A European Multicenter Study of Phenylalanine Hydroxylase Deficiency: Classification of 105 Mutations and a General System for Genotype-Based Prediction of Metabolic Phenotype

Abstract

Phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). Previous studies have suggested that the highly variable metabolic phenotypes of PAH deficiency correlate with PAH genotypes. We identified both causative mutations in 686 patients from seven European centers. On the basis of the phenotypic characteristics of 297 functionally hemizygous patients, 105 of the mutations were assigned to one of four arbitrary phenotype categories. We proposed and tested a simple model for correlation between genotype and phenotypic outcome. The observed phenotype matched the predicted phenotype in 79% of the cases, and in only 5 of 184 patients was the observed phenotype more than one category away from that expected. Among the seven contributing centers, the proportion of patients for whom the observed phenotype did not match the predicted phenotype was 4%-23% (P<.0001), suggesting that differences in methods used for mutation detection or phenotype classification may account for a considerable proportion of genotype-phenotype inconsistencies. Our data indicate that the PAH-mutation genotype is the main determinant of metabolic phenotype in most patients with PAH deficiency. In the present study, the classification of 105 PAH mutations may allow the prediction of the biochemical phenotype in >10,000 genotypes, which may be useful for the management of hyperphenylalaninemia in newborns.

Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies

“…In contrast to its proven scientific value, the test has only limited value for the dietetic treatment of patients with classic and mild PKU because the Phe 72 value will not predict the current and future individual dietary requirements (see below) and the patients may manifest during the test signs of intoxication such as nausea, vomiting, irritability, insomnia and EEG changes. The test is no longer necessary [37] and has been replaced in practice by predictive molecular and enzymatic classifications [22,38]. A recent online survey accordingly revealed that only 4% of centers still use it for estimating the phenotype of their patients [23].…”

“…More precisely, PAH deficiency may be classified into four different phenotypes: classic PKU presenting with Phe pretreatment levels N1200 μmol/L, moderate PKU with Phe pretreatment levels of 900-1200 μmol/L, mild PKU with Phe pretreatment levels of 600-900 μmol/L, and mild HPA with Phe pretreatment level b600 μmol/L [38,39].…”

“…Three different phenotypes may be classified by using Phe tolerance: classic PKU with a Phe tolerance b20 mg/kg/day, variant PKU with a Phe tolerance of 20-50 mg/kg/day, and mild HPA with a Phe tolerance N50 mg/kg/day [29]. More detailed is the classification into four different phenotypes, who defines classic PKU with a Phe tolerance b20 mg/kg/day (250-300 mg/day), moderate PKU with a Phe tolerance of 20-25 mg/kg/day (350-400 mg/day), mild PKU with a Phe tolerance of 25-50 mg/kg/ day (400-600 mg/day), and mild HPA with patients off diet [38,39].…”

“…[38] reported the identification of the complete genotype in 686 patients from 7 European centers. Based on the Phe tolerance (or in the case of mild HPA the pretreatment level) of 297 functionally hemizygous patients (patients carrying a null allele and the uncharacterized mutant allele), an arbitrary phenotype category was assigned to each of 105 mutations for which the residual enzyme activity was not known.…”

Mutational spectrum in German patients with phenylalanine hydroxylase deficiency

“…The most common Turkish mutations, L48S and IVS10-11G>A, were present on 1.5 % and 2.6 % of German PKU chromosomes in Southern Germany and on 3. Clinical severity :"assigned value" (AV) of individual mutations (Guldberg et al, 1998 Clinical severity :"assigned value" (AV) of individual mutations (Guldberg et al 1998). AV=1, mutations causing severe PKU; AV=2, mutations causing moderate PKU; AV=4, mutations causing mild PKU; AV=8; mutations causing MHP 1 Other mutations that were found on single chromosomes (relative frequency 1.3 %): IVS4+5G>T, IVS4-5C>G, R241H, R243L, A300S, T380M, V388M, R408W, IVS12+1G>A. a Novel mutation.…”