eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Phenylketonuria
Updated: Feb 13, 2009
Introduction
Background
Phenylketonuria (PKU) is an inborn error of protein metabolism that results from an impaired ability to metabolize the essential amino acid phenylalanine. Classic phenylketonuria is present when plasma phenylalanine levels exceed 20 mg/dL (1200 mmol/L) without treatment. Lesser degrees of elevation of plasma phenylalanine are considered in Hyperphenylalaninemia. Elevated phenylalanine levels negatively impact developmental function, and individuals with classic phenylketonuria almost always have mental retardation unless levels are controlled through dietary treatment. In the United States and many other countries, phenylketonuria is detected by newborn screening, and treated individuals have normal intelligence.
Pathophysiology
Most individuals with phenylketonuria have a deficiency of the enzyme phenylalanine hydroxylase. Phenylalanine hydroxylase deficiency is inherited in an autosomal recessive manner.
The mechanism by which elevated phenylalanine levels cause mental retardation is not known, although restriction of dietary phenylalanine ameliorates this effect if initiated within a few weeks of birth. This also results in normal cognitive development. A strong relationship between control of blood phenylalanine levels in childhood and intelligence quotient (IQ) is recognized. Subtle neuropsychological deficits in children with treated phenylketonuria are under investigation. Some investigators have attributed these deficits to small residual neurotransmitter abnormalities.
A small percentage of children with elevated phenylalanine levels exhibit normal phenylalanine hydroxylase but have a deficiency in synthesis or recycling of the enzyme's cofactor, tetrahydrobiopterin (see Tetrahydrobiopterin Deficiency). This condition is termed malignant phenylketonuria. The biopterin cofactor is also required for hydroxylation of tyrosine (a precursor of dopamine) and tryptophan (a precursor of serotonin). Thus, individuals with tetrahydrobiopterin cofactor deficiency have more significant neurological problems that are not fully corrected by dietary phenylalanine reduction.
Frequency
United States
Incidence of classic phenylketonuria is approximately 1 in 15,000 births.
International
Disease frequency varies by population. Turkey has the highest incidence in the world with approximately 1 in 2600 births. High incidence is also reported in the Yemenite Jewish population, as well as in regions of northern and eastern Europe, Italy, and China.
Mortality/Morbidity
Most untreated individuals with phenylketonuria have severe mental retardation. After the discovery of phenylketonuria, routine testing of institutionalized patients with mental retardation identified a 1% incidence of phenylketonuria in this group. Well-treated patients should have IQs within approximately 5-8 points of their siblings.
Psychological problems, including agoraphobia and other disorders, have been reported in individuals both on and off dietary treatment. Treated patients with phenylketonuria often experience subtle performance and attention and behavioral changes when phenylalanine levels exceed 6 mg/dL.
Race
In the United States, phenylketonuria is most common in whites. Worldwide, phenylketonuria is most common in whites and Asians.
Sex
No sex predilection is known. Women with phenylketonuria must maintain phenylalanine levels between 2-6 mg/dL during pregnancy to avoid birth defects and mental retardation in their infants.
Age
Phenylketonuria is most commonly diagnosed in newborns by newborn screening programs. Consider phenylketonuria at any age in an individual with developmental delay or mental retardation because infants are missed by newborn screening programs on rare occasions.
Clinical
History
- Most individuals with phenylketonuria (PKU) appear normal at birth.
- If newborn screening fails, 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.
- Older individuals who cease dietary treatment in childhood may have evidence of demyelination on MRI. Occasionally, deterioration of cognitive performance or motor skills also may be present.
- Intelligence quotients (IQs) may drop by 10 points or more if the diet is stopped in mid childhood.
Physical
- The most common finding of untreated phenylketonuria is mental retardation.
- The physician also may identify the following:
- Mousy odor
- Eczema
- Fair coloring as a result of tyrosine deficiency
Causes
- Phenylketonuria is caused by autosomal recessive inheritance due to mutations in the enzyme phenylalanine hydroxylase. The enzyme locus is on chromosome arm 12q. More than 100 mutations are known, and mutation frequency varies among ethnic groups.
- Genotype and phenotype are broadly related (ie, reproducible mild vs severe mutations), but unrelated individuals with identical mutations have some degree of variability in phenylalanine tolerance.
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| Multimedia: Phenylketonuria |
| References |
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References
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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].
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].
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].
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Further Reading
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
