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

Danique van Vliet,
Annemiek M. J. van Wegberg,
Kirsten Ahring,
Miroslaw Bik-Multanowski,
Nenad Blau,
Fatma D. Bulut,
Kari Casas,
Bozena Didycz,
Maja Djordjevic,
Antonio Federico,
François Feillet,
Maria Gizewska,
Gwendolyn Gramer,
Jozef L. Hertecant,
Carla E. M. Hollak,
Jens V. Jørgensen,
Daniela Karall,
Yuval Landau,
Vincenzo Leuzzi,
Per Mathisen,
Kathryn Moseley,
Neslihan Ö. Mungan,
Francesca Nardecchia,
Katrin Õunap,
Kimberly K. Powell,
Radha Ramachandran,
Frank Rutsch,
Aria Setoodeh,
Maja Stojiljkovic,
Fritz K. Trefz,
Natalia Usurelu,
Callum Wilson,
Clara D. van Karnebeek,
William B. Hanley and
Francjan J. van SpronsenEmail author View ORCID ID profile

Orphanet Journal of Rare Diseases201813:149

https://doi.org/10.1186/s13023-018-0890-7

Received: 4 May 2018
Accepted: 12 August 2018
Published: 29 August 2018

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.