Article

Severe paroxysmal dyskinesias without epilepsy in a RHOBTB2 mutation carrier

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  • Zvolen Hospital, Zvolen, Slovakia
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... To date, most studies showed that patients with RHOBTB2 variants had DEE and some of them had paroxysmal movement disorders. Only one patient with RHOBTB2 variants had paroxysmal movement disorders with no epilepsy in the literature [4]. Here, we described two cases with novel RHOBTB2 variants in detail and summarized other reported cases to further explore the RHOBTB2 gene-associated phenotypic spectrum. ...
... 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. ...
... 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, deepset eyes, and long philtrum. ...
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Background RHOBTB2 gene is associated with developmental and epileptic encephalopathy-64(DEE-64), which is characterized by epilepsy, developmental delay, microcephaly, unspecific facial dysmorphism, and paroxysmal movement disorders. Most previous studies showed that the phenotypes of RHOBTB2 gene include developmental and epileptic encephalopathy(DEE) and DEE with paroxysmal movement disorders. Only one study showed that patient with RHOBTB2 variant had paroxysmal movement disorders with no epilepsy. Case presentations Two cases with RHOBTB2 variants are presented here: Case one was diagnosed as DEE, he had recurrent afebrile focal status epilepticus and paroxysmal extrapyramidal symptoms in infancy. Interictal electroencephalogram (EEG) showed focal discharges. Brain magnetic resonance imaging (MRI) showed cortical dysplasia. Epilepsy of case one was refractory. Nevertheless, case two only showed paroxysmal movement disorders alone in adolescence. Video EEG showed focal discharges during an interictal dystonic episode and he brain MRI was normal. Conclusion The phenotypes of RHOBTB2 gene include DEE, paroxysmal movement disorders, and DEE with paroxysmal movement disorders. RHOBTB2 can be one of the pathogenic genes of paroxysmal movement disorders.
... 111 Recently, RHOBTB2 gene variants, usually presenting with epileptic encephalopathy, intellectual disability, microcephaly, facial dysmorphia, choreatic and/or dystonic dyskinesias (including paroxysmal), were anecdotally reported also with aplasia cutis congenita. 112 In Klinefelter syndrome (mostly 47, XXY), sparse body and facial hair are often present besides the cardinal features (hypogonadism, cryptorchism, infertility, gynecomastia, decreased testosterone levels and learning problems) and various movement disorders (ET-like tremor, myoclonus and even parkinsonism). 113,114 A condition seen in children is giant axonal neuropathy. ...
Article
Skin manifestations are well-recognized non-motor symptoms of Parkinson's disease (PD) and other hypokinetic and hyperkinetic movement disorders. Skin conditions are usually well visible during routine clinical examination and their recognition may play a major role in diagnostic work-up. In this educational review we: a) briefly outline skin conditions related to Parkinson's disease, including therapy-related skin complications and their management; b) discuss the role of skin biopsies in early diagnosis of PD and differential diagnosis of parkinsonian syndromes; and focus more on areas which have not been reviewed in the literature before, including c) skin conditions related to atypical parkinsonism, and d) skin conditions related to hyperkinetic movement disorders. In case of rare hyperkinetic movement disorders, specific dermatological manifestations, like presence of angiokeratomas, telangiectasias, Mongolian spots, lipomas, ichthyosis, progeroid skin changes and others may point to a very specific group of disorders and help guide further investigations.
... In the initial reports, 11/13 had a movement disorder (dystonia, dyskinesia, chorea and stereotypies), described as paroxysmal in 4/11 (paroxysmal dyskinesia, dystonic-athetoid attacks) (5,38,103). Subsequently, two case reports focusing on the PxMDs have been published, including a patient with paroxysmal dyskinesia and developmental delay without epilepsy (38,39). Recently a cohort of 11 patients was published with a complex, polymorphic movement disorder, with both paroxysmal and non-paroxysmal features (40). ...
