Diagnosis of Phenylalanine Disorders
“musty” odor, fair skin, hyperactivity, tremors, seizures, eczema, low tyrosine levels, high phenylalanine levels, and microcelphy are all symptoms of which disorder?
phenylketonuria (PKU)
This region of DNA is the binding site for protein complexes and control gene expression.
Promoter
These are specific foods that patients with PKU can eat.
Low protein food - fruits, vegetables, fats, sugars (jams, honey), plant milk, modified low protein foods, and breast milk - if diet is followed by mother
What amino acid is primarily affected in patients with PKU?
Phenylalanine
Following a low protein diet.
In Ashlyn's case, why does she have PKU but her siblings do not?
PKU is autosomal recessive
Ashlyn was defined as being a compound heterozygote, which means...
Her genotype is composed of two different mutations at the same gene locus.
How early should infants with PKU follow a diet?
As soon as possible, within 2 weeks to avoid CNS damage
The most common cause of hyperphenylalanemia is due to a mutation to this enzyme.
phenylalanine hydroxylase (PAH)
This drug turns phenylalanine into trans-cinnamic acid and ammonia.
Palynziq / Pegvaliase
With an infant that tests positive for PKU, how would you conduct your physical assessment?
look for skin rashes/eczema, measure growth, evidence of low melanin production, etc.
Ashlyn, a patient with diagnosed PKU, married a noncarrier and they have a daughter. Her daughter marries a heterozygote for the PKU gene. What are the odds their child will be a carrier?
50%
What are important social things to consider when a diagnosed patient is put on a low-protein diet?
children may struggle with adherence (social sigma), high cost/low availability to modified foods, very high effort and risk of burnout
What cofactor catalyzes the PAH reaction to convert Phe to Tyr (Tetrahydrobiopterin (BH4))
Tetrahydrobiopterin (BH4)
What drug is a synthetic, form of tetrahydrobiopterin (BH4)?
Sapropterin / Kuvan
How are almost all cases of PKU discovered?
through mandated Newborn Screening
One of Ashlyn's mutation was GGA to TGA in codon 272 in exon 7. What is the effect of this mutation?
Early termination and truncated polypeptide length due to nonsense mutation - replacement with TGA which is a stop codon
Early diagnosis and treatment is important in reducing what long-term effects?
development and neurological delays, behavioral/learning disabilities, IQ deficits, seizures, impaired cognitive function, etc.
Neurological effects are seen in patients with PKU. What is happening in the brain of these patients to cause these effects?
Decrease in myelin basic protein of the oligodendrocyte = demyelination = white matter degradation
In a patient with a genetic mutation preventing proper BH4 catalysis, what drug would likely be used?
Sapropterin
What test would you order to confirm a PKU diagnosis, and what would you expect to see in a positive result?
You would order a blood test screening for serum phenylalanine. In a positive diagnosis, we would expect the value to be well above the expected range.
One of Ashlyn's mutation was R158Q mutation (CGG to CAG). What type of mutation is this and what effects does this have?
Missense mutation that affects protein folding due to charge change (positively charged replaced by polar uncharged) which ultimately affects the gene function.
Pegvaliase reduces phenylalanine levels by introducing this, effectively catalyzing the production of ammonia and trans-cinnamic acid from phenylalanine.
phenylalanine ammonia lyase (PAL)