eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Phenylketonuria: Differential Diagnoses & Workup

Author: Georgianne L Arnold, MD, Director of Inherited Metabolic Disorders Clinic, Department of Pediatrics and Genetics, Associate Professor, University of Rochester School of Medicine and Dentistry
Contributor Information and Disclosures

Updated: Feb 13, 2009

Differential Diagnoses

Hyperphenylalaninemia
Tetrahydrobiopterin Deficiency
Tyrosinemia

Other Problems to Be Considered

Liver disease
Other causes of mental retardation
Tyrosinemia type II (Richner-Hanhart syndrome)

Workup

Laboratory Studies

  • Screening for phenylketonuria (PKU) includes the following:
    • Follow up with abnormal newborn screening results in accordance with local regulations.
    • Low-grade elevations of phenylalanine may require repeat screening.
    • More significant elevations may require definitive testing and/or referral to a metabolic treatment facility experienced with phenylketonuria.
    • Late diagnoses are usually made during amino acid analysis of individuals who are developmentally abnormal.
  • A qualified laboratory should measure plasma phenylalanine and tyrosine.
  • A qualified laboratory should perform urine analysis of biopterin and neoptrins in order to rule out defects of biopterin synthesis or recycling.
  • Follow nutritional adequacy on a regular basis because deficiencies of iron, vitamins, selenium, protein, essential fatty acids, and other nutrients have been reported in treated phenylketonuria.

Imaging Studies

  • MRI
    • Cranial MRI studies may be indicated in older individuals who have abandoned the diet and are experiencing deficits in motor or cognitive function.
    • Areas of demyelination are common. These areas appear to be related to both higher phenylalanine levels in the blood and brain and to poorer cognitive outcome.
  • Magnetic resonance spectroscopy (MRS): Preliminary indications suggest that brain phenylalanine levels can be measured by MRS and that these levels may be more predictive of outcome than blood phenylalanine levels. However, this work is done in only a few centers, and some controversy surrounds whether state-of-the-art technology makes it a useful clinical tool.

Procedures

  • Older textbooks and protocols occasionally called for phenylalanine-loading studies to help determine if a child still required phenylalanine restriction after 1 or more years; however, as the treatment range for phenylalanine levels has decreased, these studies generally have been abandoned.

More on Phenylketonuria

Overview: Phenylketonuria
Differential Diagnoses & Workup: Phenylketonuria
Treatment & Medication: Phenylketonuria
Follow-up: Phenylketonuria
Multimedia: Phenylketonuria
References
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References

  1. 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. [Medline].

  2. 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. Oct 2007;30(5):700-7. [Medline].

  3. Schindeler S, Ghosh-Jerath S, Thompson S, et al. The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Mol Genet Metab. May 2007;91(1):48-54. [Medline].

  4. 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. Dec 30 2008;105(52):20894-9. [Medline].

  5. Anderson PJ, Wood SF, Francis DE, et al. Neuropsychological function in children with early-treated phenylketonuria: impact of white matter abnormalities. Dev Med Child Neurol. 2004;46:230-8. [Medline].

  6. Bekhof J, van Spronsen FJ, Crone MR, et al. Influence of knowledge of the disease on metabolic control in phenylketonuria. Eur J Pediatr. Jun 2003;162(6):440-2. [Medline].

  7. Brumm VL, Azen C, Moats RA, et al. Neuropsyhchological outcome of subjects participating in the PKU adult collaborative study: a preliminary review. J Inherit Metab Dis. 2004;27:549-66. [Medline].

  8. Diamond A, Prevor MB, Callender G, Druin DP. Prefrontal cortex cognitive deficits in children treated early and continuously for PKU. Monogr Soc Res Child Dev. 1997;62(4):i-v, 1-208. [Medline].

  9. Fisch RO, Matalon R, Weisberg S, Michals K. Phenylketonuria: current dietary treatment practices in the United States and Canada. J Am Coll Nutr. Apr 1997;16(2):147-51. [Medline].

  10. Matalon R, Michals-Matalon K, Koch R, et al. Response of patients with phenylketonuria in the US to tetrahydrobiopterin. Mol Genet Metab. Dec 2005;86 Suppl 1:S17-21. [Medline].

  11. Scriver CR, Kaufman S, Eisensmith RC. The hyperphenylalaninemias. In: The Metabolic and Molecular Bases of Inherited Disease. Vol 1. 1995:1015-76.

  12. Smith I, Beasley MG, Ades AE. Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. Arch Dis Child. Mar 1991;66(3):311-6. [Medline].

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Further Reading

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Keywords

phenylketonuria, PKU, Folling disease, Folling's disease, hyperphenylalaninemia, phenylalanine hydroxylase deficiency, mental retardation, tetrahydrobiopterin deficiency, malignant phenylketonuria, agoraphobia, developmental delay, mousy odor, seizures, self-mutilation, behavioral disorder

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Contributor Information and Disclosures

Author

Georgianne L Arnold, MD, Director of Inherited Metabolic Disorders Clinic, Department of Pediatrics and Genetics, Associate Professor, University of Rochester School of Medicine and Dentistry
Georgianne L Arnold, MD is a member of the following medical societies: American College of Medical Genetics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, and Society for the Study of Inborn Errors of Metabolism
Disclosure: Biomarin Grant/research funds clinical trial

Medical Editor

Christian J Renner, MD, Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Robert Anthony Saul, MD, Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center
Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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