Phenylketonuria
Clinical Presentation of Phenylketonuria (PKU)
- Hypopigmentation (of the skin and iris)
- Melanin is a derivative of tyrosine and tyrosine is deficient in PKU.
- Neuropsychiatric disorder (tremor, psychosis, seizures, and cognitive dysfunction)
- Occurs toxic levels of phenylalanine and its derivatives are neurotoxic, this disorder causes
Classic vs Malignant
- Classic PKU – defect in phenylalanine hydroxylase.
- Malignant PKU - defect in dihydrobiopterin reductase, which requires NADPH to convert dihydrobiopterin back to tetrahydrobiopterin.
Pathophysiology: Toxic Metabolites of Phenylalanine
When phenylalanine accumulates at toxic levels, it transaminates into:
- Phenylpyruvate (aka phenyl ketone); hence, "phenylketonuria" describes the presence of phenylpyruvate, phenylalanine, and two key other derivatives in the urine and blood:
- Phenylacetate which has a distinct "musty/mousy odor".
- Phenyllactate.
Phenylalanine Excess / Tyrosine Deficiency
Overall, in phenylketonuria, there is an:
- Excess of phenylalanine
- Deficiency of tyrosine
So the goal of therapy is to reduce phenylalanine intake and to supplement tyrosine deficiency via the diet.
- Remember the sparing action of tyrosine on the requirements of phenylalanine
References
- Calvo, Sherri; Collins, Heather; Greenberg, Kathleen, et. al at US National Library of Medicine, Genetics Home Reference. https://ghr.nlm.nih.gov