Phenylalanine hydroxylase genotype-phenotype associations in the United States: A single center study

Rajabi, Farrah; Rohr, Frances J.; Wessel, Ann; Martell, Leslie; Dobrowolski, Steven F.; Guldberg, Per; Güttler, Flemming; Levy, Harvey L.

doi:10.1016/j.ymgme.2019.09.004

Cited by 12 publications

(13 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The strongest ancestral influence is European, mainly from Germany, Ireland, England, Italy and France 45 , which explains a comparable distribution of PKU variants in the USA and Europe. 46 African Americans have a much lower PKU incidence than Caucasian Americans. 47 It would be of interest to follow up this study with regard to the different rates of growth of major ethnic groups (Caucasian, African-American, Hispanic, Asian).…”

Section: Discussionmentioning

confidence: 97%

The Genetic Landscape and Epidemiology of Phenylketonuria

Hillert

Anikster

Bélanger-Quintana

et al. 2020

The American Journal of Human Genetics

Self Cite

186

173

View full text Add to dashboard Cite

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. 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 c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066−11G>A (IVS10−11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066−11G>A];[1066−11G>A](2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.

show abstract

Section: Discussionmentioning

confidence: 97%

The Genetic Landscape and Epidemiology of Phenylketonuria

Hillert

Anikster

Bélanger-Quintana

et al. 2020

The American Journal of Human Genetics

Self Cite

186

173

View full text Add to dashboard Cite

show abstract

“…Although there is an established correlation between genotype relative to PAH and PKU phenotype, it is not a perfect correlation. Studies focused on genotype-phenotype predictions have consistently predicted a majority of participants' phenotypes based on their genotypes, but there are always discrepancies in the remaining individuals [4][5][6] . Most people who have the same genotype will have the same phenotype.…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

“…In 2008 an oral therapy, sapropterin dihydrochloride (Kuvan, BioMarin Pharmaceuticals), a synthetic form of tetrahydrobiopterin (BH4)a cofactor of PAH, was approved by the FDA 18 . This therapy successfully lowers phe levels in many people who have mild PKU, but it typically does not provide a clinical benefit to people who have more severe, classical PKU 6,18,19 . Several studies have been conducted to measure the impact this therapy had on the quality of life of patients who responded to the medication.…”

Section: Introductionmentioning

confidence: 99%

Psychosocial Impact and Residual Resource Needs Following Institution of Enzyme Substitution Therapy for PKU

et al. 2022

View full text Add to dashboard Cite

“…ca). The detection of PAH variants and the analysis of the correlation between the genotype and clinical phenotype are extremely valuable for genetic counseling, the selection of the most suitable therapeutic options, and prognosis prediction [9][10][11][12][13]. Although several genotype-based methods for phenotype prediction have been applied for this disease, further clarification on their predictive value is required [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Characterization of phenylalanine hydroxylase gene variants and analysis of genotype–phenotype correlation in patients with phenylalanine hydroxylase deficiency from Fujian Province, Southeastern China

et al. 2022

View full text Add to dashboard Cite

Background Phenylalanine hydroxylase deficiency (PAHD) is the most prevalent inherited disorder of amino acid metabolism in China. Its complex phenotype includes many variants and genotypes among different populations. Methods and results In this study, we analyzed the phenylalanine hydroxylase gene (PAH) variants in a cohort of 93 PAHD patients from Fujian Province. We also assessed genotype and phenotype correlation in patients with PAHD. A total of 44 different pathogenic variants were identified, including five novel variants. The three most prevalent variants among all patents were c.158G > A, p.(Arg53His) (18.03%), c.721C > T, p.(Arg241Cys) (14.75%), and c.728G > A, p.(Arg243Gln) (7.65%). The frequency of the c.158G > A, p.(Arg53His) variant was highest in patients with mild hyperphenylalaninemia, whereas the frequency of the c.1197A > T, p.(Val399 =) and c.331C > T, p.(Arg111Ter) variants was highest in patients with classic phenylketonuria. The most abundant genotypes observed in PAHD patients were c.[158G > A];[728G > A], c.[158G > A];[442-1G > A], and c.[158G > A];[721C > T]. Comparing allelic phenotype to genotypic phenotype values yielded fairly accurate predictions of phenotype, with an overall consistency rate was 85.71% for PAHD patients. Conclusions Our study identified a PAH variant spectrum in PAHD patients from Fujian Province, Southeastern China. Quantitative correlation analysis between genotype and phenotype severity is helpful for genetic counseling and management.

show abstract

Phenylalanine hydroxylase genotype-phenotype associations in the United States: A single center study

Cited by 12 publications

References 50 publications

The Genetic Landscape and Epidemiology of Phenylketonuria

The Genetic Landscape and Epidemiology of Phenylketonuria

Psychosocial Impact and Residual Resource Needs Following Institution of Enzyme Substitution Therapy for PKU

Characterization of phenylalanine hydroxylase gene variants and analysis of genotype–phenotype correlation in patients with phenylalanine hydroxylase deficiency from Fujian Province, Southeastern China

Contact Info

Product

Resources

About