<scp>MRPS</scp> Genes Causing Leukoencephalopathy With Profound Cerebral Folate Deficiency in Adults

MRPS genes, which encode components of the small mitoribosomal subunit, have not been previously linked to adult-onset neurological diseases. These genes play a critical role in mitochondrial translation and the biogenesis of the oxidative phosphorylation system. Whole Genome Sequencing was performed on adult patients presenting with an unexplained neurological picture. In parallel, functional studies were carried out in patient-derived fibroblasts to assess mitochondrial translation and the status of oxidative phosphorylation pathways. Bi-allelic pathogenic variants in MRPS22, MRPS23, and MRPS34 were identified in four patients from unrelated families. All patients presented a similar complex neurological phenotype, including cerebellar ataxia, distal motor neuropathy, pyramidal syndrome, and a distinctive leukoencephalopathy on brain MRI. Additional findings included elevated cerebrospinal fluid (CSF) protein levels and profound cerebral folate deficiency. Functional analyses revealed impaired mitochondrial translation and multiple defects in oxidative phosphorylation. Treatment with oral folinic acid resulted in clinical stabilization, radiological improvement, and normalization of CSF 5-methyltetrahydrofolate levels. Our findings expand the spectrum of mitochondrial diseases caused by defects in mitoribosomal proteins, highlighting their role in adult-onset neurological disorders with distinctive brain imaging features, high CSF protein levels, and cerebral folate deficiency.