Leuders_2014_JIMD.Rep_13_101

OBJECTIVE: Identifying phenylalanine hydroxylase (PAH) mutations associated with sapropterin response in phenylketonuria (PKU) would be an advantageous means to determine clinical benefit to sapropterin therapy.
METHODS: Sapropterin response, defined as a >/=30 % reduction in phenylalanine (Phe) levels after a dose of 10 mg/kg/day sapropterin for week one and 20 mg/kg/day for week two in 112 PKU patients aged 4-45 years, was assessed in an outpatient setting. PAH was sequenced in all patients. Mutations were correlated with sapropterin response. Dietary Phe intake was increased over a 6-week period in responsive patients.
RESULTS: Forty-six of 112 patients were sapropterin responsive. Genotypes p.[L48S];[L48S] and p.[Y414C];[Y414C] were always associated with response at a low dose. The mutation Y414C (present on 16 alleles) was most frequently associated with response. Patients with presence of the mutation L48S on at least one allele (12 alleles in 7 patients) always showed response to sapropterin. Responsive patients had a mean Phe tolerance increase of 189 % (range 11-742 %). In the 66 nonresponders, mutations R408W (38 alleles) and IVS12+1G>A (18 alleles) were detected most frequently. Genotypes [IVS12+1G>A];[IVS12+1G>A], p.[L348V];[R408W], p.[P281L];[P281L], p.[R158Q];[R408W], and p.[R261Q];[R408W] were always associated with nonresponse. CONCLUSION: Data from the study contributes to growing evidence of the relationship between PAH genotype and PKU phenotype. In most cases, response to sapropterin therapy cannot be predicted based on the presence of a single mutation on one allele alone, although the complete PAH genotype may help to predict sapropterin responsiveness in PKU patients.