Two adult sisters with untreated phenylketonuria: Strikingly discordant clinical phenotype

Intellectual disability is the cardinal clinical feature of untreated phenylketonuria (PKU). Nevertheless, there are rare individuals with untreated PKU who have had normal or near normal cognition despite having never been treated. We are reporting two adult sisters with untreated PKU who are strikingly discordant in cognition and the studies we conducted to determine whether there is a significant difference between the sisters that might explain the discordancy. The older sister has the expected moderate to severe cognitive disability while the younger sister is intellectually normal having graduated from college and serving as an executive secretary until retirement. Studies that include plasma phenylalanine (Phe) and other amino acids, urine organic acids, phenylalanine hydroxylase (PAH) genotype, in vivo PAH activity, brain MRI, and whole exome sequencing failed to reveal a significant difference between the sisters. The results of published studies comparing cognitively normal and abnormal individuals with untreated PKU also failed to reveal a significant difference with the exception of a single unconfirmed study reporting a lower brain Phe level in three adults with untreated PKU (Moller HE, Weglage J, Wiedermann D, Ullrich K, 1998). It is important to identify and study cognitively normal or near normal individuals with untreated PKU in search of a factor that might explain the discordancy in clinical outcome and lead to a further understanding of pathogenesis in PKU.