In 2018, Straub et al. [3] first reported that heterozygous variants in RHOBTB2 are associated with DEE-64. Since then, there were total 19 cases reported associated with RHOBTB2 and additional clinical details are shown in Table 1 [3,4,5,6,7,8]. Eighteen patients with RHOBTB2 variants had characterized of DEE, among them, 13 patients showed paroxysmal movement disorders, including dystonia, dyskinesia, athetosis and choreatic features. Only one patient with RHOBTB2 variant reported previously had paroxysmal movement disorders without epilepsy [4]. Previous studies showed that patients with RHOBTB2 variants could manifested microcephaly, stereotyped movement, and unspecific facial dysmorphism including low nasal bridge, epicanthal folds, micrognathia, deep-set eyes, and long philtrum. In this study, we reported two patients with novel RHOBTB2 variants. One patient showed epilepsy in early infancy, he had developmental milestones delay, microcephaly and paroxysmal extrapyramidal symptoms, while the other patient only showed paroxysmal movement disorders in adolescence.
Seizure onset of patients with RHOBTB2 variants usually occurred during the infantile period. Multiple seizure types were observed, including focal seizure, GTCS, myoclonic seizure, tonic seizure, and epileptic spasms. SE was common in most patients. 65% (13/20) of epilepsy patients with RHOBTB2 variants reported in the literature and in this study experienced SE. Among the 13 patients, three of them were characterized by febrile SE, two of them experienced focal SE, as one patient in our study. All epilepsy patients with RHOBTB2 variants had developmental delays. EEG usually showed interictal focal epileptic discharges. The abnormalities of brain MRI including cortical atrophy, corpus callosum dysplasia, delayed myelination, and hippocampal atrophy were observed. All patients with brain atrophy experienced SE. Four patients with hemiplegia had a history of SE and one of them showed focal SE, indicated that SE can lead to hemiplegia. Brain MRI of some cases showed swollen or reduced focal diffusion in acute encephalopathy and subsequent focal atrophy. A previous study found that edema in acute encephalopathy could lead to different degrees of cerebral cortex atrophy in convalescence, focal SE could lead to hemispheric cerebral lesions in patients with Dravet syndrome, whereas generalized tonic–clonic SE could cause bilateral cerebral lesions [9]. Therefore, brain atrophy in patients with RHOBTB2 variants may be correlated with SE.
In this study, one patient with RHOBTB2 variant only showed paroxysmal movement disorders without afebrile seizures in adolescence. He had normal psychomotor development before episodes of dystonia occurred. Necpál, Ján et al. [4] reported a girl with RHOBTB2 variant who had paroxysmal movement disorders without epilepsy at 3 years old. Her clinical features were characterized by delays in developmental milestones, paroxysmal choreodystonia, microcephaly, and facial dysmorphism including epicanthal folds, wide nasal bridge, and long flat philtrum. These cases suggest that RHOBTB2 variants can cause paroxysmal movement disorders alone.
There were totally seven de novo RHOBTB2 variants in 19 patients reported previously. Eight patients shared the same variant p. Arg483His and five patients shared the same variant p. Arg511Gln (Table 1). All of the variants were located in BTB domains. The BTB domains bind to GTPase domain and to the ubiquitin ligase scaffold CUL3, the interaction mediates auto-ubiquitination and related to proteasomal degradation. Overexpression of RhoBTB in Drosophila showed more severe neurological phenotypes than upon knockdown, which indicated that the neurological symptoms caused by the variant in the BTB domain of RHOBTB2 gene may be due to the decrease of proteasomal degradation, followed by overexpression of RhoBTB [3]. Among the eight patients with the same variant p. Arg483His, five patients had DEE accompanied with paroxysmal movement disorders, two cases had DEE and one patient had paroxysmal movement disorders alone, which indicated that recurrent RHOBTB2 variant can lead to phenotypic variability. Two novel variants of RHOBTB2 in this study were located in the GTPase domain, they were characterized by DEE with paroxysmal movement disorders or paroxysmal movement disorders alone. This study support that RHOBTB2 is one of the pathogenic gene of epilepsy and paroxysmal movement disorders.
In this study, case one with DEE was treated with multiple antiepileptic drugs and showed refractory. In a previous study, some patients with RHOBTB2 variants who had DEE responded to levetiracetam, phenobarbital, and carbamazepine [3]. Paroxysmal movement disorders are usually difficult to treat. Case two in our study was treated by levodopa and benserazide hydrochloride and and oxcarbazepine, but there was no effect. In previous studies, RHOBTB2-associated paroxysmal movement disorders were commonly treated with carbamazepine. Straub et al. [3] reported three patients with epilepsy and paroxysmal movement disorders were treated with carbamazepine, one of them had a partial response for movement disorders. Spagnoli et al. [8] reported that paroxysmal movement disorders in one patient with RHOBTB2 variant completely resolved by carbamazepine.
Genetic etiology of paroxysmal movement disorders has been unveiled readily with the advent of next-generation sequencing (NGS). Pathogenic variant of the PRRT2 gene was identified firstly to be the cause of paroxysmal movement disorders [10]. Further studies confirmed that the phenotypes of the PRRT2 gene include paroxysmal kinesigenic dyskinesia, benign sporadic and familial infantile epilepsy, and the overlapping disorder of paroxysmal kinesigenic dyskinesia with infantile epilepsy [11]. Subsequently, more pathogenic genes related to paroxysmal movement disorders were reported, including SCN8A, DEPDC5, KCNA1, KCNMA1, PNKD and SLC2A1 [12]. SCN8A, DEPDC5, KCNA1 KCNMA1 and SLC2A1 are also epilepsy-related genes as RHOBTB2 in this study, which indicates that paroxysmal movement disorders and epilepsy may have gene pleiotropy or share similar pathogenesis.