. 2018 Aug 29;13(1):149.

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

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

Danique van Vliet¹, Annemiek M J van Wegberg^{1

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 Karnebeek^{29

30}, William B Hanley³¹, Francjan J van Spronsen³²

Affiliations

¹ University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, 9700, RB, Groningen, The Netherlands.
² Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands.
³ Department of PKU, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark.
⁴ University Children's Hospital, Jagiellonian University, Krakow, Poland.
⁵ Dietmar-Hopp Metabolic Center, University Children's Hospital, Heidelberg, Germany.
⁶ Department of Pediatrics, Cukurova University Faculty of Medicine, Adana, Turkey.
⁷ Medical Genetics, Sanford Health, Fargo, ND, USA.
⁸ Mother and Child Health Care Institute of Serbia Dr Vukan Cupic, School of Medicine, University of Belgrade, Belgrade, Serbia.
⁹ Department of Medical, Surgical and Neurological Sciences, Medical School, University of Siena, Policlinico Santa Maria Alle Scotte, Siena, Italy.
¹⁰ Department of Pediatrics, Hôpital d'Enfants Brabois, CHU Nancy, Vandoeuvre les Nancy, France.
¹¹ Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University, Szczecin, Poland.
¹² Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
¹³ Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates.
¹⁴ Department of Internal Medicine, Division of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands.
¹⁵ Department of Pediatrics, Oslo University Hospital, Oslo, Norway.
¹⁶ Clinic for Pediatrics, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.
¹⁷ Metabolic Disease Unit, Sheba Medical Center, Edmond and Lily Safra Children's Hospital, Tel Aviv, Israel.
¹⁸ Department of Pediatrics, Child Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.
¹⁹ Department of Internal Medicine, Oslo University Hospital, Oslo, Norway.
²⁰ Genetics Division, Department of Pediatrics, Keck School of Medicine, University of Southern California, California, Los Angeles, USA.
²¹ Department of Clinical Genetics, United Laboratories, Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
²² Department of Genetics and Metabolism, Chapel Hill hospital, University of North Carolina, Chapel Hill, USA.
²³ Department of Chemical Pathology and Metabolic Medicine, Guys and St Thomas' Hospitals NHS foundation trust, London, UK.
²⁴ Department of General Pediatrics, Muenster University Children's Hospital, Muenster, Germany.
²⁵ Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran.
²⁶ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
²⁷ Institute of Mother and Child, Centre of Reproductive Health and Medical Genetics, Chisinau, Moldova.
²⁸ Newborn Metabolic Screening Unit, LabPlus, Auckland City Hospital, Auckland, New Zealand.
²⁹ Departments of Pediatrics and Clinical Genetics, Academic Medical Centre, Emma Children's Hospital, Amsterdam, The Netherlands.
³⁰ Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
³¹ Clinical and Biochemical Genetics, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Canada.
³² University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, 9700, RB, Groningen, The Netherlands. f.j.van.spronsen@umcg.nl.

PMID: 30157945
PMCID: PMC6116368
DOI: 10.1186/s13023-018-0890-7

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

Danique van Vliet et al. Orphanet J Rare Dis. 2018.

. 2018 Aug 29;13(1):149.

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

Authors

Affiliations

¹ University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, 9700, RB, Groningen, The Netherlands.
² Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands.
³ Department of PKU, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark.
⁴ University Children's Hospital, Jagiellonian University, Krakow, Poland.
⁵ Dietmar-Hopp Metabolic Center, University Children's Hospital, Heidelberg, Germany.
⁶ Department of Pediatrics, Cukurova University Faculty of Medicine, Adana, Turkey.
⁷ Medical Genetics, Sanford Health, Fargo, ND, USA.
⁸ Mother and Child Health Care Institute of Serbia Dr Vukan Cupic, School of Medicine, University of Belgrade, Belgrade, Serbia.
⁹ Department of Medical, Surgical and Neurological Sciences, Medical School, University of Siena, Policlinico Santa Maria Alle Scotte, Siena, Italy.
¹⁰ Department of Pediatrics, Hôpital d'Enfants Brabois, CHU Nancy, Vandoeuvre les Nancy, France.
¹¹ Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University, Szczecin, Poland.
¹² Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
¹³ Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates.
¹⁴ Department of Internal Medicine, Division of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands.
¹⁵ Department of Pediatrics, Oslo University Hospital, Oslo, Norway.
¹⁶ Clinic for Pediatrics, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.
¹⁷ Metabolic Disease Unit, Sheba Medical Center, Edmond and Lily Safra Children's Hospital, Tel Aviv, Israel.
¹⁸ Department of Pediatrics, Child Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.
¹⁹ Department of Internal Medicine, Oslo University Hospital, Oslo, Norway.
²⁰ Genetics Division, Department of Pediatrics, Keck School of Medicine, University of Southern California, California, Los Angeles, USA.
²¹ Department of Clinical Genetics, United Laboratories, Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
²² Department of Genetics and Metabolism, Chapel Hill hospital, University of North Carolina, Chapel Hill, USA.
²³ Department of Chemical Pathology and Metabolic Medicine, Guys and St Thomas' Hospitals NHS foundation trust, London, UK.
²⁴ Department of General Pediatrics, Muenster University Children's Hospital, Muenster, Germany.
²⁵ Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran.
²⁶ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
²⁷ Institute of Mother and Child, Centre of Reproductive Health and Medical Genetics, Chisinau, Moldova.
²⁸ Newborn Metabolic Screening Unit, LabPlus, Auckland City Hospital, Auckland, New Zealand.
²⁹ Departments of Pediatrics and Clinical Genetics, Academic Medical Centre, Emma Children's Hospital, Amsterdam, The Netherlands.
³⁰ Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
³¹ Clinical and Biochemical Genetics, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Canada.
³² University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, 9700, RB, Groningen, The Netherlands. f.j.van.spronsen@umcg.nl.

PMID: 30157945
PMCID: PMC6116368
DOI: 10.1186/s13023-018-0890-7

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: Brain vulnerability; Intellectual disability; Late-diagnosed; Phenylalanine; Phenylketonuria; Untreated.

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Competing interests

The authors declare that they have no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

**Fig. 1**
Outline of the reviewing process of the systematic literature search as performed by DvV and AMJvW

**Fig. 2**
Schematic picture outlining the hypotheses regarding the possible mechanism (s) underlying the inter-individual differences in brain vulnerability to high plasma Phe concentrations between PKU patients including: 1) a difference in the transport of Phe and other large neutral amino acids across the blood-brain barrier, 2) a difference in the transport of Phe and other large neutral amino acids across membranes of different cell types within the brain, and 3) a difference in the vulnerability of one or more of the intracerebral processes to high brain Phe concentrations

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Ethics approval and consent to participate

Consent for publication

Competing interests

Publisher’s Note

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous