Abrupt and Severe Onset of Dystonia, Chorea and Hemiplegic Episodes in a Young Boy with a Novel Heterozygous Missense Variant in the <scp>GTPase</scp> Domain of <scp>RHOBTB2</scp>

Pathogenic mutations in Rho-related BTB domain-containing protein 2 (RHOBTB2) gene cause a rare syndrome characterized by developmental and epileptic encephalopathy, often with complex movement disorders.1, 2 We describe a young boy with a novel de novo heterozygous missense variant in the GTPase domain of RHOBTB2 who developed acute onset, rapidly progressive dystonia, chorea, and hemiplegic attacks. A 7-year-old boy with a known RHOBTB2 variant and mild cerebellar dysgenesis presented with acute neurologic deterioration. At baseline, he had mild global developmental delay but could walk, run, jump, and speak in short sentences. Over several days, he developed severe right-sided weakness with dystonic posturing, left-sided dystonic and choreiform movements, tongue protrusion, and reduced speech. He was unable to sit, stand, or walk without support. He was afebrile, alert with intact comprehension, and had normal extraocular movements, mild axial hypotonia with variable limb tone, and an upgoing right toe. Over the following months he had mild improvement of symptoms but experienced recurrent episodes of right-sided hemiparesis and dystonia (Video 1), which improved with sleep. There was no encephalopathy or cognitive regression. Episodes typically lasted hours to days (ranging from 30 min to few weeks), occurring without obvious provoking factors. Carbidopa-levodopa, clonazepam, levetiracetam, baclofen, amantadine, clonidine, and trihexyphenidyl were tried, but these were ineffective or sedating. Oxcarbazepine helped but caused behavioral changes. Over the past 2 years, acetazolamide and flunarizine have reduced the frequency and severity of episodes (short attacks every few months). Carbamazepine was added 6 months ago for slightly increased episodes, with only one brief dystonic episode on this regimen. An extensive autoimmune, metabolic, and infectious workup, including CSF studies, MRI brain and spine, and EEG, was unrevealing (Table 1). He had trio-based exome sequencing a few years earlier for his developmental delay which identified a de novo heterozygous missense variant in the GTPase domain of RHOBTB2 (NM_001160036.1, c.342C>G, p.Asp114Glu) (Fig. 1). This variant has not been reported previously but is considered likely pathogenic due to low frequency in the general population (gnomAD) and in silico analysis (PROVEAN) showing deleterious effects on protein structure and function. While initially thought to be non-contributory due to lack of seizures and only mild developmental delay, given his severe movement disorder, his presentation is now attributed to RHOBTB2-related disorder (RRD). RRD, first identified in 2018 as a cause of severe early infantile developmental and epileptic encephalopathy, is increasingly associated with a prominent movement disorder characterized by paroxysmal attacks as well as severe acute exacerbations, including hemiplegic episodes.1-5 The majority of patients (>80%) have persistent and/or paroxysmal movement disorders, most often dystonia and dyskinesias, which can be focal, hemibody or generalized.4-6 While the paroxysmal movements in RRD can be brief (seconds-minutes) and recur several times daily, RRD can also manifest as our patient did, with a dramatic onset of prolonged motor symptoms.7 RHOBTB2 therefore should be considered when encountering “severe acute motor exacerbations” of neurogenetic and neurometabolic disorders, as recently described.7 Additional features of RRD include intellectual disability, microcephaly, brain malformations (including cerebellar dysgenesis, seen in our patient), behavioral dysregulation, and dysmorphisms.1, 3, 4 Accordingly, RHOBTB2 should also be considered in the differential diagnosis for epilepsy-dyskinesia and Rett-like syndromes.1 Our case further highlights RHOBTB2 as a cause of alternating hemiplegia of childhood (AHC) in patients who do not carry ATP1A3 mutations, though ATP1A2, SLC2A1, SNC4A, ADCY5, GNAO1, TANGO2, and TBC1D24, as well as non-AHC etiologies for episodic hemiplegia, such as stroke-like episodes in metabolic disorders, should also be considered in the differential. One distinguishing feature of RRD compared to ATP1A3-related AHC is the later age of onset of attacks (20 vs. <18 months).4 As in classic AHC, acute exacerbations in RRD may be triggered by febrile illness, head trauma, and stress. Similarly, carbamazepine and oxcarbazepine may help control episodes.5, 8, 9 While most reported RHOBTB2 cases involve missense mutations in or near one of the BTB domains (44), a smaller subset (8) have GTPase domain mutations, which causes more variable and often milder phenotypes, similar to our patient before his acute decline.3, 6 In one study, 43% (3/7) with GTPase variants had seizures compared to 93% (41/44) with BTB mutations. No patients (0/4) with GTPase variants had severe developmental delay or intellectual disability, compared to 85% (30/35) with BTB mutations.6 In vitro studies suggest that BTB mutations increase RHOBTB2 expression (possibly due to impaired proteasomal degradation) and affect ion channel function, leading to increased seizure susceptibility and severe motor deficits.1, 10 In contrast, GTPase variants do not affect proteasome degradation or electrophysiological activity, indicating that mutation location strongly influences RRD phenotypes.10 Our case expands the phenotypic spectrum of GTPase domain variants, reinforces genotype–phenotype correlations, and underscores that movement disorders may dominate the clinical picture. It also highlights that paroxysmal and acute motor exacerbations help distinguish RRD from other neurodevelopmental disorders, and that RHOBTB2 is a key differential diagnosis for AHC. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. P.T.H.: 1B, 1C, 3A I.O.B.: 1A, 3B M.S.: 1A, 3B Ethical Compliance Statement: The authors confirm that approval of an institutional review board was not required for this work. Informed consent from the patient's family was obtained in writing. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: The authors declare that there are no funding sources or conflicts of interest to report. Financial Disclosures for the Previous 12 Months: The authors each receive research funding from the National Institutes of Health. IOB also receives research funding from the Michael J. Fox Foundation.