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.
Newborn screening for phenylketonuria (PKU) started with Robert Guthrie (1916–1995) who developed the bacterial inhibition test for the semiquantitative analysis of phenylalanine, which was the first test suitable for high throughput analysis. In addition, he introduced the 'Guthrie filter card' as a transport medium for dried blood which is still used today.
Realizing the potential of his approach for early diagnosis and the fact that a low-phenylalanine diet prevented the neurological sequelae of untreated PKU, Robert Guthrie became the first and utmost advocate of newborn screening for PKU. Following the first PKU newborn screening program in Buffalo, N.Y., USA, in the 1960s, additional newborn screening programs were initiated around the world in the 1960s and 1970s. Newborn screening has since been recognized as an important public health measure, and most countries have ongoing newborn screening programs for PKU and other inborn errors of metabolism. Since the first programs, it has been recognized that early diagnosis of PKU and subsequent initiation of a low phenylalanine diet results in normal neurological outcomes – in contrast to the severe mental retardation in untreated PKU. Today's newborn screening laboratories use photometric assays or tandem mass spectrometry for analysis of phenylalanine rather than the bacterial inhibition test. This has led to an increased number of cases with hyperphenylalaninemia that often do not require dietary treatment. Any elevated phenylalanine level in a neonate needs to be followed by a second specimen for repeat analysis of phenylalanine and tyrosine. Confirmation of elevated phenylalanine levels with low to normal tyrosine levels requires analysis of urine pterines and dihydropterine reductase activity in red cells to rule out an inborn error of biopterin metabolism. In any neonate whose blood phenylalanine levels exceed 6 mg/dl, a tetrahydrobiopterin loading test should be performed and dietary therapy should be initiated. The level at which dietary therapy is started may be different between the USA, UK and continental
Phenylketonuria (PKU) is caused by deficient activity of the enzyme phenylalanine hydroxylase, needed to convert the essential amino acid (AA) phenylalanine (phe) to tyrosine. In order to prevent neurological damage, lifelong adherence to a low-phe diet that is restricted in natural foods and requires ingestion of a phe-free AA formula to meet protein needs is required. The goal of nutritional management for those with PKU is to maintain plasma phe concentrations that support optimal growth, development, and mental functioning while providing a nutritionally complete diet. This paper reviews developing a lifelong dietary prescription for those with PKU, outcomes of nutritional management, compliance with the low-phe diet across the life cycle, and new options for nutritional management. An individualized dietary prescription is needed to meet nutrient requirements, and the adequacy of phe intake is monitored with assessment of blood phe levels. Elevated phe concentrations may occur due to illness, excessive or inadequate phe intake, or inadequate intake of AA formula. Although normal growth and development occurs with adherence to the low-phe diet, it is important to monitor vitamin, mineral and essential fatty acid status, especially in those who do not consume sufficient AA formula. Given the growing population of adults with PKU, further research is needed to understand the risks for developing osteoporosis and cardiovascular disease.
There are promising new options to liberalize the diet and improve metabolic control such as tetrahydrobiopterin therapy or supplementation with large neutral AAs. Moreover, foods made with glycomacropeptide, an intact protein that contains minimal phe, improves the PKU diet by offering a palatable alternative to AA formula. In summary, continued efforts are needed to overcome the biggest challenge to living with PKU – lifelong adherence to the low-phe diet.
Since its discovery by Følling in 1934, phenylketonuria (PKU) has been the subject of numerous research studies spanning many disciplines including human genetics, biochemistry, development, neurobiology and others. During the last 75 years, different mutations in the genes responsible for the disease have been mapped, the biochemical basis has been elucidated and the flawed mechanisms leading to the clinical outcome have been revealed. Moreover, the newborn screening programs based on the Guthrie test and the subsequent biochemical analysis in newborn children, in addition to the low-protein diet, have all made a tremendous impact on the way inherited inborn errors of metabolism have been looked upon in these modern times. In fact, this simple yet most effective treatment for PKU – the low-protein diet – is considered a breakthrough in treatment of the disease enabling the retention of low levels of phenylalanine in the blood, thus preventing the high and persistent phenylalanine levels from damaging normal brain development.
However, despite the simplicity and high effectiveness of the low-protein diet treatment, the incompliance of some PKU patients and the consequences that are associated with it have led scientists to constantly seek new and alternative methods for treatment. In this review, we discuss major advances in PKU therapy, including suggested new cures. We remain optimistic that one or more of the potential cures reviewed here will evolve into future medications for PKU patients.
Phenylketonuria (PKU) is an inborn error of metabolism involving a deficiency of the enzyme phenylalanine hydroxylase. This condition results in elevated levels of phenylalanine and low levels of tyrosine. If left untreated, severe neuropathology and neurobehavioral sequelae manifest. The implementation of newborn screening and early dietary treatment has significantly reduced such morbidity. Despite relatively preserved general intellectual functioning, in early-treated PKU individuals subtle cognitive and behavioral deficits are still apparent. This paper provides a review of the evidence for impairment in information processing, executive function, memory and learning, academic achievement and behavior. This paper also reviews the two primary theories proposed to date relating to the underlying mechanisms for the cognitive and behavioral deficits encountered in treated PKU patients, namely prefrontal dysfunction and white matter abnormalities. Although more research is required, the literature to date suggests that early-treated PKU individuals are at risk of subtle neurobehavioral deficits across a range of neuropsychological domains. Thus, PKU patients should be closely monitored so that problems are detected early and appropriate interventions are put in place to ensure that individuals reach their full potential.