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Presentation

History

Most individuals with phenylketonuria (PKU) appear normal at birth. If an affected patient does not undergo newborn screening or has false-negative results (rare), progressive developmental delay is the most common presentation. Other findings in untreated children in later infancy and childhood may include vomiting, mousy odor, eczema, seizures, self-mutilation, and severe behavioral disorders.

The cohort of patients identified in the early days of newborn screening were begun on diet modification as neonates and continued on that diet until they were school-aged and were then generally transitioned to a normal diet. While these patients escaped the most severe manifestations of PKU, many described poor focus and deteriorating cognitive skills. Those same individuals who ceased dietary treatment in childhood may also have evidence of white matter changes visible on magnetic resonance imaging (MRI), and those patients may experience an intelligence quotient (IQ) decline of 10 points or more.

Physical Examination

The clinical manifestations of PKU are largely of historical interest, because the damaging features of the disease are virtually always prevented through early diagnosis and treatment. Skin findings are as follows:

Fair skin and hair – This is the most characteristic skin manifestation, resulting from impairment of melanin synthesis; it can be striking in Black and Japanese patients, although not all untreated patients are fair, and treated patients often have typical pigmentation

Fair skin and hair resulting from impairment of melanin synthesis.
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Eczema (including atopic dermatitis)
Light sensitivity
Increased incidence of pyogenic infections
Increased incidence of keratosis pilaris
Decreased number of pigmented nevi
Sclerodermalike plaques
Hair loss^[1]

Other manifestations of untreated PKU are as follows:

Intellectual disability (the most common finding overall)
Musty or mousy odor
Epilepsy (50%)^[2]
Extrapyramidal manifestations (eg, parkinsonism)
Eye abnormalities (eg, hypopigmentation)

Complications

Subtle attention and performance deficits in organization and planning persist in treated patients. These deficits are in some cases related to phenylalanine levels and may interfere with academic achievement.

The incidence of neuropsychiatric disease in PKU appears to be higher than in the general population and includes increased risk of depression, anxiety, and inattention, among others. It has been shown that these symptoms are exacerbated by high phenylalanine levels and improved by lower phenylalanine levels. These findings underscore the need for lifelong diet maintenance.^[18]

