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Description and Cause
Phenylketonuria (PKU) is a metabolic disorder inherited as an autosomal recessive trait. A mutant gene produces a defect in the enzyme phenylalanine hydroxylase (PAH), which prevents the conversion of phenylalanine (an essential amino acid found in protein-containing foods) to tyrosine. Over 400 different mutations of the PAH gene have been identified. The build-up of phenylalanine is toxic to the central nervous system and may cause mental retardation and other serious developmental disabilities if untreated in infancy. PKU is a heterogeneous disorder. Absent or profound deficiency of PAH is associated with high elevations of blood phenylalanine level, while partial deficiency of the PAH enzyme results in non-PKU hyperphenylalaninemia with a less severely elevated blood phenylalanine level. There are also other variant forms of PKU, including biopterin synthesis deficiency.
Maternal PKU (MPKU) is a syndrome occurring in the children of mothers with PKU. It is caused by exposure to toxic levels of phenylalanine in utero. Although these children will not have PKU (unless the father is a carrier or has PKU), they may have abnormalities including mental retardation, microcephaly, intrauterine growth retardation and congenital heart defects, among others.
Children with untreated PKU may appear normal until about age 6 months, and then gradually demonstrate developmental problems. Clinical manifestations of classic, untreated PKU include:
Usually fair-skinned with blond hair and blue eyes or fairer complexion than family members (due to phenylalanine’s role as precursor of melanin).
Vomiting in infancy
*Note: Vitamin B12 deficiency may occur as a result of treatment if diet is not carefully monitored – iron deficiency is a more common problem in this respect.
Behavioral aberrations including:
Clinical symptoms can be prevented or ameliorated through dietary control of blood phenylalanine level. Because phenylalanine is an essential amino acid, blood levels can be controlled by limiting the amount of phenylalanine in the diet. Treatment through phenylalanine-restricted diet includes use of medical foods containing no or small amounts of phenylalnine and modified low-protein products, as well as provision of required amounts of phenylalanine through small amounts of natural protein. Response is monitored through periodic measurement of blood phenylalnine levels in conjunction with analysis of nutritional intake and review of nutrition status. Moreover, it is recommended that the diet be maintained throughout life to prevent later deterioration. However, stopping the diet may result in drops in IQ, learning disabilities, hyperactivity, irritability, tremors, eczema, and personality disorders among others. The diet may not prevent all adverse effects from PKU such as:
Behavioral improvement as well as amelioration of physical manifestations has been reported in previously untreated adults with PKU after introduction of a phenylalanine restricted diet.
Too severe restriction of phenylalanine intake resulting in phenylalnine deficiency, which can occur if blood levels are not properly monitored, may result in:
Clinical manifestations of this syndrome in infants include:
Research shows that the earlier a pregnant woman with PKU initiates a low-phenylalanine diet (keeping blood phenylalanine levels below 6 mg/dl), the higher her chances of having a healthy child. Ideally, the diet and satisfactory metabolic control should begin prior to conception.
These conditions occur at higher rates in individuals with PKU compared to controls.
MEDICAL MANAGEMENT CONSIDERATIONS
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Note: These considerations are in addition to the normal medical care provided to an individual without PKU.
The biggest challenge in PKU is adherence to diet. Treatment plans must address biochemical, nutritional and psychosocial issues.
Infancy or Early Childhood (Birth to 5 years)
Late Childhood (5 to 13 years)
Adolescence and Adulthood (13 years and over)
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Peer-reviewed Journal Articles/Academies
Cerone, R. et al. (1999). Phenylketonuria: diet for life or not? Acta Paediatrica, 88 (6), 664-666.
Koch, R.K. (1999). Issues in Newborn Screening for Phenylketonuria. American Family Physician 60(5), 1462-1466.
Pietz, J. et al. (1998). Metabolic Diseases: Neurological Outcome in Adult Patients with Early-treated Phenylketonuria. European Journal of Pediatrics, 157(10) 824-830.
Pietz, J. (1998). Neurological Aspects of Adult Phenylketonuria. Current Opinion in Neurology, 11(6), 679-88.
Rouse, B. et al. (2000). Maternal Phenylketonuria Syndrome: Congenital Heart Defects, Microcephaly, & Developmental Outcomes. Journal of Pediatrics 136(1), 57-61.
Weglage, J. et al. (1996). Deficits in Selective and Sustained Attention Processes in Early Treated Children with Phenylketonuria—Result of Impaired Frontal Lobe Functions? European Journal of Pediatrics, 155(3), 200-204.
Weglage, J. et al. 1996. Psychosocial Aspects in Phenylketonuria. European Journal of Pediatrics, 155(1), 101-104.
Yannicelli, S., & Ryan, A. (1995). Improvements in Behaviour and Physical Manifestations in Previously Untreated Adults with Phenylketonuria Using a Phenylalanine-Restricted Diet: a National Survey. Journal of Inherited Metabolic Disease, 18(2), 131-134.
Special Interest Groups/Other Publications
Batshaw, M.L., (1997). PKU and Other Inborn Errors of Metabolism. In: Children with Disabilities. (Eds.), M.L. Batshaw, 4th ed., 389-404. Baltimore: Paul H. Brooks.
Bilginsoy, C. et al. (2005) Living with Phenylketonuria: Perspectives of Patients & Their Families. Journal of Inherited Metabolism Disease, 28, 639-649.
Hurley, R.A. (1998). Handbook of Syndromes and Metabolic Disorders: Radiologic and Clinical Manifestations. St. Louis: Mosby-Year Book.
Kelley, R.I., (1996). Metabolic Diseases. In Developmental Disabilities in Infancy and Childhood. (Eds.) A.J. Capute & P.J. Accardo, 2nd ed., Vol I, 113-136. Baltimore: Paul H. Brookes.
National Instihttp://www2.niddk.nih.gov/Research/ScientificAreas/Metabolism/IntegrativeMetabolism/NETD.htmtute of Child Health and Human Development. Inborn Errors of Metabolism. Accessed July 12, 2000.
Rutherford, P.P., Poustie, V.J. (2005). Protein Substitute for children & Adults with Phenylketonuria, The Cochrane Library, 4, 1-10.
University of Washington: PKU Clinic (2006). What is PKU? Retrieved April 17, 2006.
Waisbren, S.E. Phenylketonuria. (1999). In S. Goldstein and C.R. Reynolds, Handbook of Neurodevelopmental and Genetic Disorders in Children, New York: The Guilford Press.
RESOURCES FOR FAMILIES
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National PKU News
Children’s PKU Network (CPN)
March of Dimes Birth Defects Foundation
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Theodore A. Kastner, M.D., M.S.
Mary Ann Lewis, Dr.P.H., R.N., F.A.A.N.
James R. Popplewell, M.D.
Joan M. Reese, M.D., M.P.H.
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This document does not provide advice regarding medical diagnosis or treatment for any individual case, and any opinions or statements contained in this document are not intended to serve as a standard of medical care. Physicians are encouraged to view the considerations presented in this document in light of evolving scientific information. This document is not intended for use by the layperson. Reproduction of this document may be done with proper credit given to California Department of Developmental Services.
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