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Phenylketonuria Genotypes Vary With Geography, Disease Severity in International Study

NEW YORK – Using data from existing databases, an international team has mapped the global distribution of variants in the phenylalanine hydroxylase (PAH) gene and how they correspond to more or less severe forms of phenylketonuria (PKU), an inborn errors of amino acid metabolism.

"This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome," co-corresponding authors Nenad Blau and Sven Garbade, researchers at the University Children's Hospital in Heidelberg, Germany, and their colleagues wrote.

As they reported in the American Journal of Human Genetics on Tuesday, Blau, Garbade, and colleagues from Germany, Israel, and other parts of the world started with array-based genotyping data and pre-treatment metabolic test results for almost 16,100 individuals from dozens of countries who had pre-treatment blood metabolite features consistent with classical PKU, mild PKU, or a related condition known as mild hyperphenylalaninemia (MHP).

In addition to efforts to map PKU prevalence in 64 countries based on published data and data provided by screening centers, the researchers used genotyping and phenotyping profiles to track the distribution and frequency of hundreds of PAH variants, identifying distinct genotypes in different populations and parts of the world.

"A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south," the authors wrote, noting that "the distribution of PKU variants across Europe was consistent with successive waves of historical migration."

Generally speaking, the team explained, lower activity of the enzyme PAH leads to enhanced blood levels of phenylalanine, which is normally converted to tyrosine by the hydroxylase. In the absence of treatment and dietary interventions, this can cause symptoms ranging from developmental delays and intellectual disability to seizures, growth, and motor problems.

"Lower residual enzyme activity usually results in higher blood [phenylalanine] concentrations and a more severe clinical phenotype if left untreated," the authors wrote.

With data for 19,092 individuals from 51 countries, the researchers focused in on 758 PAH variants implicated in PKU in the past, identifying compound heterozygous culprits in 72.9 percent of the PKU cases. The remaining 27.1 percent of participants carried homozygous alterations in the PAH gene.

"Compared with severe classic PKU variants, milder variants were much rarer in number but determined the milder metabolic phenotype," the authors reported, noting that "homozygous mild variants have a higher [allelic phenotype value] and thus a milder phenotype when occurring in a compound heterozygous state with a null allele."

Overall, the team noted that more than half of the genotypes they looked at seemed to be exclusive to individual study participants. Even so, an analysis looking at phenylalanine concentrations in the blood and other metabolic features in relation to allelic phenotype value scores for thousands of individuals suggested that it may be possible to accurately predict PKU patients' phenotypes and responsiveness to tetrahydrobiopterin, a cofactor that normally helps the PAH enzyme convert phenylalanine to tyrosine.

Together, the authors suggest, the study "provides an overview of the current distribution of the most important PAH variants and patient genotypes in various world regions. This information, together with [allelic phenotype values], helps to predict the metabolic phenotype and the possible treatment options for PKU subjects."

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