3-1).

Late onset neurological symptoms involving the motor system have been reported in adult patients with early treated phenylketonuria (Thompson et al 1990, Lancet). Impairment of fine motor skills is known to be a valid indicator of mild forms of brain damage in children. We investigated 20 children (10 f, 10 m, age 13.1 (12-14)) with early treated PKU still under diet and 20 controls, matched for age, sex and social status of the family. We employed a test battery (Motorische Leistungsserie, Schoppe), which requires different dimensions of fine motor abilities. The subtests are (1) steadiness (keeping a stable position), (2) line following (slow directed movements), (3) metal sticks (pegboard with long or short sticks), (4) aiming (fast aiming movements), (5) tapping, (6) pursuit rotor (visual-motor integration). We found significantly impaired fine motor skills in PKU patients compared to controls in all tested variables. The results for dominant and nondominant hand were comparable. Performance in subtests 1 and 2 (measuring stillness of hand, esp. tremor) was significantly correlated to the actual blood level of phenylalanine (796 (67 -1489) uMol/l phenylalanine; test 1: PCC 0.48, p

Increased prevalence rates of psychopathology and manifest psychiatric disorders (i.e. agoraphobia) have been observed in patients with treated PKU. We investigated 24 adult patients with PKU type I (13 f, 11 m; age 20.8 years) with a highly structured 2-h psychiatric interview (MADELI, Esser 1989). Data were compared to a random sample of 181 18-year-old adults (CO). Overall we found a normal rate for psychiatric disturbances in PKU (PKU 21%, CO 16%). Though overall scale indexes were not significantly different, functional and emotional symptoms were slightly increased (scale index PKU 2.2, CO 1.45) and antisocial symptoms were reduced (PKU 0.38, CO 0.95)). Single symptoms were more frequent in PKU: Generalized anxiety (PKU 21%, CO 5%), phobia (PKU 38%, CO 16%), depressed mood (PKU 42%, CO 19%), problematic peer relations (PKU 71%, CO 42%) and siblings rivalry (PKU 29%; CO 7.5%) were significantly increased. 5 cases met the criteria of ICD-10 diagnoses. We found no correlation between psychiatric symptoms and phenylalanine levels as well as IQ (WAIS-R). Educational style of mothers was more frequently rated as ‘disturbed’ (‘overprotecting’ PKU 42%, CO 11%, ‘restrictive-controlling’ PKU 25%, CO 4%). Psychopathology in PKU has been attributed either to a disturbed regulation of neurotransmitters or psychological factors (related to the chronic disease and its dietary treatment). Our data favor a psychological explanation for abnormal behaviour in patients with PKU. (Grant DFG 196/3-1).

To avoid fetal damage in women with PKU, strict preconception and pregnancy control of blood phenylalanine concentrations (PHE) have been recommended (1). To find out if these recommendations prevented neurological damage we studied the neurodevelopmental outcome of 24 infants from 23 pregnancies in which strict dietary control was introduced prior to conception. 18 had reached 1 year. Measures of outcome were related to mean PHE, and to number of daya PHE exceeded 300 μmol/l in the first trimester. They included head circumference (OFC) and neurological examination at term and 1 year and developmental quotient (Griffiths GQ) at 1 year. The OFC standard deviation scores (SDS) at term and 1 year in infants of mothers with mean PHE ⋝ 300 (305-496) μmol/l were significantly smaller than those with mean PHE of

In a retrospective study the psycho-social context of 34 early treated patients with PKU (mean age 14.6 y) and their parents were evaluated.

Dietary treatment in phenylketonuria (PKU) prevents severe impairment of psychomotor development. However, mere are unequivocal recommendations in regards to diet liberlization. Aim of this retrospective sfudy was to examine intellectual development in eighty-six individuals with “classical” PKU, who were treated early in life. Intellectual development was recorded using the Kramer, Hawik & Hawle test at the age of 4, 6, 8, and 12years. Intellectual development was not influenced by the time dietary treatment was started, probably due to the fact that treatment in all patients was introduced within the first two months (mean±SD: 23±8 days, range: 6 to 61 days). Compared with their non-PKU brothers and sisters PKU children showed significantly lower IQ at the age of 6 years (105±14 vs 114±14, P< 0.001). IQ of the parents did not differ from IQ of the PKU children at the age of 12 years. A significant association was observed between the quality of diet control (measured by Guthrie-test) and intellectual outcome: IQ at 6.8. and 12 years significantly correlated with qualify of diet control during all observation periods (r= 0.388. P

