ULTRASTRUCTURAL INVESTIGATIONS OF THE CEREBRAL CORTEX IN MOUSE MODELS OF BBSOAS

The Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS; OMIM 615722; ORPHA 401777) is a neurodevelopmental disease caused by mutations in the NR2F1 gene, a transcriptional regulator known for its multiple key roles in brain development and postnatal brain plasticity1. The clinical phenotypes are heterogeneous and include optic nerve atrophy or hypoplasia, cortical visual impairment, intellectual disability, motor impairment, and autism spectrum disorder. With an estimated prevalence between 1 in 100,000 to 250,000 people worldwide, BBSOAS has been diagnosed in more than 300 patients2. However, more cases are being reported yearly, suggesting that this frequency might be underestimated. There is currently no cure for BBSOAS, but with early intervention and appropriate therapies, it is possible to improve the quality of life of affected children. To contribute to our understanding of the pathophysiology of the disease, this study focuses on electron microscopy analysis of brain tissues using a mouse model of BBSOAS. Both juvenile and adult Nr2f1-het mice were examined ultrastructurally to detect any changes in the thickness and shape of the myelin fiber and the size of the mitochondria in the cerebral cortex. The results indicate a reduction in the thickness of the myelin sheath and loss of its characteristic multilaminar structure, a reduction in neurofilaments in the axoplasm, and abnormalities in the mitochondrial morphology. Our results align with what was previously reported at the optic nerve level3 and highlight new alterations that open novel perspectives for future investigations on the pathogenesis of BBSOAS in other brain areas.