Growth and skeletal maturation in children with phenylketonuria.

Growth and skeletal maturation was evaluated in 82 children participating in the German Collaborative Study of Children Treated for Phenylketonuria (PKU). Height, weight, head circumference and bone age were recorded at regular intervals for the first 6 years of life. The mean SD score (SDS) for height was not significantly different from zero at study entry, but decreased mainly during the second year of life to a nadir of -0.78 in boys and -0.54 in girls at 2.5 years. During the subsequent years, a significant trend towards a regain of height SDS was noted in both sexes. Weight-for-height SDS was close to zero in both sexes, with a significant continuous increasing trend throughout the observation period. Head circumference SDS decreased in boys during the first year of life from -0.28 to -0.68, whereas girls showed only a minor change. During the further follow-up period, head circumference SDS remained at approximately -0.3 in boys and 0.0 in girls. While the mean verbal and performance IQ of the total study population at 5 and 6 years of age did not differ from a group of 212 healthy non-PKU children, patients with a head circumference SDS less than the population median at 2 years of age exhibited poorer cognitive abilities at school age than those patients with a relative head size greater than the population median. The children with a head circumference less than the median at 2 years had smaller head sizes already at birth; in addition, the change in relative head size during the first 2 years was correlated significantly with cognitive abilities at school age in boys. Mean bone age was identical to chronological age at each time point of observation. The rate of maturation was one year of bone age per year of chronological age. No correlation between phenylalanine intake or phenylalanine concentrations and the rates of body or head growth or skeletal maturation could be established. We conclude that despite adequate weight gain, moderate growth retardation occurred during the first 2 years of life in this group of children treated for PKU. Growth was more compromised in boys than in girls and tended to be compensated during later follow-up. Early infantile head circumference and growth appear to be predictors of cognitive development.

Examination of urine metabolites in the newborn period and during protein loading tests at 6 months of age--Part 1.

In the course of the collaborative study of children treated for PKU, urine samples from a total of 165 patients were analysed at six different times: in the newborn period before onset of therapy, after beginning of dietary management, during and immediately after a protein loading test at 6 months of age. In 95.9% of newborns with elevated Phe levels in plasma, metabolites of this amino acid as well as of Tyr could be detected. Of all metabolites phenylpyruvate always showed the highest concentration, followed by phenyllactate and o-hydroxy-phenylacetate. During the protein loading test an increase of the same metabolites occurred. At the age of 6 months the percentage of p-hydroxylated compounds related to the sum of all metabolites was lower than in the newborn period. Comparing the results of urine analyses at 6 months of age after the protein loading tests with the classification of HPA into the reaction types I-III, it can be clearly stated that patients with the milder forms II and III have already lower levels of Phe metabolites in urine before onset of therapy compared to the reaction type I. In retrospect 52% of the newborns could therefore be classified as reaction type I even before beginning of dietary management. The analysis of urinary Phe metabolites before the onset of therapy therefore provides sufficient information about the reaction type.

Six-year follow up of phenylalanine intakes and plasma phenylalanine concentrations.

The daily Phe intakes of normally growing 1- to 6-year-old treated PKU patients were evaluated. The children received protein in amounts that varied from 2.26 +/- 0.47 g/kg body weight per day (mean +/- SD) at the age of 6 to 1.81 +/- 0.35 at the age of 72 months. Mean Phe intakes declining from 34 +/- 7 at the age of 6 months to 15 +/- 5 mg/kg body weight per day at the age of 72 months were required to maintain mean median plasma Phe levels around 6.0 mg/dl.

Significance of the in vivo deuterated phenylalanine load for long-term phenylalanine tolerance and psycho-intellectual outcome in patients with PKU.

In 20 patients with PAH deficiency, in vivo RA was determined by an intravenous deuterated Phe load. Sixteen patients had RAs of less than 0.4% of normal, 3 a clearly detectable activity between 0.8 and 1.4% of normal. Long-term Phe tolerance as measured by the distribution of plasma Phe levels in categories (0-3.9, 4.0-9.9, 10-15.9 and over 16 mg/dl) was much improved in patients with RAs greater than 0.8%. There was a negative correlation between RA and number of plasma Phe levels greater than 16 mg/dl. Relationship between full scale IQ at the age of 9 years and dietary control showed a positive correlation between IQ and the number of Phe levels between 0-10 mg/dl (k = .50 p less than 0.05). Highest (negative) correlation (k = -0.67 p less than 0.007) was found between full scale IQ and the number of Phe values greater than 16 mg/dl as measured over 9 years. On the one hand detectable RA of PAH reduces the risk of high Phe levels and thus may also reduce the risk of brain damage in untreated or suboptimally treated patients with PAH. On the other hand enzyme measurement of PAH is no predictive parameter for Phe tolerance in an individual patient since RA may be very similar in phenylketonuric/hyperphenylalaninaemic patients. For practical purposes the oral protein loading test at the age of 6 months will give the most reliable results for differential diagnosis of PAH deficiency.

EEG development in early treated PKU patients from birth to 6 years of age.

In 126 early treated PKU patients (type I and type II) a close EEG follow up was performed from birth up to 6 years of age. A total of 1465 EEGs were performed before and after onset of dietary treatment and on 11 more subsequent occasions. The composition of the background activity was normal up to 6 years when only a small number of the children (19) showed no dominant alpha activity. The frequency of epileptiform activity of generalised as well as focal type was low in the first 2 years of life, but afterwards slightly enhanced in comparison to normal control groups. Other findings like generalised theta paroxysms or focal slow waves were rarely observed. Under a standardised protein load at 6 months (52 patients) and at 5 years of age (42 patients) a moderate generalised slowing of the background activity but no other abnormalities were noted.

