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

To 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.

We 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.

Whole-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.

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.