Phenylketonuria

From Iusmgenetics

Contents 1 Phenylketonuria (PKU) 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.4.1 Maternal PKU 1.5 Pathogenesis 1.6 Phenotypic information 1.7 Diagnosis 1.7.1 Newborn screen for PKU 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.12 Questions and answers

[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