Phenylketonuria's impact on physical growth in a Spanish cohort

Phenylketonuria is an inborn error of metabolism affecting the phenylalanine metabolic pathway, which converts phenylalanine to tyrosine via phenylalanine 4-hydroxylase and its cofactor (6R)-L-erythro- 5,6,7,8-tetrahydrobiopterin (BH4). Phenylketonuria treatment is based on strict vegetarian diets, with very low phenylalanine intake and supplemented with phenylalanine-free formulas. This phenylalaninerestricted diet has proven to be effective in preventing the development of long-term neurological damage caused by phenylalanine accumulation. However, such diets have occasionally been reported to hinder normal development, since some individuals presented growth retardation. Furthermore, in an attempt to improve outcomes in these patients, several alternative approaches for the treatment of phenylketonuria have emerged, such as therapy based on administration of the cofactor BH4. This treatment allows patients to consume a near normal diet, or at least, a less strict low-protein diet, which results in higher natural protein intake. However, little is known about how BH4 treatment affects physical development. Firstly, in order to evaluate the impact of the phenylketonuria diet on anthropometric characteristics (weight, height, body mass index and growth rate), we conducted a retrospective longitudinal study. The aim was to further explore the hypothesis of higher natural protein intake being associated with attaining improved physical outcomes. Anthropometric characteristics and nutrition were evaluated from birth to adulthood in a cohort of phenylketonuria and mild-hyperphenylalaninaemia patients, who were exclusively on protein-restricted diets, and were compared to the Spanish reference population. Patients with phenylketonuria showed growth impairment in early stages, with higher phenylalanine intakes being associated with improved developmental outcomes over this period. Our results suggest that prescribing very stringent diets in early stages might predispose these patients to later growth retardation, with growth outcomes in adulthood being well below the 50th percentile for healthy subjects. Secondly, we conducted a retrospective longitudinal study of anthropometric characteristics in a cohort of patients with phenylketonuria on BH4 treatment and compared their developmental outcomes with those of a group of patients on a phenylalanine-restricted diet, in order to determine whether BH4 treatment was associated with an improvement in growth development. Data were collected every 6 months over two periods of time (two and five years). No improvement was observed in the anthropometric variables in the BH4-treated group, from prior to initiating treatment to when they had taken the drug for 2 or 5 years. In addition, growth impairment was also observed in patients on low-phenylalanine diets. In fact, individuals on long-term BH4 treatment seemed to achieve similar developmental outcomes to those on more restricted diets. In conclusion, our study identified growth impairment in patients with phenylketonuria on BH4 treatment, despite the fact that their natural protein intake increased.