The influence of mutations on enzyme activity and phenylalanine tolerance in phenylalanine hydroxylase deficiency

Abstract

The phenylalanine hydroxylase (PAH) deficiency trait is heterogeneous with a continuum of metabolic phenotypes ranging from classical phenylketonuria (PKU) to mild hyperphenylalaninaemia (MHP). More than 200 mutations in the PAH gene are associated with PAH deficiency. From theoretical considerations or in vitro expression studies each mutation has a particular influence on enzyme activity, which explains the variation in dietary tolerance for phenylalanine (Phe). This paper gives a summary of the effect of each type of mutation on PAH activity and illustrates how the combination of mutations (the genotype) is associated with the Phe tolerance (the metabolic phenotype). Mutations within a population generally include a few prevalent mutations and a high number of rare mutations. The particular distribution of mutations implies that many PAH-deficient patients carry the same mutation combination, enabling the establishment of genotype-phenotype correlations by comparing clinical parameters in patients with identical genotypes. Because certain mutations always cause MHP irrespective of the mutation on the second allele, mutation typing of hyperphenylalaninaemic neonates will differentiate between PKU and MHP. In addition, genotyping will provide a tool for precise diagnosis of the metabolic phenotype of the neonate with PKU and thereby permit earlier implementation of dietary therapy better tailored to each individual patient.

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

“…This distribution is apparently multimodal and the peaks appear to represent classic (a), moderate (b), and mild PKU (c), and mild HPA (d), respectively. These findings can be compared to the classification of Güttler and Guldberg [45] by treating the dietary tolerance at the target Phe level as the equilibrium state of Phe metabolism. In the kinetic model [46] this corresponds to:…”

“…A more detailed separation of the metabolic phenotypes was established by Güttler and Guldberg [45] through estimating Phe tolerance at 5 years of age (see also above). Neither of these systems can, at any age, predict the individual Phe tolerance.…”

Development of Metabolic Phenotype in Phenylketonuria: Evaluation of the Blaskovics Protein Loading Test at 5 Years of Age

“…After description of the 6ML data (Lutz et al 1990;M€ onch et al 1990;Langenbeck et al 2009) and of preliminary results of 5YL (Schmidt et al 1989), we here present for all 5YL study patients the analytical results of phe disposal in blood and of urinary excretion of acidic phe transamination metabolites. Synopsis of the 5YL blood and urine data suggests maturation of phe transamination and/or renal metabolite transport between 6 months and 5 years as the reason for both the predictability of phe tolerance from 2 years on (van Spronsen et al 2009) and reliable classification of PKU/HPA through age 5 phe tolerance data (G€ uttler and Guldberg 1996).…”

Importância do diagnóstico e tratamento da fenilcetonúria

“…20,36 As diferenças na capacidade de metabolização da fenilalanina deram origem a diversos estudos para classificar as variantes da PKU. 13,31,33,36,39,41 Foram identificadas mais de 250 mutações da PAH, e a correlação dos genótipos da PAH e os fenótipos das HPAs/PKU têm sido reportados, ao menos parcialmente, como reflexo do grau de heterogeneidade étnica provida pelas imigrações.…”

“…20,36 As diferenças na capacidade de metabolização da fenilalanina deram origem a diversos estudos para classificar as variantes da PKU. 13,31,33,36,39,41 Foram identificadas mais de 250 mutações da PAH, e a correlação dos genótipos da PAH e os fenótipos das HPAs/PKU têm sido reportados, ao menos parcialmente, como reflexo do grau de heterogeneidade étnica provida pelas imigrações. 33 Burgard et al 13 (1996), na tentativa de estabelecer uma base molecular para explicar a variabilidade metabólica, observaram uma significante correlação entre a atividade residual da enzima e os parâmetros de diagnóstico das hiperfenilalaninemias, por meio do isolamento do cDNA da PAH e da caracterização da maioria das mutações do gene.…”