Infantile-Onset Paroxysmal Movement Disorder and Episodic Ataxia Associated with a TBC1D24 Mutation

Zimmern, Vincent; Riant, Florence; Roze, Emmanuel; Ranza, Emmanuelle; Lehmann‐Horn, Frank; Bellescize, Julitta de; Ville, Dorothée; Lesca, Gaëtan; Korff, Christian

doi:10.1055/s-0039-1688410

Cited by 12 publications

(16 citation statements)

References 15 publications

(10 reference statements)

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“…There was a gradual improvement over time due to trigger avoidance. Also, paroxysmal facial and limb myoclonus with onset in early infancy, triggered by fever and fatigue has been published (42).…”

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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“…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 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. The phenomenology of the movement disorder has also be reported as hyperkinetic (tremor or fine myoclonus), involving the oromandibular region or the voice after prolonged chewing or singing (17). Episodes last seconds to hours and are alleviated or ceased by resting.…”

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%

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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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“…Mutations affecting TBC1D24 are associated with an expanding spectrum of phenotypes including developmental delay, hearing impairment, Deafness, onychodystrophy, osteodystrophy and mental retardation syndrome (DOORS) syndrome (Mendelian Inerhitance in Man but now used almost exclusively as an acronym, not usual to expand (MIM) 220500), and a range of epilepsies . Different movement disorders, including ataxia, spasticity, and episodic dystonia, have also been reported, including, most recently, exercise‐induced dystonia . Here we report 2 unrelated patients with biallelic TBC1D24 variants in whom exercise‐induced dystonia was a major disease feature.…”

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confidence: 96%