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.

Variants of uncertain significance in newborn screening disorders: implications for large-scale genomic sequencing

“…In ACADM, of 32 individuals with a VUS, 23 were found to also have the p.K329E (previously known as p.K304E), which is responsible for more than 50% of pathogenic alleles. 17 In contrast to GALT and ACADM, the most common pathogenic variant in PAH accounts for less than 25% of alleles in the BioPKU database, 19 so it was not unexpected to find that no single PAH pathogenic variant was seen more than three times with a VUS.…”

Mutational spectrum of phenylketonuria in Jiangsu province

“…In addition, the only precise method for determining patient responsiveness to the drug is the BH4 loading test, which is particularly important for patients with only one responder allele and those with new allele variants [14]. In PKU patients, the dosage used for BH4 treatment is 10-20 mg/kg body weight [2], and the price for BH4 is 36.5 USD/100 mg tablet (http://www.drugbank.ca/ drugs/DB00360); therefore, the cost for BH4 treatment is very high. Most of the mild PKU patients are BH4 responsive and have mild symptoms if left untreated; therefore, mainly, the mild PKU patients profit from this expensive treatment who need it the least.…”

“…BH4, a catalytic cofactor for PAH, activates residual PAH activity and partially restores oxidative Phe metabolism in numerous patients with PKU. Blau et al [2] reported that oral BH4 decreased blood Phe levels in patients with PAH deficiency. Whether the patient with PKU is BH4 responsive determines the need to treat him or her using BH4.…”

Genetic Discoveries Highlight Environmental Factors as Key Drivers of Liver Disease

“…Over the last 25 years, more than 950 allelic variations of PAH have been identified, of which 60% are missense mutations, with the remaining consisting of altered splice site and deletion variants (http://www.biopku.org/home/pah/ asp) [10] . Growing evidence supports a genotype-phenotype correlation between allelic variants, enzyme activity and responsiveness to THB.…”

“…Growing evidence supports a genotype-phenotype correlation between allelic variants, enzyme activity and responsiveness to THB. In the near future, highthroughput automated sequencing of PAH will lead to better disease recognition when applied to confirm and refine a diagnosis [10] .…”