Molecular genetics and diagnosis of phenylketonuria: state of the art

Abstract

Detection of individuals with phenylketonuria (PKU), an autosomal recessively inherited disorder in phenylalanine degradation, is straightforward and efficient due to newborn screening programs. A recent introduction of the pharmacological treatment option emerged rapid development of molecular testing. However, variants responsible for PKU do not all suppress enzyme activity to the same extent. A spectrum of over 850 variants, gives rise to a continuum of hyperphenylalaninemia from very mild, requiring no intervention, to severe classical PKU, requiring urgent intervention. Locus-specific and genotypes database are today an invaluable resource of information for more efficient classification and management of patients. The high-tech molecular methods allow patients’ genotype to be obtained in a few days, especially if each laboratory develops a panel for the most frequent variants in the corresponding population.

Keywords::

• BH4
• hyperphenylalaninemia
• kuvan
• PKU
• tetrahydrobiopterin

Financial & competing interests disclosure

This work is part of the RD-CONNECT initiative and was supported by the FP7-HEALTH-2012-INNOVATION-1 EU Grant No. 305444 (to NB). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Advances made over the past 10–20 years in basic science led to new treatments of clinically proven benefit for phenylketonuria patients.

• The dried blood spots showed highly specific and accurate results for both biochemical and molecular testing of patients with hyperphenylalaninemias.

• A large number of variants (>850), many being private, urged establishment of locus-specific and genotype databases and development of new techniques for the molecular diagnosis of phenylketonuria.

• Increasing number of online available tools for variant-severity and protein damage analysis enabled investigation of the genotype–phenotype correlation by the use of prediction algorithms.

• Next-generation sequencing has emerged as a new technology in molecular laboratory. This technology possesses many advantages: the increased diagnostic sensitivity, the shorter analysis time and lower costs, particularly for a panel of target genes.

Notes