Functional disruption of pyrimidine nucleoside transporter CNT1 results in a novel inborn error of metabolism with high excretion of uridine and cytidine.

Genetic defects in the pyrimidine nucleoside transporters of the CNT transporter family have not yet been reported. Metabolic investigations in a patient with infantile afebrile tonic-clonic seizures revealed increased urinary uridine and cytidine excretion. Segregation of this metabolic trait in the family showed the same biochemical phenotype in a healthy older brother of the index. Whole exome sequencing revealed biallelic mutations in SLC28A1 encoding the pyrimidine nucleoside transporter CNT1 in the index and his brother. Both parents and unaffected sibs showed the variant in heterozygous state. The transporter is expressed in the kidneys. Compelling evidence is available for the disrupting effect of the mutation on the transport function thus explaining the increased excretion of the pyrimidine nucleosides. The exome analysis also revealed a pathogenic mutation in PRRT2 in the index, explaining the epilepsy phenotype in infancy. At present, both the index (10 years) and his older brother are asymptomatic. Mutations in SLC28A1 cause a novel inborn error of metabolism that can be explained by the disrupted activity of the pyrimidine nucleoside transporter CNT1. This is the first report describing a defect in the family of CNT concentrative pyrimidine nucleoside transporter proteins encoded by the SLC28 gene family. In all likelihood, the epilepsy phenotype in the index is unrelated to the SLC28A1 defect, as this can be fully explained by the pathogenic PRRT2 variant. Clinical data on more patients are required to prove whether pathogenic mutations in SLC28A1 have any clinical consequences or are to be considered a benign metabolic phenotype.