Expanding the Biochemical Phenotype of ReNU Syndrome: A Case Report

Pathogenic variants in RNU4‐2 , encoding for a critical component of the major spliceosome, cause a newly recognized autosomal dominant disorder. Patients with RNU4‐2/ReNU syndrome exhibit global developmental delay, microcephaly, dysmorphic features, seizures, hypotonia, and multi‐organ involvement. Here, we detailed clinical findings and laboratory evaluation of a 3‐year‐old girl harboring a common RNU4‐2 pathogenic variant. Her clinical presentation and disease course were similar to previously described. Furthermore, akin to other cases, an undiagnosed mitochondrial disorder was initially suspected because of hypoglycemia and lactic acidosis during metabolic stresses and abnormalities in circulating mitochondrial markers. The patient's muscle biopsy suggested mild mitochondrial abnormalities. We employed untargeted metabolomics to further characterize the patient; to our knowledge, this is the first report including metabolomic data in a ReNU syndrome patient. Clinically relevant changes were detected in several lipids, including low concentrations of several plasmalogen species. Plasmalogen deficiency, confirmed by a targeted biochemical assay, was comparable to defects of peroxisomal plasmalogen biosynthesis. Laboratory evaluation of mitochondrial and peroxisomal function in other ReNU syndrome patients is paramount for assessing the role of these organelles, if any, in the pathophysiology of this condition.