Uridine and cytidine are essential pyrimidine nucleosides fo
Uridine and cytidine are essential pyrimidine nucleosides for the brain and the central nervous system and uridine is involved in a number of vital cellular functions, in addition to nucleic Dalbavancin synthesis [26,, , ]. Uridine behaves as an anticonvulsant in a number of seizure models and uridine competitively inhibited GABA binding to rat cerebellar membranes, frontal cortex, hippocampus and thalamus [26,28]. It is, therefore, conceivable that a hCNT1 deficiency affects intracellular uridine levels and that the altered homeostasis of uridine in the brain is underlying the mild cerebral dysfunction, as indicated by electroencephalographic analysis of our patient.
There is an increased awareness that a combined phenotype of two co-existing monogenic defects resulting in blended phenotypes is an appreciable cause of disease . The rapid deterioration of the patient resulting in multi-organ failure and early death prompted us to investigate whether or not there was another coexisting monogenetic defect in the patient. WGS analysis and subsequent determination of the mode of inheritance demonstrated the presence of two in trans pathogenic variants c.50delT; p.(Leu17Argfs*34) and c.853_855del; p.(Lys285del) in the PRF1 gene. Both variants have previously been identified in patients suffering from Familial Hemophagocytic Lymphohistiocytosis type 2 (FHL-2) [, , ]. FHL-2 is caused by variants of perforin, a toxic pore-forming protein located in cytoplasmic granules that plays a key role in the elimination of viral-infected cells by cytotoxic T-lymphocytes and natural killer cells [16,31,32]. Patients with FHL suffer from fever, (hepato)splenomegaly, bi- or tricytopenia's, hypertriglyceridemia, elevated ferritin, hypofibrinogenemia, hemaphagocytosis, low or absent natural killer cells and markedly elevated lactate dehydrogenase levels [16,31,32]. The excessive cytokine production and immune dysregulation results in tissue damage and ultimately general organ failure. The average survival of patients with FHL, in the absence of treatment, is <2 months . The clinical presentation of our patient: fever, hepatosplenomegaly, persistent lactic acidosis, severely disturbed liver enzymes and ultimately multi organ failure fits well with the reported phenotype of patients with FHL-2. To our knowledge, it is not known whether other patients with PRF1 variants, and suffering from FHL-2, presented with uridine-cytidineuria as well.
It is tempting to speculate that the hCNT1 deficiency might have caused the myoclonia and aggravated the clinical demise of our patient. Uridine and cytidine are essential compounds to sustain proliferation of T-lymphocytes and impaired uptake of these pyrimidine nucleosides might have further hampered a proper immune response to a viral infection . It has recently been reported that a proper control of nucleoside intracellular pools in T-cells is a major determinant of T cell survival upon activation and this might explain some phenotypic features of patients lacking lysosomal hENT3 function . In this regard, although hCNT1 mRNA levels in T-cells are almost negligible, they are up-regulated following cell stimulation with phytohemagglutinin (PHA) ex vivo . Therefore, an adaptive response of hCNT1 in T-cells could also contribute to modulate nucleoside pools and this function could have been hampered in our patient. In our case, it is conceivable that the presence of two co-existing monogenic defects resulted in a blended clinical and biochemical phenotype. Thus, the clinical presentation of isolated hCNT1 deficiency remains to be established.
Funding Work at the Pastor-Anglada laboratory has been funded by grant SAF2014-52067-R (Ministerio de Economía y Competitividad, MINECO, Spain), Fundación Ramón Areces and Universitat de Barcelona. This laboratory is a member of CIBER EHD, an initiative of Instituto de Salud Carlos III, Spain. Aida Mata-Ventosa is being funded by a Ph.D. training grant from Formación de Profesorado Universitario (FPU), Ministerio de Educación, Cultura y Deporte (Spain). Work at the Bidon-Chanal laboratory has been funded by grant 2017SGR1746. Work at the Centre for Molecular Medicine and Therapeutics has been funded by the Canadian Institutes of Health Research (grant number #301221); and informatics infrastructure supported by Genome British Columbia and Genome Canada (ABC4DE Project). Clara van Karnebeek is a recipient of the Michael Smith Foundation for Health Research Scholar Award. Britt Drögemöller was funded through the CIHR Postdoctoral Fellowship and the Michael Smith Foundation for Health Research Trainee Award.