Treatments and Clinical Management of Phenylketonuria

Since PKU’s discovery and subsequent screening and dieting, the occurrence of untreated PKU associated with serious neurological pathologies has drastically decreased. This success has been largely contributed by the successful newborn screening and disease management technique of the Guthrie test. The Guthrie test works by looking at the effect of blood or urine on the growth of Bacillus subtilis on minimal media which is being inhibited by B-2-thienylalanine. If phenylalanine, phenylpyruvic acid, and phenyllactic acid are present in the blood or urine specimen, the inhibition by B-2-thienylalanine will be prevented. This method of phenylalanine testing results in the concentration of these compounds (phenylalanine and its derivatives) in the specimens (Guthrie 1963). The Guthrie test is used still to this day to observe phenylalanine levels in the blood of PKU patients in order to determine the effectiveness of their diet and/or other treatment therapies. Another form of screening that has been useful is genotyping which is coupled with the PAH Mutation Analysis Consortium Database (Nowacki 1997) which has been able to establish exact genotypes of the PAH in order to pinpoint the specific mutation causing the phenotypes. Genotype and phenotype correlations can be made with past patients with that specific phenotype to potentially suggest the severity of the PKU genotype (Vockley 2014). Maternal maintenance of blood phenylalanine levels is crucial for the neurological pathologies of the baby. High maternal phenylalnine levels have been associated with lower IQ of the fetus (Vockley 2014). The screening capabilities have led to the success of the prevented neurological pathologies that have been associated with PKU.

 

Guthrie test that led to a way of treatment management and infant screening of phenylallanine concentrations in the blood.
Guthrie test that led to a way of treatment management and infant screening of phenylallanine concentrations in the blood.

 

There are many different treatment options for PKU. None of them can eliminate the problem completely, but the most effective treatment to date is to eat a low phenylalanine diet (Vockley 2014). It is essential that the diet is started as soon as possible because if the diet is not implemented then there results in the accumulation of phenylalanine in the blood that has been associated with all the pathologies of PKU. The foods below have been demonstrated to make-up the recommended diet of a patient with PKU.

 

Diet for patients with PKU. The diet is a phenylalanine restricted diet.
Diet for patients with PKU. The diet is a phenylalanine restricted diet.

This treatment of a low phenylalanine diet does require a drastic decrease in the amount of protein consumed, which in turn reduces the amount of other essential amino acids from being consumed. Therefore, the doctor and a nutritionist should be utilized in order to make sure the other essential amino acids are getting consumed (Vockley 2014). The second most common treatment for PKU is the administration of Sapropterin dichloride, which is a synthetic version of BH4 or the natural cofactor of PAH. Depending on the PAH mutation, if the PAH mutation is BH4-responsive the administration of Sapropterin has been demonstrated to be effective at increasing PAH activity by acting as a pharmacological chaperone that ensures proper folding of PAH (Gersting 2008). Jaffe et al. (2013) suggest that this small molecule chaperon could help stabilize the ACT:ACT domain interface that is defective by many of the regulatory domain containing PAH mutations.  In BH4-responsive PAH deficiency, this cofactor derivative could potentially help make higher levels of phenylalanine in the blood more tolerable.

 

 

 

Sapropterin is used a pharmocological chaperone which is a synthetic derivative of tetrahydrobiopterin.
Sapropterin is used a pharmocological chaperone which is a synthetic derivative of tetrahydrobiopterin.

For PAH mutations that are unresponsive to the sapropterin treatment or any mutation in the PAH, a new compound that is extremely close to clinical use is the implementation of polyethylene-conjugated phenylalanine ammonia lyase, which has been effective at lowering the concentration of phenylalanine in the blood (Vockley 2014). Phenylalanine ammonia lyase converts phenylalanine to non-toxic metabolite trans-cinnamic acid and trace amounts of ammonia (Sarkissian 2005). This treatment either taken orally or injected can lower phenylalanine concentrations in the blood by the use of this recombinant enzyme, similar to the use of Lactaid for individuals that are lactose intolerant. Another interesting treatment is trying to protect effects of phenylalanine in the brain. PKU patients have been associated with the higher concentrations of phenylalanine in the brain. Large neutral amino acids compete for transport across the blood brain barrier by the use of an amino acid transporter protein. However, when concentrations of the phenylalanine in the blood are high they will outcompete the other amino acids resulting in the accumulation of phenylalanine in the brain (Pietz 1999). Pietz et al. (1999) suggest that long term supplementation of other large neutral amino acids could result in increased competition by other amino acids resulting in the decrease of phenylalanine passing the blood brain barrier and accumulating on the other side. This supplementation could be useful at lower the phenylalanine concentration in the brain which has been associated with hypomyelination and decrease in the production of essential neurotransmitters. The last suggested treatment for PKU is the use of the antioxidant lipoic acid to combat the effects of oxidative stress that has been observed. Phenylalanine has been associated with down regulation and inhibition of essential antioxidant metabolic enzymes as well as the activation of superoxide dismutase. Lipoic acid supplementation has been effective in mice (Moraes 2013) (Moraes 2014).