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Paroxysmal movement disorders (PxMDs) are a clinical and genetically heterogeneous group of movement disorders characterized by episodic involuntary movements (dystonia, dyskinesia, chorea and/or ataxia). Historically, PxMDs were classified clinically (triggers and characteristics of the movements) and this directed single-gene testing. With the advent of next-generation sequencing (NGS), how we classify and investigate PxMDs has been transformed. Next-generation sequencing has enabled new gene discovery ( RHOBTB2, TBC1D24 ), expansion of phenotypes in known PxMDs genes and a better understanding of disease mechanisms. However, PxMDs exhibit phenotypic pleiotropy and genetic heterogeneity, making it challenging to predict genotype based on the clinical phenotype. For example, paroxysmal kinesigenic dyskinesia is most commonly associated with variants in PRRT2 but also variants identified in PNKD, SCN8A, and SCL2A1 . There are no radiological or biochemical biomarkers to differentiate genetic causes. Even with NGS, diagnosis rates are variable, ranging from 11 to 51% depending on the cohort studied and technology employed. Thus, a large proportion of patients remain undiagnosed compared to other neurological disorders such as epilepsy, highlighting the need for further genomic research in PxMDs. Whole-genome sequencing, deep-sequencing, copy number variant analysis, detection of deep-intronic variants, mosaicism and repeat expansions, will improve diagnostic rates. Identifying the underlying genetic cause has a significant impact on patient care, modification of treatment, long-term prognostication and genetic counseling. This paper provides an update on the genetics of PxMDs, description of PxMDs classified according to causative gene rather than clinical phenotype, highlighting key clinical features and providing an algorithm for genetic testing of PxMDs.
... Both baseline dyskinetic movements and the paroxysmal exacerbations may respond to deep brain stimulation, although the optimal programming parameters are not yet defined (116). Additional genes in which paroxysmal dyskinetic events have been variably associated with epilepsy and/or an abnormal include SYT1 and RHOBTB2 (117)(118)(119). ...
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Paroxysmal movement disorders include paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, paroxysmal exercise-induced dyskinesia, and episodic ataxias. In recent years, there has been renewed interest and recognition of these disorders and their intersection with epilepsy, at the molecular and pathophysiological levels. In this review, we discuss how these distinct phenotypes were constructed from a historical perspective and discuss how they are currently coalescing into established genetic etiologies with extensive pleiotropy, emphasizing clinical phenotyping important for diagnosis and for interpreting results from genetic testing. We discuss insights on the pathophysiology of select disorders and describe shared mechanisms that overlap treatment principles in some of these disorders. In the near future, it is likely that a growing number of genes will be described associating movement disorders and epilepsy, in parallel with improved understanding of disease mechanisms leading to more effective treatments.
... As for SCN8A, pathogenic variants in this gene have been identified in families with PRRT2-negative PKD [88•, 98] or mimics of myoclonus-dystonia [99]. Similarly, mutations in RHOBTB2 were recently found in cases with epileptic encephalopathy associated with paroxysmal movement disorders [100] that can also occur also in absence of epilepsy [101]. ...
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By whole exome sequencing, we identified three de novo RHOBTB2 variants in three patients with epileptic encephalopathies (EEs). Interestingly, all three patients showed acute encephalopathy (febrile status epilepticus), with magnetic resonance imaging revealing hemisphere swelling or reduced diffusion in various brain regions. RHOBTB2 encodes Rho‐related BTB domain‐containing protein 2, an atypical Rho GTPase that is a substrate‐specific adaptor or itself is a substrate for the Cullin‐3 (CUL3)‐based ubiquitin/proteasome complex. Transient expression experiments in Neuro‐2a cells revealed that mutant RHOBTB2 was more abundant than wild‐type RHOBTB2. Co‐expression of CUL3 with RHOBTB2 decreased the level of wild‐type RHOBTB2 but not the level of any of the three mutants, indicating impaired CUL3 complex‐dependent degradation of the three mutants. These data indicate that RHOBTB2 variants are a rare genetic cause of EEs, in which acute encephalopathy might be a characteristic feature, and that precise regulation of RHOBTB2 levels is essential for normal brain function. This article is protected by copyright. All rights reserved
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