Developmental and epileptic encephalopathy related to a heterozygous variant of the <i>RHOBTB2</i> gene: A case report from French Guiana

Defo, Antoine; Verloès, Alain; Elenga, Narcisse

doi:10.1002/mgg3.1929

Cited by 5 publications

(6 citation statements)

References 6 publications

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“…RHOBTB2 encodes an atypical Rho-related BTB-containing protein 2, a GTPase. Heterozygous variants have been reported to lead to developmental and epileptic encephalopathies, 42 , 43 postnatal microcephaly, intellectual impairment and Rett-like phenotype. 44 Paroxysmal movement disorders, including chorea, dystonia and dyskinesias, were reported in a series of 13 patients.…”

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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Section: Synaptopathiesmentioning

confidence: 99%

Genetic Links to Episodic Movement Disorders: Current Insights

Garg¹,

Mohammad²,

Shukla³

et al. 2023

TACG

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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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“…9 Department of Pediatrics, Division of Medical Genetics, Duke Health, Durham, NC, USA. 10 Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy. 11 Child Neuropsychiatry Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy.…”

Section: Introductionmentioning

confidence: 99%

“…As comprehensive sequencing of the coding regions of ATP1A3 had not identified a causal mutation, these cases are referred to as ATP1A3-negative, either typical AHC patients or patients with one or more of the hallmark clinical traits observed in the condition (AHC-like). Exome sequencing in parallel studies has shown that rare protein-disrupting variants in ATP1A2 [8,9] and RHOBTB2 [10,11] contribute to AHC, although these collectively explain a very small fraction of cases. Hence we here sought to (1) use targeted whole-gene sequencing of ATP1A3 to look for noncoding pathogenic variants in our cohort of 26 ATP1A3-negative patients, and (2) use exome sequencing to further identify other genes that may be responsible for the observed phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Exome sequencing of ATP1A3-negative cases of alternating hemiplegia of childhood reveals SCN2A as a novel causative gene

Panagiotakaki,

Tiziano,

Mikati

et al. 2023

Eur J Hum Genet

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Alternating hemiplegia of childhood (AHC) is a rare neurodevelopment disorder that is typically characterized by debilitating episodic attacks of hemiplegia, seizures, and intellectual disability. Over 85% of individuals with AHC have a de novo missense variant in ATP1A3 encoding the catalytic α3 subunit of neuronal Na +/ K + ATPases. The remainder of the patients are genetically unexplained. Here, we used next-generation sequencing to search for the genetic cause of 26 ATP1A3-negative index patients with a clinical presentation of AHC or an AHC-like phenotype. Three patients had affected siblings. Using targeted sequencing of exonic, intronic, and flanking regions of ATP1A3 in 22 of the 26 index patients, we found no ultra-rare variants. Using exome sequencing, we identified the likely genetic diagnosis in 9 probands (35%) in five genes, including RHOBTB2 (n = 3), ATP1A2 (n = 3), ANK3 (n = 1), SCN2A (n = 1), and CHD2 (n = 1). In follow-up investigations, two additional ATP1A3-negative individuals were found to have rare missense SCN2A variants, including one de novo likely pathogenic variant and one likely pathogenic variant for which inheritance could not be determined. Functional evaluation of the variants identified in SCN2A and ATP1A2 supports the pathogenicity of the identified variants. Our data show that genetic variants in various neurodevelopmental genes, including SCN2A, lead to AHC or AHC-like presentation. Still, the majority of ATP1A3-negative AHC or AHC-like patients remain unexplained, suggesting that other mutational mechanisms may account for the phenotype or that cases may be explained by oligo-or polygenic risk factors.

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Developmental and epileptic encephalopathy related to a heterozygous variant of the RHOBTB2 gene: A case report from French Guiana

Cited by 5 publications

References 6 publications

Genetic Links to Episodic Movement Disorders: Current Insights

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

Exome sequencing of ATP1A3-negative cases of alternating hemiplegia of childhood reveals SCN2A as a novel causative gene

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