Early-treated children with PKU are protected from mental retardation. However, recent studies have found IQ loss in these children, especially after termination of the low phenylalanine diet. We have studied IQ and IQ change in 91 early-treated children with PKU and 29 untreated or partially treated children with mild hyperphenylalaninemia (MH) who have been followed for up to 22 years. Their most recent psychological evaluations were compared to similar assessments done 5 years previously. In children with PKU, age (10.8 ± 4.7 yrs.) was negatively correlated with IQ (mean IQ = 98.4 ± 16.7) (r=-.30, p=.002). With age controlled, the treatment variable that best predicted IQ was the percent of blood phenylalanine levels ≥ 16 mg/dl while on diet (r2=0.86). These results suggest that IQ is significantly affected by dietary control during treatment. Over a 5 year period, mean IQ changes were -4.3 ± 14.8 in children with PKU off-diet, +7.4 ± 14.1 in children with PKU on-diet, and +2.8 ± 10.5 in children with MH. IQ change did not correlate with IQ score. With age controlled, the best predictor of IQ loss was diet discontinuation (r2=.159); natural (pre- or post-diet) blood phenylalanine level was the second best predictor (r2=.083). This suggests that loss of IQ is greater in children who have terminated the diet, particularly in those with higher natural blood phenylalanine levels. These findings may have implications for the issue of diet continuation or discontinuation during school age years.

Inborn errors of amino acid metabolism are frequently associated with growth disorders, the pathogenesis of which is unknown. We have performed arginine-insulin tolerance tests and measurements of circadian hormone secretion in patients with PKU (n=2), H (1), C (1), HU (4) and normal control children (4). Integrated mean GH, insulin and blood sugar levels were obtained using the Sigmamotor ML-6 constant withdrawal pump. Blood was collected over ice and divided into hourly portions (n=24) to permit detection of possible pulse secretion of GH and correlations to the patients' sleep-wake activity as recorded by EEG. Two patients with HU, whose plasma and urine aminograms were normalized by diet and vitamin B6, were re-investigated after treatment had been discontinued for > 5 weeks. Summary of findings: (1) GH concentrations in HU were markedly elevated in patients out of metabolic control as compared to subjects with near normal aminograms. (2) GH concentrations were within the normal range in H and one patient with PKU, but increased in another girl with PKU and tall stature. (3) The lowest GH concentration among all subjects was observed in a 5-year old boy with C who was also severely dwarfed.- Supported by German Research Foundation, Grant Sche. 119/1

Appropriate dietary management in PKU children was demonstrated to be effective in preventing mental retardation. There is, however, evidence that intellectual functionning is altered to some degree, despite early diagnosis and treatment. Recent reports suggest that PKU children may have impairment of motor-perceptual functionning, short term memory, concentration or attention, linguistic skills and other cognitive deficits which could explain the poor learning performances. Pemolin(amphetamin substitute) has been shown to improve learning difficulties in children with "hyperkinetic behavior". 7 children with classical PKU, 5 to 11 year-old, were selected in this study for their poor academic performance. They had been on diet within 6 weeks of age. Till the age of 5 years, their dietary control was considered good or excellent. The children were examined before and after 6 months of treatment of pemolin (daily dosage ranged between 1.9 and 2.35 mg/kg body weight). The examination included neurodevelopmental and psychoeducational testing (WISC or WPPSI, Bender test, Benton test, Conners' teacher questionnaires).

Changing nursery practices have raised the question of the diagnostic validity of newborn PKU screens drawn before the third day of life. To answer this question, a survey of PKU patients and unaffected siblings was conducted. The following phenylalanine blood levels (phe, mg/dl) were measured in these two groups

1233 SAFETY AND EFFICACY OF A NEW FORMULA FOR TREATMENT OF CHILDREN WITH PHENYLKETONURIA (PKU)

PLATELET CONTENT OF PHENYLALANINE (PHE) AND TYROSINE (TYR) SUCH AS PLATELET UPTAKE OF 3 H-PHE AND 3 H-TYR IN CHILDREN SUFFERING FROM PHENYLKETONURIA (PKU)