Phenylketonuria (PKU) emanates from an autosomal recessive deficiency of phenylalanine hydroxylase; an enzyme responsible for converting phenylalanine to a neurotransmitter precursor known as tyrosine.1 Left untreated, PKU can produce irreversible neurological damage to include developmental challenges.1(47) Thus, rapid interventions upon diagnosis is critical to avoid such pathophysiological outcomes. A standard intervention includes avoidance of proteins rich in phenylalanine. However, research has indicated that micronutrient deficiencies can occur from such an approach.1(47)The following will explore the same in greater detail as well as solutions to overcome said nutrient deficits.
During childhood, individuals with PKU consume diets very restricted in protein and must receive supplemental amino acids devoid of phenylalanine.1(48) However, as children with PKU grow up, the brain may become less sensitive to phenylalanine and might have a slightly higher degree of leniency toward foods with protein. However, research has suggested that individuals with PKU still tend to have lower levels of B6 and B12; micronutrients found predominantly in meat and protein sources.1(48) The main sources of B12 is found within poultry, meat, and seafood while B6 is found in beans, meat, poultry, fish, some fruits, and vegetables.1(48) Thus, low animal sources rich in protein can induce said deficiencies.
Low B12 can become problematic because of its role in controlling homocysteine levels. B12 combines with 5-methyl tetrahydrofolate and homocysteine to produce methionine; a substance that serves as an antioxidant and is essential in the synthesis of proteins.2A lack of B12 slows homocysteine turnover thereby increasing levels of homocysteine; excess homocysteine is a contributing factor in the development of atherosclerosis.3 B6 is a micronutrient involved in the metabolism of carbohydrates, fats, proteins, and neutrotransmitters.1(48)Major forms of if B6 in animal tissues include pyridoxine, pyridoxal and pyridoxamine and deficiencies can induce seborrheic dermatitis, weakness, fatigue, neurological problems, and dysregulation of homocysteine metabolism.1(48)3(363)
Solutions to mitigating such micronutrient deficiencies whilst minimizing phenylalanine exposure could include supplementation with B12 and B6. Hvas et al1(48) conducted a study in Denmark whereby individuals with PKU were examined to determine B12 and B6 status. PKU patients in Denmark are registered at the John F. Kennedy Institute enabling researchers to contact them with relative ease. Thus, the researchers contacted PKU patients who were above 17 years of age and, who as adults, ceased to follow the prescribed diet without any supplements of amino acids (26 patients) or received large neutral amino acids in tablets, PreKUnil (67 patients).1(48)The study population was narrowed down to 7 patients who did not receive any supplement and 24 patients who received PreKUnil.1(49)
Symptoms that were considered and tracked from said population included muscle weakness, sensory disturbances, and autonomic abnormalities.1(48-49) Furthermore, all patients in the study filled out food frequency questionnaires to include information on medications and supplements (minerals and vitamins). 31 patients were considered who were on unrestricted diets since adolescent years. The majority of patients received an amino acid supplement without phenylalanine (PreKUnil).
Interestingly, 75% of patients displayed signs of early B12 deficiency as well as increased red blood cell volume (the beginnings of macrocytosis) and at least one neurological sign. Furthermore, 29% of the patients also had increased plasma homocysteine levels; a risk factor for cardiovascular disease that is associated with low B12 and low B6 levels.1(52) However, when compared to patients who took a multivitamin (11 patients) rich in B12/B6, homocysteine levels were significantly lower, suggesting the justification of supplementation among patients with PKU.1(52)
In conclusion, PKU emanates from an autosomal recessive deficiency of phenylalanine hydroxylase; an enzyme responsible for converting phenylalanine to a neurotransmitter precursor known as tyrosine.Left untreated, PKU can produce irreversible neurological damage to include developmental challenges. For individuals on low protein diets and amino acid supplementation without the presence of phenylalanine, it may be beneficial to monitor symptoms of B12/B6 deficiencies and/or have a blood test to measure the same. If deficiencies are found, supplementation with B12 and B6 might be indicated.
References
1. Hvas AM, Nexo E, Nielson JB. Vitamin B12 and vitamin B6 supplementation is needed among adults with phenylketonuria (PKU). J Inherit Metab Dis. 2006;29:47-53. doi:10.1007/s10545-006-0108-3.
2. Zoo F, Gu Q, Li S, et al. Effects of different methionine sources on methionine metabolism in the IPEC-J2 cells. Biomed Res Int. 2019;1-11. doi:https://doi.org/10.1155/2019/5464906.
3. Kenney WL, Wilmore JH, Costill DL. Physiology of Sport and Exercise. 5th ed. Champaign, IL: Human Kinetics; 2012.
-Michael McIsaac