2026 American Academy of Neurology Abstract Website

Objective:

To explore the clinical spectrum of patients with RHOBTB2 gene mutations and their varying presentations of movement disorders.

Background:

RHOBTB2 related disorders are a rare group of developmental epileptic encephalopathies (DEE) first described in 2018. The implicated gene, Rho-related BTB domain-containing protein 2, was first reported as a tumor suppressor gene. Decreased RHOBTB2 levels have been noted across various cancer types. RHOBTB2 is highly expressed in the brain, and animal model data supports its role in neuronal function and development. Certain RHOBTB2 variants impair protein degradation, leading to accumulation in neurons and DEE.

Design/Methods:

A multicenter retrospective case series of four previously unreported patients, ages 4 to 27 years, with pathogenic variants in the RHOBTB2 gene. Clinical data, EEGs, genetic testing, and MRIs were reviewed.

Results:

All patients had epilepsy and developmental delay. Three had seizure onset by age 4 months, and one at age 6. Three experienced dystonia, and two patients had dyskinesias. One patient had an episode of acute encephalopathy after status epilepticus and acute hemiplegia. Autism spectrum disorders and microcephaly were present in two patients. Three patients experienced at least one episode of acute hemiplegia following status epilepticus or febrile illness, with recovery occurring over greater than three months. EEGs were consistent with focal epilepsy. MRIs revealed diffuse cerebral atrophy and, during hemiplegic episodes, showed multifocal areas of cortical diffusion restriction or perfusion deficits on ASL. Two patients had pathogenic variants at p.Arg483His and others at p.Arg507Cys and p.Arg511Gln.

Conclusions:

Patients with RHOBTB2 related disorders encompass a wide spectrum of clinical symptoms. Unique to our patients is the length of recovery from hemiplegic episodes over several months; the longest reported in literature is two weeks. RHOBTB2-related disorders should be considered in patients with very slow and prolonged recovery following hemiplegic episodes. Management focuses on ongoing epilepsy treatment and supportive rehabilitative services.