Can untreated PKU patients escape from intellectual disability? A systematic review

Abstract

BackgroundPhenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients.MethodsTo this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 μmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers.ResultsIn total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms.ConclusionsBased on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0890-7) contains supplementary material, which is available to authorized users.

A policy Analysis of Phenylketonuria Screening National Program in Iran

“…Nowadays, most developed countries carry out PKU screening, and any newborn with PKU is immediately exposed to a Phe-restricted diet to lower plasma Phe concentrations. This combination of early diagnosis and initiation of treatment results in normal IQ for most PKU patients (10).…”

A porcine model of phenylketonuria generated by CRISPR/Cas9 genome editing

“…Finally, there may be other genetic factors affecting CNS Phe metabolism or transport that are protective in the pig. Intriguingly, there are late-diagnosed and untreated PAH-deficient individuals who are refractory to HPA neurotoxicity and are not intellectually disabled ( 65 , 66 ). Comparative genomic analysis between pigs and humans could be used to assess candidate genes controlling this putative protective effect.…”

Cognitive Outcomes and Relationships with Phenylalanine in Phenylketonuria: A Comparison between Italian and English Adult Samples

“…While Phe may be particularly toxic for developing brains, we need evidence of the safety of accumulating high Phe levels on aging brains. Finally, it is important to understand whether some individuals are less affected by high Phe since there is some evidence of individual variation [ 6 , 22 , 23 , 24 ]. For a few people with PKU, it may be less important to keep on a strict diet.…”