Phenotypic and functional immune alterations in a patient with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

SILVERA-RUIZ, SILENE M.; GEMPERLE, CORINNE; PEANO, NATALIA; OLIVERO, VALENTINA; BECERRA, ADRIANA; HABERLE, JOHANNES; GRUPPI, ADRIANA; LAROVERE, LAURA ELENA; MOTRICH, RUBEN DARIO

Buenos Aires

Congreso; Reunión de Sociedades de Biociencias 2021; 2021

Background. The urea cycle disorder hyperornithinemia–hyperammonemia–homocitrullinuria (HHH) syndrome is caused by SLC25A15 gene mutations that lead to deficiency of the ORC1 transporter. Interestingly, SLC25A15 mRNA is highly expressed in CD4 T lymphocytes. However, immune alterations have not been reported in HHH patients up to date. Methods. Biochemical and molecular diagnosis of HHH syndrome. Assessment of phenotypic and functional immune parameters: lymphoproliferation against polyclonal and memory antigens, T helper cell subsets, cytokine secretion in culture supernatants, immunoglobulin serum levels, and glycosylation of leukocyte surface and serum proteins. Results. A 3-years-old Argentinian female patient was admitted to the hospital with an episode of recurrent otitis, somnolence, confusion and lethargy. Laboratory tests revealed hyperammonemia, metabolic alkalosis, elevated transaminases, haemostasis alterations and increased urinary orotic acid excretion. Noteworthy, serum proteinogram showed a reduction in the gamma globulins. Direct sequencing of the SLC25A15 gene revealed two novel heterozygous non-conservative substitutions in the exon 6: c.649G>A (p.Gly217Arg) and c.706A>G (p.Arg236Gly) confirming the diagnosis of HHH syndrome. In silico analysis indicated that the mutations inhibit ornithine transport almost completely. Interestingly, immune analysis revealed striking phenotypic and functional alterations in the T and B cell compartments and in the glycosylation of serum immunoglobulins. Conclusions. Our study identified two non-previously described mutations in the SLC25A15 gene underlying the HHH syndrome associated to functional and phenotypic immunologic alterations that would render patients more susceptible to infections. Our results highlight the importance of a comprehensive analysis to gain further insights in the underlying pathophysiology of the HHH syndrome.