Investigating the frequency of the G23D mutation causing DHPR deficiency in the Maltese population.

Abstract

Hyperphenylalanenemia (HPA), is the most prevalent disorder caused by an inborn error of amino acid metabolism. In HP A, the circulating phenylalanine levels are elevated and such conditions may arise due to phenylketonuria caused by phenylalanine hydroxylase (P AH) deficiency or due to a defect in the synthesis or recycling of the PAH cofactor 5,6,7,8,tetrahydrobiopterin (BH4). In the Maltese population, no newborns have ever been described with phenylketonuria but 5 male patients have been identified with hyperphenylalanemia due to dihydropteridine reductase (DHPR) deficiency (Smooker, Howells & Cotton, 1993) (de Sanctis et al., 2000). A single mutation, G23D, was identified in these 5 Maltese patients (Farrugia et al., 2007). This mutation involves a G A nucleotide substitution at position 68 in exon 1 of the Quinoid dihydropteridine reductase (QDPR) gene (Wierenga et al., 1986). In this study, the neonatal allele frequency and carrier rate for G23D has been established by high resolution melting point (HRM) analysis and confirmed by restriction enzyme digest. The newly obtained allele frequency is 0.0032 equating to a carrier rate of 0.64%. Although less than reported in previous studies carried out on the Maltese newborn population, this is the same as the frequency reported in 2 adult population cohorts (Zahra, 2009). This allele frequency is still high when compared to the frequency of DHPR deficiency worldwide. The most probable cause for this is a founder effect followed by exponential growth of the Maltese population.