Results of psychological testing of patients aged 3-6 years.

Cognitive development of early treated PKU children (132) was investigated by intelligence tests, tests for visual perception, motor and language development. Deviations from test norms occurred at 5 years of age concerning performance IQ, mathematical thinking, and visual perception. With the exception of mathematical thinking, "normal" results were obtained at the age of 6 years. Correlation with levels of plasma Phe revealed a relation between quality of dietary control and performance IQ. Results are discussed in light of methodological aspects and with respect to treatment consequence.

Preliminary neuropsychological test results.

A series of information processing tasks was administered to 22 PKU children aged 8.5 years who had been under dietary treatment since birth as well as to 20 controls of the same age. This contribution presents the results of two tasks from this series: a continuous performance task and a calculation task. The continuous performance task revealed a sustained attention deficit in the PKU group. In the calculation task the PKU children were slower than the controls and this difference increased with task difficulty. When the PKU sample was divided in two groups (above and below the median value of the concurrent plasma Phe level), the high Phe level group performed much worse in comparison to the low Phe level group. The latter group actually matched performance level of the controls. This could be observed for both tasks. The serum Phe level, assessed since birth over 6 month periods, correlated highly with task performance. As regards sustained attention, the Phe level measured during the 2 years preceeding test administration appeared to be an even better predictor for task performance than the concurrent Phe level, a finding which seems to underline the chronic effect of Phe on basic attention mechanisms. The results so far seem to stress the value of well-controlled dietary restrictions.

Study design and description of patients.

A West German multicentre study (eight centres) of PKU was designed in 1976. The subjects of the study are the differential diagnosis, factors influencing the therapeutic outcome, and the extension of dietary therapy into adolescence. Between 1978 and 1984, 165 patients were enrolled, of whom 38 were of non-German nationality. The educational and occupational status of the West German parents were comparable to the population of the Federal Republic of Germany. In the central data bank located at the University Childrens Hospital in Heidelberg, data from recurrent medical examinations and from biochemistry, dietetics, neurology, psychometry and demography were collected. The differential diagnosis of the elevated plasma Phe level in the newborn period resulted in the detection of 2 patients with a PTPS-deficiency, and of 163 with an apo-enzyme defect. Depending upon the magnitude of the Phe levels during the first weeks of life, preliminary treatment groups were formed. They were revised at the age of 6 months with a protein challenge. The levels of Phe during the protein challenge resulted in three types of response. Of these, type III can apparently forgo dietary restrictions resulting in plasma Phe concentrations of around 10 mg/dl. Preliminary results of the whole study are now presented.

DNA haplotype analysis at the phenylalanine hydroxylase locus in the Turkish population.

Thirty-nine Turkish phenylketonuria (PKU) families were investigated for their DNA haplotypes at the phenylalanine hydroxylase (PAH) locus. There was a threefold higher incidence of consanguinity in the population studied compared with the general Turkish population. The PAH DNA haplotype 6 was found to be almost exclusively associated not only with the mutant PAH genes but also with the classic phenotype in 39% of the Turkish patients. This haplotype was of not importance in northern European populations. The two DNA haplotypes (1 and 4) that were almost equally frequent among the normal and the mutant PAH genes in northern European populations show virtually the same distribution in Turkish individuals. In all populations studied, these haplotypes are associated with different phenotypes.

[Differential diagnosis of increased phenylalanine blood level in infancy. Results of the German collaborative study on phenylketonuria (PKU)/hyperphenylalaninemia (HPA)]. / Differentialdiagnose des erhöhten Phenylalanin-Blutspiegels im Säuglingsalter. Ergebnisse der deutschen Verbundstudie über Phenylketonurie (PKU)/Hyperphenylalaninämie (HPA).

Between 1978 and 1984 165 children with elevated Phe blood levels in newborn screening were included in a German multicentric study. The differential diagnosis, comprising Phe concentrations in the blood under a tetrahydrobiopterin (BH4) load (30 mg BH4), determination of pterins in the urine and dihydropteridin reductase (DHPR) in erythrocytes, resulted in two patients with a 6-pyruvoyltetrahydrobiopterin synthase (PTPS) deficiency. Those patients with a defect in the apoenzyme phenylalanine hydroxylase (PH) were treated with a low Phe diet, when the Phe blood concentrations exceeded 10 mg/dl under an adapted formula (n = 154). At the age of six months, in 155 infants a protein challenge containing 180 mg Phe/kg body weight for three days was performed, followed by a fourth day with 5 mg Phe/kg. Corresponding to the US Collaborative Study [19] 3 types of response were chosen according to the course of the Phe blood level under the challenge (n = 145). Type I response (n = 112) shows a continuous increase of the Phe more than 20 mg/dl even under the Phe restriction at day 4. Type II response (n = 14) shows also increasing Phe blood levels above 20 mg/dl, followed by a spontaneous decrease below 20 mg/dl still during the high Phe challenge and even lower at the fourth day with low Phe intake. Type III response (n = 19) had only a small increase of the Phe blood concentration, mostly below 15 mg/dl during the whole challenge period.(ABSTRACT TRUNCATED AT 250 WORDS)