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PHENYLKETONURIA

Background
Medical Management Considerations
References
Resources for Families
Advisory Committee
Publication Information

Learning Points

  • Restate the occurrence of Phenylketonuria (PKU) in the United States (1:15,000).
  • Recognize that PKU is a metabolic disorder inherited as an autosomal recessive trait (both parents must be PKU carriers).
  • Differentiate between:
    • absent or profound deficiency of PAH (associated with high elevations of blood phenylalanine level);
    • partial deficiency of the PAH enzyme (results in non-PKU hyperphenylalaninemia with a less severely elevated blood phenylalanine level); and,
    • Maternal PKU (a syndrome occurring in the children of mothers with PKU and caused by exposure to toxic levels of phenylalanine in utero).
  • Confirm that all 50 states have newborn screening programs which offer screening for PKU and realize that criteria for diagnosis and follow-up vary from state to state.
  • Acknowledge that the biggest challenge in PKU is adherence to diet.
  • Upon diagnosis of PKU, implement a phenylalanine-restricted diet as soon as possible and in consultation with a metabolic specialist experienced in the treatment of PKU.
  • Describe the issues that treatment plans for patients with PKU should address (e.g., biochemical, nutritional and psychosocial issues).
  • Refer patient/families to appropriate resources on PKU.

BACKGROUND
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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.

Occurrence

  • 1:15,000 in the United States
  • As PKU is an autosomal recessive disorder, both parents must be PKU carriers, and when this occurs, there is a one in four chance of the child having PKU.
  • Approximately one out of 50 people are carriers
  • Boys and girls are equally susceptible to inheriting PKU.
  • The incidence is higher in Caucasians and Native Americans and lower in African Americans, Latinos and Asians.

Diagnosis

  • Prenatal diagnosis using a cloned human phenylalanine hydroxylase gene probe to analyze DNA from cultured amniotic fluid cells (possible for families in which both mutations have been identified)
  • Carrier detection (possible for families in which mutation has been identified)
  • All 50 states have newborn screening programs which offer screening for PKU (most permit parents to refuse screening test) which use either the Guthrie bacterial inhibition assay, fluorometric analysis or tandem mass spectrometry to detect elevated phenylalanine levels. Criteria for diagnosis and follow-up vary from state to state. Other metabolic disorders, including tyrosinemia and disorders of pterin metabolism must be ruled out.

Characteristic Features

PKU

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).

Neurologic symptoms:

  • Mental retardation
  • Poor coordination
  • Tremor
  • Dystonia – abnormal muscle tone of one or more muscles
  • Athetoid movements
  • Hyperactivity
  • Progressive loss of motor function; ataxia
  • Seizures

Other Abnormalities

Vomiting in infancy

  • Unusual odor detected on breath, skin and urine from accumulation of phenylacetic acid
  • Agoraphobia
  • Eczema
  • Abnormal electroencephalograms
  • Vitamin B12 deficiency*

*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:

  • Aggression
  • Self-inflicted injury
  • Impulsivity
  • Hyperactivity
  • Psychosis

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:

  • Lower IQ scores
  • Visual-motor deficits
  • Deficits in executive functioning such as sustaining attention and reaction time

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:

  • Significant growth retardation
  • Lethargy
  • Death

Maternal PKU

Clinical manifestations of this syndrome in infants include:

  • Low birth weight
  • Microcephaly
  • Developmental delay
  • Mental retardation
  • Heart defects
  • Facial dysmorphism
  • Premature closure of cranial sutures

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.

Common Associations

These conditions occur at higher rates in individuals with PKU compared to controls.

  • Attention deficit hyperactivity disorder (ADHD)
  • Learning disabilities
  • Psychiatric problems including depression
  • Childhood autism

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)

  • Refer patient to the nearest PKU treatment center immediately
  • Implementation of phenylalanine restricted diet as soon as possible after birth in consultation with a metabolic specialist experienced in the treatment of PKU
  • Assist family in accessing funding for specialized diet through private insurance or State programs (e.g., CCS or WIC)
  • Refer to psychologist for testing for learning disabilities during preschool years, if clinically indicated

Late Childhood (5 to 13 years)

  • Continue collaboration with treating metabolic center
  • Assist family in accessing funding for specialized diet
  • Monitor visual-motor skills, information processing, arithmetic and reading comprehension
  • Refer to psychologist for testing for learning disabilities if clinically indicated
  • Recommend occupational therapy for children with poor visual-motor skills
  • Refer for neuropsychological testing if there is increasing frequency of problems in executive functioning and attention
  • Monitor communication between parents, psychologist and schools

Adolescence and Adulthood (13 years and over)

  • Encourage maintenance of diet throughout lifetime
  • Educate women about risks and management for maternal PKU, especially avoidance of unplanned pregnancy if not on specialized diet with good control of phenylalanine levels
  • Continue collaboration with treating metabolic center
  • Assist family in accessing funding for specialized diet

REFERENCES
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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
(206) 525-8140
E-mail: schuett@pkunews.org

Children’s PKU Network (CPN)
(858) 509-0767
E-mail: PKUnetwork@aol.com

March of Dimes Birth Defects Foundation
1-800-367-6630

ADVISORY COMMITTEE
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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.

PUBLICATION INFORMATION
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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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