Comprehensive Structural MRI Phenotyping in Oligophrenin 1-Related Disorder Reveals Characteristic Brain...

The Oligophrenin 1 (OPHN1) gene, located on Xq12, encodes a Rho GTPase-activating protein that regulates the Rho/Ras signalling pathways essential for cell migration, morphogenesis, dendritogenesis, and synaptic plasticity. Pathogenic variants in OPHN1 have been shown to be associated with structural brain malformations. Early neuroimaging reports described nonspecific findings such as an enlarged cisterna magna, ventriculomegaly, and cerebellar hypoplasia, whereas subsequent studies identified more distinctive abnormalities, including frontotemporal volume reduction and caudate head hypoplasia, and vermian and asymmetric cerebellar hypoplasia. In this series, we applied a systematic approach to detailed MRI phenotyping in patients with confirmed OPHN1 variants. We identified a consistent constellation of structural abnormalities, including cerebellar vermian and hemispheric hypoplasia with dysfoliation, brainstem malformations including aberrant tracts such as anterior mesencephalic cap dysplasia, and abnormal transverse pontine fibers; and supratentorial features such as caudate hypoplasia, frontal-predominant ventriculomegaly, and commissural anomalies. Additional findings, such as dysgyria, hippocampal and olfactory bulb abnormalities, optic nerve hypoplasia, cerebellar heterotopia, and cranial mesenchymal anomalies, further expand the recognized phenotype. The combination of gray and white matter involvement, together with DTI evidence of aberrant fibers, supports a pathogenic mechanism involving abnormal regional development, disrupted cerebrocerebellar connectivity, and impaired axonal guidance.