Severe paroxysmal dyskinesias without epilepsy in a RHOBTB2 mutation carrier

Necpál, Ján; Zech, Michael; Valachová, Alica; Sedláček, Zdeněk; Bendová, Šárka; Hančárová, Miroslava; Okáľová, Katarína; Winkelmann, Juliane; Jech, Robert

doi:10.1016/j.parkreldis.2020.06.028

Cited by 9 publications

(7 citation statements)

References 2 publications

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“…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).…”

Section: Predominant Dyskinesia Genesmentioning

confidence: 99%

Paroxysmal Movement Disorders

2021

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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.

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Section: Predominant Dyskinesia Genesmentioning

confidence: 99%

Paroxysmal Movement Disorders

2021

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“…Severe paroxysmal choreodystonia, along with aplasia cutis congenita, without epilepsy, was reported in another patient with a heterozygous missense variant, c.1448G>A [p.Arg483His]. 46 …”

Section: Synaptopathiesmentioning

confidence: 99%

Genetic Links to Episodic Movement Disorders: Current Insights

Garg¹,

Mohammad²,

Shukla³

et al. 2023

TACG

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Episodic or paroxysmal movement disorders (PxMD) are conditions, which occur episodically, are transient, usually have normal interictal periods, and are characterized by hyperkinetic disorders, including ataxia, chorea, dystonia, and ballism. Broadly, these comprise paroxysmal dyskinesias (paroxysmal kinesigenic and non-kinesigenic dyskinesia [PKD/PNKD], paroxysmal exercise-induced dyskinesias [PED]) and episodic ataxias (EA) types 1–9. Classification of paroxysmal dyskinesias has traditionally been clinical. However, with advancement in genetics and the discovery of the molecular basis of several of these disorders, it is becoming clear that phenotypic pleiotropy exists, that is, the same variant may give rise to a variety of phenotypes, and the classical understanding of these disorders requires a new paradigm. Based on molecular pathogenesis, paroxysmal disorders are now categorized as synaptopathies, transportopathies, channelopathies, second-messenger related disorders, mitochondrial or others. A genetic paradigm also has an advantage of identifying potentially treatable disorders, such as glucose transporter 1 deficiency syndromes, which necessitates a ketogenic diet, and ADCY5 -related disorders, which may respond to caffeine. Clues for a primary etiology include age at onset below 18 years, presence of family history and fixed triggers and attack duration. Paroxysmal movement disorder is a network disorder, with both the basal ganglia and the cerebellum implicated in pathogenesis. Abnormalities in the striatal cAMP turnover pathway may also be contributory. Although next-generation sequencing has restructured the approach to paroxysmal movement disorders, the genetic underpinnings of several entities remain undiscovered. As more genes and variants continue to be reported, these will lead to enhanced understanding of pathophysiological mechanisms and precise treatment.

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“…1 and 2). [4][5][6][9][10][11][12][13][14][15][16] The comprehensive analysis of the literature review can be accessed within the Supplementary material S2.…”

Section: Literature Reviewmentioning

confidence: 99%

Exploring the Spectrum of RHOBTB2 Variants Associated with Developmental Encephalopathy 64: A Case Series and Literature Review

de Pedro Baena,

Sariego Jamardo,

Castro

et al. 2023

Movement Disord Clin Pract

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BackgroundRho‐related BTB domain‐containing protein 2 (RHOBTB2) is a protein that interacts with cullin‐3, a crucial E3 ubiquitin ligase for mitotic cell division. RHOBTB2 has been linked to early infantile epileptic encephalopathy, autosomal dominant type 64 (OMIM618004), in 34 reported patients.MethodsWe present a case series of seven patients with RHOBTB2‐related disorders (RHOBTB2‐RD), including a description of a novel heterozygous variant. We also reviewed previously published cases of RHOBTB2‐RD.ResultsThe seven patients had ages ranging from 2 years and 8 months to 26 years, and all had experienced seizures before the age of one (onset, 4–12 months, median, 4 months), including various types of seizures. All patients in this cohort also had a movement disorder (onset, 0.3–14 years, median, 1.5 years). Six of seven had a baseline movement disorder, and one of seven only had paroxysmal dystonia. Stereotypies were noted in four of six, choreodystonia in three of six, and ataxia in one case with multiple movement phenotypes at baseline. Paroxysmal movement disorders were observed in six of seven patients for whom carbamazepine or oxcarbazepine treatment was effective in controlling acute or paroxysmal movement disorders. Four patients had acute encephalopathic episodes at ages 4 (one patient) and 6 (three patients), which improved following treatment with methylprednisolone. Magnetic resonance imaging scans revealed transient fluid‐attenuated inversion recovery abnormalities during these episodes, as well as myelination delay, thin corpus callosum, and brain atrophy. One patient had a novel RHOBTB2 variant (c.359G>A/p.Gly120Glu).ConclusionRHOBTB2‐RD is characterized by developmental delay or intellectual disability, early‐onset seizures, baseline movement disorders, acute or paroxysmal motor phenomena, acquired microcephaly, and episodes of acute encephalopathy. Early onsets of focal dystonia, acute encephalopathic episodes, episodes of tongue protrusion, or peripheral vasomotor disturbances are important diagnostic clues. Treatment with carbamazepine or oxcarbazepine was found to be effective in controlling acute or paroxysmal movement disorders. Our study highlights the clinical features and treatment response of RHOBTB2‐RD.

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Severe paroxysmal dyskinesias without epilepsy in a RHOBTB2 mutation carrier

Cited by 9 publications

References 2 publications

Paroxysmal Movement Disorders

Paroxysmal Movement Disorders

Genetic Links to Episodic Movement Disorders: Current Insights

Exploring the Spectrum of RHOBTB2 Variants Associated with Developmental Encephalopathy 64: A Case Series and Literature Review

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