Hyperphenylalaninaemias in Estonia: Genotype–Phenotype Correlation and Comparative Overview of the Patient Cohort Before and After Nation-Wide Neonatal Screening

Abstract

The present study provides a retrospective overview of the cohort of phenylketonuria (PKU) patients in Estonia. Based on the available data, the patients clearly cluster into two distinct groups: the patients with late diagnosis and start of therapy (N = 46), who were born before 1993 when the national newborn screening programme was launched, and the screened babies (N = 48) getting their diagnoses at least in a couple of weeks after birth.Altogether 153 independent phenylalanine hydroxylase (PAH) alleles from 92 patients were analysed in the study, wherein 80% of them were carrying the p.Arg408Trp variation, making the relative frequency of this particular variation one of the highest known. Additionally, 15 other different variations in the PAH gene were identified, each with very low incidence, providing ground for phenotypic variability and potential response to BH therapy. Genealogical analysis revealed some "hotspots" of the origin of the p.Arg408Trp variation, with especially high density in South-East Estonia. According to our data, the incidence of PKU in Estonia is estimated as 1 in 6,700 newborns.

Phenylketonuria in the Latvian population: Molecular basis, phenylalanine levels, and patient compliance

“…Despite this decrease, the p.Arg408Trp variant is still a leading cause of PKU with 49% (50 of 102 unrelated patient) of our PKU patients being homozygous for this mutation. These new data now establish Latvia as having the lowest frequency of the p.Arg408Trp variant of all the Baltic countries (Estonia 80% [ 12 ] and Lithuania 73% [ 8 ]). A recently published study from Russia reported the frequency of this variant to be 50.9%.…”

“…Unidentified PKU causing variants in the PAH gene is also reported in other populations e.g. in Estonia in 2 of 94 patients were not identified none of pathogenic variants and in 2 of 94 patients were not identified second pathogenic variant [ 12 ]. It is proposed that PCR amplification and sequencing of all exons and adjacent introns achieves pathogenic variant detection in case of PKU - > 95–99%, and large deletion/ duplication analysis <0.05% of variants [ 2 ].…”

The evaluation of phenylalanine levels in Estonian phenylketonuria patients during eight years by electronic laboratory records

“…Here we have not isolated the cases where female patients have become pregnant and therefore had stricter regulations of the diet. One reason for the difficulty of maintaining the Phe levels in blood in the observed patients may be the severity of particular PAH mutation, as the p.Arg408Trp variation vastly predominant in Estonian population [ 9 ] completely abolishes PAH activity, if present in homozygous state.…”

“…The initial created database included 4290 entries from 69 patients. All patients were carefully classified by genotype/phenotype data and these results have been previously published [ 9 ]. All data from individuals with initially suspicious samples obtained by newborn screening, but not confirmed with HPA, were excluded, as well as Phe levels confirming the newborn screening results and data obtained from a Phe loading/cofactor tetrahydrobiopterin (BH 4 ) test.…”

“…All data from individuals with initially suspicious samples obtained by newborn screening, but not confirmed with HPA, were excluded, as well as Phe levels confirming the newborn screening results and data obtained from a Phe loading/cofactor tetrahydrobiopterin (BH 4 ) test. The information about BH 4 responsiveness testing has been published earlier [ 9 ]. As the objective of the study was to draw insight into the quality and trajectory of ongoing therapy, nine of the subjects and all of their blood Phe values were excluded from the database due to late diagnosis associated with deep intellectual disability and/or refusal of treatment.…”