A limited spectrum of phenylalanine hydroxylase mutations is observed in phenylketonuria patients in western Poland and implications for treatment with 6R tetrahydrobiopterin

Abstract

Phenylketonuria (PKU) is an autosomal recessive defect in hepatic metabolism of phenylalanine, which is secondary to mutations in the phenylalanine hydroxylase (PAH) gene. Sixty-seven ethnically Polish PKU patients, followed at the Outpatient Department of Pediatrics and Developmental Medicine in Poznan, Poland, were assessed for mutations in the PAH gene. Two mutations were identified in 61 of 67 patients and a single mutation was identified in the remaining six patients. The four most prevalent mutations (p.R408W, 68%; c.1066-11G4A, 6%; c.1315+1G4A, 5.2%; c.822-832delGCCCATGTATA, 3.7%) accounted for 83% of the mutant alleles. Fifteen additional mutations were identified of which most (13/15) were observed in an individual patient. Before knowledge of PAH genotypes, 19 patients were challenged with a 20 mg kg À1 dose of 6R tetrahydrobiopterin (BH 4 ) and serum phenylalanine concentration was monitored in hospital over 24 h. Two patients responded to the BH 4 challenge with a reduction of serum phenylalanine concentration 430% from baseline. PAH genotypes of the two responsive patients uld have been predicted, as they contained mutations recognized as BH 4 responsive, whereas the 17 patients who were unresponsive would have been predicted as their mutations were either recognized as non-responsive or were highly deleterious frame-shift mutations. Overall, only 7.5% (5/ 67) of patients had PAH mutations recognized as responsive to co-factor therapy. Among the PKU patients from western Poland, PAH mutations responsive to BH 4 therapy are poorly represented; therefore, genotyping may be useful for identifying candidate patients likely to respond to BH 4 before physiological challenge.

A preliminary mutation analysis of phenylketonuria in southwest Iran

“…Therefore, PKU represents the epitome of human biochemical genetics for the paradigm of a treatable genetic disorder (Scriver and Waters, 1999;Dobrowolski et al, 2009;Antshel, 2010;Harding and Blau, 2010). PAH mutation analysis has utility in evaluating the clinical phenotype of PKU, for genetic consultation of patients' families, prenatal diagnosis, carrier detection, and also in refining diagnoses and anticipating dietary requirements (Guldberg et al, 1998;Güttler and Guldberg, 2000;Dobrowolski et al, 2007Dobrowolski et al, , 2009. Many BH4-responsive mutations have been identified in various studies, and it has been estimated that more than 30% of all HPA patients respond to BH4, thus revealing that identification of PAH mutations could be useful for BH4-based therapies (Zurflüh et al, 2008;Staudigl et al, 2011).…”

Molecular epidemiology and genotype–phenotype correlation in phenylketonuria patients from South Spain

“…6,7 Genotype-phenotype correlations have been extensively analyzed revealing they can be a strong and reliable predictive tool. 7,[8][9][10] Accordingly, depending on the specific genotype, a better-tailored diet and the potential BH4 responsiveness can be established. Almost 1200 genotypes associated with BH4 responsiveness are described and listed in the BIOPKU database (www.biopku.org/biopku).…”

Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing

“…The wide variability of common mutations between ethnic groups and geographical areas makes PAH deficiency a genetic disease of great allelic heterogeneity. Comprehensive catalog of PAH mutation spectrum will be of value to evaluate genotype-phenotype correlations, to provide genetic consultations to patients’ families as well as prenatal diagnosis, and to refine diagnoses in and anticipate the dietary requirements of affected patients 33 34 35 .…”