Molecular Correlations in Phenylketonuria: Mutation Patterns and Corresponding Biochemical and Clinical Phenotypes in a Heterogeneous California Population

Abstract

We studied 133 California phenylketonuria (PKU) patients and one obligate heterozygote to delineate the molecular basis of PKU in a population with greater ethnic diversity than in previous studies, and to determine whether a correlation exists between genotype and clinical phenotype, with the latter defined by both the diagnostic pretreatment blood phenylalanine (PHE) level and cognitive (IQ) test scores. To determine PAH genotypes, we used PCR-mediated amplification, denaturing gradient gel electrophoresis, and direct sequencing on dried whole blood samples. Where possible, mutation severity was defined according to predicted in vitro PAH enzyme activity estimated by using Cos cell expression analysis for a given mutation. We then asked whether mutation severity, as defined by such expression analysis, correlated with pretreatment PHE levels or with IQ test results. A mutation was identified in 236 (88%) of 267 mutant alleles. Seventeen new mutant alleles were found; A47E, T81P, I102T, E182G, T328D, Y343P, K371R, Y387H, A389E, E422K, IVS9nt5, IVS11nt20, delS70, del364-368/del198-220, delF299, delT323, and -1C/T. In striking contrast to a number of studies in other populations, in this study, based on predicted PAH activity, we observed no correlation between mutation severity and pretreatment PHE levels. There was also no correlation between genotype and IQ. We conclude that in samples collected from an ethnically heterogeneous population, there is no correlation of mutation severity with either pretreatment PHE levels or IQ measurement in treated patients. We caution that genetic counseling in PKU should incorporate the notion that prognosis may not be predicted with precision based on mutation analysis in a given patient.

Mutation analysis of the PAH gene in phenylketonuria patients from Rio de Janeiro, Southeast Brazil

“…Homozygosity rate in Rio de Janeiro PKU population revealed a high genetic heterogeneity (j = 0.063), similar to that found in South Portugal (0.059) (Rivera et al, 2011), Galicia (0.054) (Couce et al, 2013), USA (nationwide index of 0.06) (Guldberg et al, 1996), and in California for the European descent subgroup (0.06) (Enns et al, 1999). Nevertheless, considering that the higher the value of j, the more homogeneous the population with respect to the PAH locus, our population was more homogeneous than the PKU population of Spain (0.029) (Aldamiz- Echevarria et al, 2016), and the Hispanic population of California (0.04) (Enns et al, 1999).…”

Genotype‐phenotype correlations and BH4 estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil

“…We found a moderate correlation between predicted PRA and the inverse of pretreatment Phe levels (r = 0.456, n = 80). Earlier work, summarized by Enns et al (1999), also found this correlation. But those authors themselves did not corroborate it.…”

“…Earlier work, summarized by Enns et al. (), also found this correlation. But those authors themselves did not corroborate it.…”

Aspectos clínicos da fenilcetonúria em serviço de referência em triagem neonatal da Bahia

“…O fenótipo bioquímico, estabelecido pela dosagem de Fal ao diagnóstico, nos permite inferir a atividade enzimática residual e, portanto, a resposta à dietoterapia. Entretanto, tal correlação necessita do suporte do conhecimento das mutações causadoras de doença em cada caso, [16][17][18] estudo esse já em andamento neste mesmo Serviço, em parceria com a FIOCRUZ da Bahia.…”