Uridine-Cytidineuria

A number sign (#) is used with this entry because of evidence that uridine-cytidineuria (URCTU) is caused by homozygous or compound heterozygous mutations in the SLC28A1 gene (606207) on chromosome 15q25.

Description

Uridine-cytidineuria (URCTU) is an inborn error of metabolism comprising increased excretion of the pyrimidine nucleosides. This condition has been identified incidentally and may be a benign metabolic phenotype (summary by Wevers et al., 2019).

Clinical Features

Wevers et al. (2019) reported a boy born of nonconsanguineous Danish parents of Jordanian descent who underwent a urine metabolic screen while hospitalized with afebrile tonic-clonic seizures; screening detected highly elevated excretion of uridine and cytidine. Analysis of purines and pyrimidines in family members revealed that a healthy older brother also excreted similarly increased amounts of uridine and cytidine. Urinary excretion of other purines and pyrimidines, including adenosine, was normal. Plasma concentrations of all purines and pyrimidines were normal. The seizures in the index patient were thought to be unrelated to the increased urinary uridine and cytidine (see MOLECULAR GENETICS).

Perez-Torras et al. (2019) reported a male child born of nonconsanguineous parents originating from the Dutch Antilles who had persistent strongly elevated urinary excretion of uridine and cytidine. Plasma levels of uridine were normal, and of cytidine only slightly elevated. The patient presented with myoclonia and fever, developed persistent lactate acidosis and severely disturbed liver enzymes, and died of multiorgan failure at 9 weeks of age. The patient was found to have familial hemophagocytic lymphohistiocytosis type 2 (FHL2; 603553) independent of the uridine-cytidineuria.

Molecular Genetics

In 2 brothers with highly elevated urinary excretion of uridine and cytidine, Wevers et al. (2019) detected a homozygous missense mutation in the SLC28A1 gene (S546P; 606207.0001), encoding concentrative nucleoside transporter-1 (CNT1). The mutation affected a conserved residue and had been shown to abolish CNT1 nucleoside transporter function (Cano-Soldado et al., 2012). The mutation segregated with the phenotype in the family. The index patient, who had experienced medication-responsive afebrile tonic-clonic seizures in infancy, was found also to carry a heterozygous mutation in the PRRT2 gene (c.649dup; 614386.0001) that accounted for the seizure phenotype.

In a male infant with uridine-cytidineuria, Perez-Torras et al. (2019) detected compound heterozygosity for 2 missense variants in the SLC28A1 gene, arg510 to cys (R510C; 606207.0002) and arg561 to gln (R561Q; 606207.0003). Functional studies showed that the variants affected the 3-dimensional structure, altered glycosylation, and decreased the half-life of the CNT1 protein. Coexpression of both variants dramatically impaired transport activity. The patient was also compound heterozygous for mutations in the PRF1 gene (e.g., 170280.0001), indicating familial hemophagocytic lymphohistiocytosis type 2 (FHL2; 603553).

Population Genetics

Wevers et al. (2019) noted that most laboratories involved in screening for inborn errors of metabolism do not evaluate uridine and cytidine when looking for defects in the purine and pyrimidine pathways. They considered it very possible that cases with high pyrimidine nucleoside excretion have been and are overlooked. They also noted that the overlapping specificity of the various CNT transporters may explain why a defect in CNT1 does not lead to clinical neurologic signs and symptoms.