A Novel RORA Hinge-Region Variant in Adult IDDECA With Cerebellar Atrophy and Marked Response to Valproate.

objectivesTo expand the RORA mutational and clinical spectrum by reporting a novel hinge-region variant associated with an adult progressive phenotype and a marked therapeutic response to valproate.

methodsWe describe a 61-year-old woman with lifelong intellectual disability who developed subacute severe motor deterioration in adulthood. Evaluation included brain MRI and whole-exome sequencing.

resultsWhole-exome sequencing identified a novel heterozygous variant, c.551C>G (p.Pro184Arg), in the hinge region (domain D) of RORA, a region not previously implicated in human disease. While RORA-related disorders are typically described as neurodevelopmental conditions, our patient showed progressive motor decline with loss of independent ambulation. Brain MRI demonstrated marked vermian atrophy, supporting a possible progressive component. Withdrawal of valproate was followed by severe clinical worsening, whereas reintroduction led to marked improvement in tremor and gait, restoring independent ambulation. DISCUSSION: This case expands the mutational and phenotypic spectrum of RORA-related disorders and suggests that hinge-region variants may contribute to a more severe phenotype. It also supports a role for cortical hyperexcitability in the motor manifestations and highlights a potentially treatable component, with implications for clinical management.