Molecular Basis of Phenylketonuria: From Genotype to Clinical Management
In the age of neonatal screening and the presymptomatic treatment of individuals with phenylketonuria, disease definition has shifted from a set of clinical symptoms observed in untreated patients to an inherited predisposition that requires dietary intervention to avoid brain damage and intellectual impairment. The analysis of correlations between genotype and phenotype must thus be targeted to the need and modalities of preventive treatment. In phenylketonuria, mutation analysis is not a prerequisite to correct diagnosis and therapy including treatment with the cofactor tetrahydrobiopterin (BH 4 ). Nevertheless, the functional impact of individual mutations has been extensively investigated over the last years, and there are well-studied correlations between the genotype and various phenotypic aspects. Knowing and understanding the genotype at a very early stage often allows a prediction of the severity of phenylalanine hydroxylase deficiency and provides a better picture of the disease characteristics in the individual patient. This may assist in the clinical management. Identification of homozygosity or compound heterozygosity for null mutations indicates that this patient will not benefit from BH 4 treatment, whilst identification of a well-known BH 4 -sensitive mutation in a patient who has been classified as non-responsive in a BH 4 test should be an indication to re-examine the classification and, if necessary, repeat the test. Care must be taken to recognize potential errors in the results of molecular studies, and to interpret them in relation to clinical and biochemical findings in the individual.