Biallelic Mutations of <i>TBC1D24</i> in Exercise‐Induced Paroxysmal Dystonia

Steel, Dora; Heim, Jennifer; Kruer, Michael C.; Sanchis‐Juan, Alba; Raymond, Lucy; Eunson, Paul; Kurian, Manju A.

doi:10.1002/mds.27981

Cited by 8 publications

(11 citation statements)

References 7 publications

(6 reference statements)

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“…Paroxysmal-exercise induced movement disorder (dystonia) is described in two children with onset in infancy with paroxysmal dystonic episodes, triggered by physical exertion and co-existing with epilepsy, ataxia, dysarthria and cerebellar dysfunction (6). There was a gradual improvement over time due to trigger avoidance.…”

Section: Predominant Dyskinesia Genesmentioning

confidence: 99%

“…However, a large number (∼50%) remained without a genetic cause, despite exhibiting the classical features of PxMDs (4). The advent of NGS has enabled the discovery of new genes associated with PxMDs (RHOBTB2, TBC1D24, PDE2A) and the expansion of the phenotypes of known PxMDs (5)(6)(7)(8). For example, pathogenic variants in PRRT2 are now associated with PKD, PNKD, PED, hemiplegic migraine and self-limiting infantile seizures (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

confidence: 99%

Paroxysmal Movement Disorders

2021

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“…Bi-allelic mutations in the TBC1D24 gene, which encodes for a presynaptic protein involved in vesicle tracking, have been described in a wide range of neurological disorders that include epileptic syndromes, DOORS syndrome (deafness, onychodystrophy, osteodystrophy, intellectual disability and seizures) or syndromic and non-syndromic deafness (14). Recently PED as a prominent clinical feature associated with epilepsy has been reported in few patients (15)(16)(17). Episodes starts usually between 1 and 2 years of age and are characterized by dystonia triggered by exercise or fatigue; patients present with episodes of trunk bending laterally or backward without clear discomfort, some other cases have arm dystonia after writing or performing motor tasks.…”

Section: Pediatric Paroxysmal Exercise-induced Neurological Symptoms: Phenotypic and Genotypic Spectrum Movement Disordersmentioning

confidence: 99%

“…Episodes last seconds to hours and are alleviated or ceased by resting. No specific treatment results in marked benefit, although a possible effect of acetazolamide (17) and carbamazepine (16) has been suggested. Therefore, avoidance of precipitating factors remains the most effective therapeutic strategy.…”

Section: Pediatric Paroxysmal Exercise-induced Neurological Symptoms: Phenotypic and Genotypic Spectrum Movement Disordersmentioning

confidence: 99%

Pediatric Paroxysmal Exercise-Induced Neurological Symptoms: Clinical Spectrum and Diagnostic Algorithm

et al. 2021

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Paroxysmal exercise-induced neurological symptoms (PENS) encompass a wide spectrum of clinical phenomena commonly presenting during childhood and characteristically elicited by physical exercise. Interestingly, few shared pathogenetic mechanisms have been identified beyond the well-known entity of paroxysmal exercise-induced dyskinesia, PENS could be part of more complex phenotypes including neuromuscular, neurodegenerative, and neurometabolic disease, epilepsies, and psychogenetic disorders. The wide and partially overlapping phenotypes and the genetic heterogeneity make the differential diagnosis frequently difficult and delayed; however, since some of these disorders may be treatable, a prompt diagnosis is mandatory. Therefore, an accurate characterization of these symptoms is pivotal for orienting more targeted biochemical, radiological, neurophysiological, and genetic investigations and finally treatment. In this article, we review the clinical, genetic, pathophysiologic, and therapeutic landscape of paroxysmal exercise induced neurological symptoms, focusing on phenomenology and differential diagnosis.

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“…Two cases of response to levodopa in PED caused by SLC2A1 mutations (9, 140) further add to the unexpected link between these dopaminergic deficiency and PED. PED episodes associated with epilepsy can also happen in ATP1A3-related disease (in addition to chronic dystonia and parkinsonism) as well as in mutations in TBC1D24 (141)(142)(143). In clinical practice, many other cases of PED remain with undetermined etiology.…”

Section: Paroxysmal Exertional Dyskinesia and Epilepsymentioning

confidence: 99%

Paroxysmal Genetic Movement Disorders and Epilepsy

et al. 2021

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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.

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Biallelic Mutations of TBC1D24 in Exercise‐Induced Paroxysmal Dystonia

Cited by 8 publications

References 7 publications

Paroxysmal Movement Disorders

Paroxysmal Movement Disorders

Pediatric Paroxysmal Exercise-Induced Neurological Symptoms: Clinical Spectrum and Diagnostic Algorithm

Paroxysmal Genetic Movement Disorders and Epilepsy

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