Phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). Previous studies have suggested that the highly variable metabolic phenotypes of PAH deficiency correlate with PAH genotypes. We identified both causative mutations in 686 patients from seven European centers. On the basis of the phenotypic characteristics of 297 functionally hemizygous patients, 105 of the mutations were assigned to one of four arbitrary phenotype categories. We proposed and tested a simple model for correlation between genotype and phenotypic outcome. The observed phenotype matched the predicted phenotype in 79% of the cases, and in only 5 of 184 patients was the observed phenotype more than one category away from that expected. Among the seven contributing centers, the proportion of patients for whom the observed phenotype did not match the predicted phenotype was 4%-23% (P<.0001), suggesting that differences in methods used for mutation detection or phenotype classification may account for a considerable proportion of genotype-phenotype inconsistencies. Our data indicate that the PAH-mutation genotype is the main determinant of metabolic phenotype in most patients with PAH deficiency. In the present study, the classification of 105 PAH mutations may allow the prediction of the biochemical phenotype in >10,000 genotypes, which may be useful for the management of hyperphenylalaninemia in newborns.

Careful neurological investigation revealed subtle symptoms of brain damage even after early-initiated treatment in adult patients with phenylketonuria. At present it cannot be excluded that further neurological deterioration could emerge later in life. Thus, patients with phenylketonuria - either on or off diet - should be monitored throughout life.

Our results support a psychological perspective for the development of psychiatric symptoms in PKU. Thus, optimizing medical treatment necessary to prevent brain damage should be accompanied by psychiatric monitoring and psychological support for the families.

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.

Optimal regimen for insulin therapy should lead to normal longitudinal growth and weight gain in children with diabetes mellitus. However, reports published so far indicate that this goal of paediatric diabetology is currently not achieved in a considerable number of patients. In a cross-sectional sample of 89 children with insulin dependent diabetes mellitus (IDDM) for more than 3 years, we found the relation of height to weight to be significantly different compared to 102 healthy school children of similar age. Using bivariate analysis, body shape in these children with diabetes was shifted towards small and obese (P less than 0.05) compared to control children. We subsequently initiated a longitudinal study and followed children from the onset of diabetes for the following 3 years, recording height, weight and bone age as well as glycosylated haemoglobin and daily insulin requirement. At diagnosis, height SDS was identical in children with IDDM (+0.04 +/- 0.10) compared to control children (-0.07 +/- 0.10; M +/- SE), while weight SDS was -0.26 +/- 0.10 in children with diabetes (controls: + 0.01 +/- 0.01). Bone age was identically retarded in newly diagnosed IDDM children (-0.73 +/- 0.12 SDS) and in our control group of children from the same regional background (-0.50 +/- 0.12; n.s.). In this group of children with diabetes mellitus followed prospectively, height to weight relationship differed from controls after 2 and after 3 years of the disease (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)