Phenylketonuria
From Iusmgenetics
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.