Differential Diagnoses

Martynyuk AE, Ucar DA, Yang DD, et al. Epilepsy in phenylketonuria: a complex dependence on serum phenylalanine levels. Epilepsia. 2007 Jun. 48(6):1143-50. [QxMD MEDLINE Link].
Cleary MA, Walter JH, Wraith JE, et al. Magnetic resonance imaging of the brain in phenylketonuria. Lancet. 1994 Jul 9. 344(8915):87-90. [QxMD MEDLINE Link].
Hood A, Antenor-Dorsey JA, Rutlin J, Hershey T, Shimony JS, McKinstry RC, et al. Prolonged exposure to high and variable phenylalanine levels over the lifetime predicts brain white matter integrity in children with phenylketonuria. Mol Genet Metab. 2015 Jan. 114 (1):19-24. [QxMD MEDLINE Link].
Sarkissian CN, Gámez A, Scriver CR. What we know that could influence future treatment of phenylketonuria. J Inherit Metab Dis. 2009 Feb. 32(1):3-9. [QxMD MEDLINE Link].
Yannicelli S, Ryan A. Improvements in behaviour and physical manifestations in previously untreated adults with phenylketonuria using a phenylalanine-restricted diet: a national survey. J Inherit Metab Dis. 1995. 18(2):131-4. [QxMD MEDLINE Link].
Brooks, M. FDA OKs Novel Enzyme Therapy for Rare Disease Phenylketonuria. Medscape Medical News. 2018 May 25. Available at https://www.medscape.com/viewarticle/897246.
Burton BK, Grange DK, Milanowski A, et al. The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. J Inherit Metab Dis. 2007 Oct. 30(5):700-7. [QxMD MEDLINE Link].
[Guideline] Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014 Feb. 16 (2):188-200. [QxMD MEDLINE Link].
Donati A, Vincenzi C, Tosti A. Acute hair loss in phenylketonuria. J Eur Acad Dermatol Venereol. 2009 May. 23(5):613-5. [QxMD MEDLINE Link].
Santos LL, Castro-Magalhaes M, Fonseca CG, et al. PKU in Minas Gerais State, Brazil: mutation analysis. Ann Hum Genet. 2008 Nov. 72:774-9. [QxMD MEDLINE Link].
Stojiljkovic M, Jovanovic J, Djordjevic M, et al. Molecular and phenotypic characteristics of patients with phenylketonuria in Serbia and Montenegro. Clin Genet. 2006 Aug. 70(2):151-5. [QxMD MEDLINE Link].
Guldberg P, Henriksen KF, Sipila I, Guttler F, de la Chapelle A. Phenylketonuria in a low incidence population: molecular characterisation of mutations in Finland. J Med Genet. 1995 Dec. 32(12):976-8. [QxMD MEDLINE Link]. [Full Text].
Williams RA, Mamotte CD, Burnett JR. Phenylketonuria: an inborn error of phenylalanine metabolism. Clin Biochem Rev. 2008 Feb. 29(1):31-41. [QxMD MEDLINE Link]. [Full Text].
Bosch AM, Tybout W, van Spronsen FJ, de Valk HW, Wijburg FA, Grootenhuis MA. The course of life and quality of life of early and continuously treated Dutch patients with phenylketonuria. J Inherit Metab Dis. 2007 Feb. 30(1):29-34. [QxMD MEDLINE Link].
Macdonald A, Davies P, Daly A, et al. Does maternal knowledge and parent education affect blood phenylalanine control in phenylketonuria?. J Hum Nutr Diet. 2008 Aug. 21(4):351-8. [QxMD MEDLINE Link].
Bilder DA, Kobori JA, Cohen-Pfeffer JL, Johnson EM, Jurecki ER, Grant ML. Neuropsychiatric comorbidities in adults with phenylketonuria: A retrospective cohort study. Mol Genet Metab. 2017 Mar 6. [QxMD MEDLINE Link].
Lee PJ, Ridout D, Walter JH, Cockburn F. Maternal phenylketonuria: report from the United Kingdom Registry 1978-97. Arch Dis Child. 2005 Feb. 90(2):143-6. [QxMD MEDLINE Link]. [Full Text].
Bilder DA, Noel JK, Baker ER, Irish W, Chen Y, Merilainen MJ, et al. Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria. Dev Neuropsychol. 2016 May-Jun. 41 (4):245-260. [QxMD MEDLINE Link].
Vernon HJ, Koerner CB, Johnson MR, Bergner A, Hamosh A. Introduction of sapropterin dihydrochloride as standard of care in patients with phenylketonuria. Mol Genet Metab. 2010 Jul. 100(3):229-33. [QxMD MEDLINE Link]. [Full Text].
Ho G, Christodoulou J. Phenylketonuria: translating research into novel therapies. Transl Pediatr. 2014 Apr. 3 (2):49-62. [QxMD MEDLINE Link].
Bekhof J, van Rijn M, Sauer PJ, Ten Vergert EM, Reijngoud DJ, van Spronsen FJ. Plasma phenylalanine in patients with phenylketonuria self-managing their diet. Arch Dis Child. 2005 Feb. 90(2):163-4. [QxMD MEDLINE Link]. [Full Text].
Sarkissian CN, Gamez A, Wang L, et al. Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria. Proc Natl Acad Sci U S A. 2008 Dec 30. 105(52):20894-9. [QxMD MEDLINE Link]. [Full Text].
Thomas J, Levy H, Amato S, Vockley J, Zori R, Dimmock D, et al. Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM). Mol Genet Metab. 2018 May. 124 (1):27-38. [QxMD MEDLINE Link]. [Full Text].
Burton BK, Northrup H, Zori R. Efficacy and safety of pegvaliase 60 mg dose in adult patients with phenylketonuria. J Inherit Metab Dis. 2019. 42 (suppl 1):102.
Pietz J, Kreis R, Rupp A, et al. Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest. 1999 Apr. 103(8):1169-78. [QxMD MEDLINE Link]. [Full Text].
Maillot F, Lilburn M, Baudin J, Morley DW, Lee PJ. Factors influencing outcomes in the offspring of mothers with phenylketonuria during pregnancy: the importance of variation in maternal blood phenylalanine. Am J Clin Nutr. 2008 Sep. 88(3):700-5. [QxMD MEDLINE Link].
Waisbren SE, Noel K, Fahrbach K, et al. Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab. 2007 Sep-Oct. 92(1-2):63-70. [QxMD MEDLINE Link].
Bell SM, Wendt DJ, Zhang Y, Taylor TW, Long S, Tsuruda L, et al. Formulation and PEGylation optimization of the therapeutic PEGylated phenylalanine ammonia lyase for the treatment of phenylketonuria. PLoS One. 2017. 12 (3):e0173269. [QxMD MEDLINE Link].
Ounap K, Lillevali H, Metspalu A, Lipping-Sitska M. Development of the phenylketonuria screening programme in Estonia. J Med Screen. 1998. 5(1):22-3. [QxMD MEDLINE Link].
Brooks M. Sapropterin Can Be Effective Long-Term in PKU. Medscape. May 24 2013. Available at http://www.medscape.com/viewarticle/804730. Accessed: June 12, 2013.
Keil S, Anjema K, van Spronsen FJ, Lambruschini N, Burlina A, Bélanger-Quintana A, et al. Long-term Follow-up and Outcome of Phenylketonuria Patients on Sapropterin: A Retrospective Study. Pediatrics. 2013 Jun. 131(6):e1881-8. [QxMD MEDLINE Link].

