Phenylketonuria

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Contents

[edit] Phenylketonuria (PKU)

[edit] General background information

[edit] Mode of inheritance

  • Autosomal recessive
  • Demonstrates allelic heterogeneity
    • >400 known disease causing mutations
  • Demonstrates locus heterogeneity
    • Mutations in PAH, dihydropteridine reductase, and biopterin synthesis can all cause PKU
  • Disease frequency: 1 / 10K
    • Usually compound heterozygotes
  • Carrier frequency: 1 / 50
  • Rare in Japan, Finland
  • African origin

[edit] Single important gene

  • pah
  • pah codes for phenylalanine hydroxylase (PAH)
  • PAH (phenylalanine hydroxylase) converts phenylalanine to tyrosine which is then used or degraded.
  • PAH (phenylalanine hydroxylase) requires BH4 (tetrahydrobiopterin)

[edit] Etiology

  • PKU has multiple etiologies that go along with its locus heterogeneity.
  • We classify the etiologies into primary and secondary.
    • Primary causes of PKU: PAH deficiency (which can be classic PKU or mild-variant PKU)
    • Secondary causes of PKU: BH4 recycling deficiency (called malignant PKU)
      • 1-3% of PKU pts


  • Mutations in the pah (phenylalanine hydroxylase) gene cause a deficiency of converting Phe to Tyr causing Phe levels to reach toxicity.
    • There are over 400 pah mutations that cause phenylketonuria.
    • Phenylketonuria pts are usually compound heterozygotes'
  • At toxic levels, phenylalanine keeps large, neutral amino acids from crossing the BBB.
  • Recall that PKU has locus heterogeneity: mutations (in addition to those at PAH) in dihydropteridine reductase and biopterin synthesis can all cause PKU.
    • These cases are called malignant PKU because it cannot be readily treated with phe restriction.
    • 1-3% of pts
    • Even on low phe diets, pts develop profound neurological problems.
    • Pts with malignant PKU have deficiencies in other enzymes, too, as BH4 is a cofactor for several enzymes:
      • Tyrosine hydroxylase doesn't work: dopamine / epinephrine / norepinephrine deficiencies
      • Tryptophan hydroxylase doesn't work: serotonin deficiency

[edit] Maternal PKU

  • During gestation, a fetus can suffer a PKU disease state if the mother manifests hyperphenylalaninemia (perhaps because she has PKU or a mild variant).
  • Note that in utero exposure to an hyperphenylalanine state affects the feturs regardless of the fetus's genotype.

[edit] Pathogenesis

  • There are severe, moderate, and mild cases.
    • Severe cases have less than 1% PAH activity.
    • Moderate cases have 1-5% PAH activity.
    • Mild cases have >5% PAH activity.

[edit] Phenotypic information

  • Recall that phe at toxic levels inhibits transport of large, neutral aa across the BBB; thus, most symptoms are neurological.
  • Neuro:
    • Developmental delay
    • Microcephaly
    • Severe mental retardation
    • Seizures
    • Autistic-like behavior
  • Integumentary:
    • Pale pigmentation / fair skin
    • Eczema
    • Mousy body / urine odor
      • Due to phenylacetate


  • Maternal PKU (that is, a PKU state experienced in utero) can have different, severe developmental symptoms:
    • mid-facial hypoplasia (think cleft palate)
    • intrauterine and postnatal growth deficiency
    • congenital heart defects
    • microcephaly
    • mental retardation

[edit] Diagnosis

  • PKU, if left to clinical dx, is rarely diagnosed before 6 months of age--only after mental retardation has become obvious.
  • Serum phenylalanine levels can be used to diagnose; levels > 20mg% are diagnostic.
  • Upon a positive newborn screen should prompt an investigation with a ddx of classic PKU, milder variant of PKU, cofactor BH4 deficiency, maternal PKU, and tyrosinemias

[edit] Newborn screen for PKU

  • Neonatal screening is used for PKU
  • Process:
    • Obtain blood sample from baby from 24-48 hours post birth; use a heel stick and blot the blood on the 5 filter-paper dots.
    • Mail to newborn screening lab.
    • If abnormal, the primary care physician is contacted.
    • Repeat blood sampling to confirm the test.
    • Counsel the family.


  • Initially performed with a bacterial inhibition assay (BIA).
  • Now we use tandem mass spectrometry.
  • Newborn screen thresholds are around > 2-4 mg%.
  • Newborn must have 24 hours of protein feeding for proper test performance.
    • This makes sense because in utero and the 24 hours post deliver the baby's serum phe levels will reflect the mother's phe levels.
  • If a newborn is screened before 24 hours, they must be rescreened before two weeks of age.
  • A confirmatory test is done if a screen is positive.

[edit] Treatment

  • The primary treatment approach to PKU is the removal / limitation of phenylalanine from the pt's diet.
    • Pts are allowed 250-500 mg of phenylalanine
    • Avoid nutrasweet (aspartic acid + phe)
  • Regular monitoring assures the pt's phe levels are appropriate.
  • Special commercial formulas are available.
  • The earlier the diet is implemented the better the outcome
    • Diet should be commenced within 2 weeks of birth
    • Commencement within 7 days results in normal growth and development
    • Note that PKU features are all reversible EXCEPT MENTAL RETARDATION
    • Even a late start is good because many symptoms including maternal PKU syndrome are reversed.
  • Diet should be continued indefinitely.
    • Dysmyelination occurs when phe control is lost.
    • A fall in IQ is associated with loss of dietary phe control.


  • Counsel the family.


  • Sapropterine (Kuvan) provides BH4 cofactor
    • Oral treatment is available and relatively new


  • Women with PKU (or mild variants) should be on well controlled diets before conception.
  • It may be difficult to keep the mother's phe levels within normal ranges during pregnancy but efforts should be made.
  • All babies born to an uncontrolled PKU mother will be affected by the hyperphenylalanine state, regardless of the fetus genotype.

[edit] Recent research

[edit] 5 important facts

[edit] Not to be confused with

[edit] Questions and answers

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