Can untreated PKU patients escape from intellectual disability? A systematic review
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REVIEW
Open Access
Can untreated PKU patients escape from intellectual disability? A systematic review Danique van Vliet1, Annemiek M. J. van Wegberg1,2, Kirsten Ahring3, Miroslaw Bik-Multanowski4, Nenad Blau5, Fatma D. Bulut6, Kari Casas7, Bozena Didycz4, Maja Djordjevic8, Antonio Federico9, François Feillet10, Maria Gizewska11, Gwendolyn Gramer12, Jozef L. Hertecant13, Carla E. M. Hollak14, Jens V. Jørgensen15, Daniela Karall16, Yuval Landau17, Vincenzo Leuzzi18, Per Mathisen19, Kathryn Moseley20, Neslihan Ö. Mungan6, Francesca Nardecchia18, Katrin Õunap21, Kimberly K. Powell22, Radha Ramachandran23, Frank Rutsch24, Aria Setoodeh25, Maja Stojiljkovic26, Fritz K. Trefz5, Natalia Usurelu27, Callum Wilson28, Clara D. van Karnebeek29,30, William B. Hanley31 and Francjan J. van Spronsen1*
Abstract Background: Phenylketonuria (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. Methods: To 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. Results: In 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. Conclusions: Based 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. Keywords: Phenylketonuria, Phenylalanine, Late-diagnosed, Untreated, Brain vulnerability, Intellectual disability
Background Phenylketonuria (PKU; OMIM 261600) is an inborn error of metabolism, characterized by impaired activity of the hepatic enzyme phenylalanine hydroxylase (PAH; EC 1.14.16.1) that normally converts phenylalanine (Phe) to tyrosine. Since the discovery of increased plasma Phe concentrations (hyperphenylalaninemia) as the underlying * Corr
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