Media Gallery

Phenylalanine hydroxylase converts phenylalanine to tyrosine.
Fair skin and hair resulting from impairment of melanin synthesis.

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Author

Eric T Rush, MD, FAAP Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Clinical Geneticist, Children's Mercy Hospital of Kansas City

Eric T Rush, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion Pharmaceuticals, Ultragenyx Pharmaceutical, Biomarin Pharmaceuticals, ObsEva, Inozyme Pharma, Ascendis Pharma Serve(d) as a speaker or a member of a speakers bureau for: Alexion Pharmaceuticals, Ultragenyx Pharmaceutical, and Biomarin Pharmaceuticals Received research grant from: Alexion Pharmaceuticals, Ultragenyx Pharmaceuticals.

Chief Editor

Luis O Rohena, MD, PhD, FAAP, FACMG Deputy Chief, Department of Pediatrics, Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD, PhD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Georgianne L Arnold, MD Faculty, Department of Pediatrics, Divison of Genetics, University of Pittsburgh School of Medicine

Georgianne L Arnold, MD is a member of the following medical societies: American College of Medical Genetics and Genomics, Society for Inherited Metabolic Disorders, Society for the Study of Inborn Errors of Metabolism, American Society of Human Genetics

Disclosure: Received grant/research funds from Biomarin for clinical trial.

Robert D Steiner, MD, FAAP, FACMG Professor (Clinical), Department of Pediatrics, University of Wisconsin School of Medicine and Public Health; Editor-in-Chief, Genetics in Medicine; Chief Medical Officer, PreventionGenetics

Robert D Steiner, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: PreventionGenetics, ACMG, Acer Therapeutics, Biomarin; Best Doctors, Health Advances, Precision for Health, PTC Therapeutics, CTX Alliance, Aeglea, Eton, Leadiant Serve(d) as a speaker or a member of a speakers bureau for: France Foundation, Medscape Received research grant from: Alexion Received income in an amount equal to or greater than $250 from: Marshfield Clinic, France Foundation, Medscape, PreventionGenetics, ACMG, Acer Therapeutics; Raptor, Retrophin/Travere, Censa; Biomarin; Best Doctors, Health Advances, Precision for Health, PTC Therapeutics, Aeglea, Leadiant Travel Support for: CTX Alliance.

Acknowledgements

David F Butler, MD Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Mark A Crowe, MD Assistant Clinical Instructor, Department of Medicine, Division of Dermatology, University of Washington School of Medicine

Mark A Crowe, MD is a member of the following medical societies: American Academy of Dermatology and North American Clinical Dermatologic Society

Disclosure: Nothing to disclose.

William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System

William D James, MD is a member of the following medical societies: American Academy of Dermatology, and the Society for Investigative Dermatology.

Disclosure: Royalty from Elselvier.

Djordjije Karadaglic, MD, DSc Professor, School of Medicine, University of Podgorica, Podgorica, Montenegro

Djordjije Karadaglic, MD, DSc is a member of the following medical societies: American Academy of Dermatology, European Academy of Dermatology and Venereology, and Serbian Association of DermatoVenereologists

Disclosure: Nothing to disclose

Zeljko P Mijuskovic, MD, PhD Associate Professor of Dermatology, Department of Dermatology and Venereology, Military Medical Academy, Serbia

Zeljko P Mijuskovic, MD, PhD is a member of the following medical societies: European Academy of Dermatology and Venereology, European Society for Dermatological Research, International Society of Dermatology, and Serbian Association of DermatoVenereologists

Disclosure: Nothing to disclose.

Christian J Renner, MD Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Ljubomir Stojanov, MD, PhD Lecturer in Metabolism and Clinical Genetics, University of Belgrade School of Medicine, Serbia

Disclosure: Nothing to disclose.

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Phenylketonuria (PKU) Clinical Presentation

History

Physical Examination

Complications

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