An Asymptomatic Patient of Phenylketonuria: A Case Report of 2 Siblings

Abstract

: A 6-year-old girl presented to our hospital with a genetic result indicating a homozygous pathogenic variant (c.G898T) in the phenylalanine hydroxylase (PAH) gene and a heterozygote variant (c.94dupT) in the HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) gene. The study was performed due to her brother’s earlier diagnosis of phenylketonuria (PKU) through a genetic analysis (homozygote for PAH). Her 4-year-old brother was also admitted to our hospital with symptoms of hypotonicity, which started at birth and deteriorated when he was 6 months old. He developed a prolonged fever from the age of 8 months until the age of 3 years. All infectious and rheumatologic workups were normal. He was screened for PKU twice at birth, both showing negative results. The plasma phenylalanine (Phe) level was checked several times in the first 2 years of his life, and all of them were in the borderline range (2 - 4 mg/dL). He was tested again at the age of 2 years for the plasma Phe level twice, both showing positive results (14 and 8 mg/dL, respectively). Both positive results for the plasma Phe level led to a genetic study, indicating that this case is homozygote for both variants, c.G898T in the PAH gene and c.94dupT in the HACE1 gene. Then, a Phe-restricted diet was given. At the age of 3 years, a Kuvan test was performed on the patient, indicating a non-BH4-responsive PKU (classic type of PKU). However, to reduce diet restriction, he was treated with Kuvan and responded to the treatment. The symptoms (such as hypotonia and developmental retardation) improved after treatment with Kuvan, probably due to HACE1 gene dysfunction.