Heterozygous <scp><i>EIF2AK2</i></scp> Variant Causes Adolescence‐Onset Generalized Dystonia Partially Responsive to <scp>DBS</scp>

Magrinelli, Francesca; Moualek, Dalila; Tazir, Mériem; Pacha, Lamia Ali; Verghese, Abraham; Bhatia, Kailash P.; Maroofian, Reza; Houlden, Henry

doi:10.1002/mdc3.13371

Cited by 10 publications

(6 citation statements)

References 11 publications

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“…However, the clinical phenotype is variable and more complex neurologic disorders with motor delay, lower limb spasticity, mild developmental delay with cognitive impairments, and nonspecific brain imaging abnormalities were described [74]. One case of DYT-33 dystonia responsive to globus pallidus DBS was described [75].…”

Section: Autosomal Dominantmentioning

confidence: 99%

Classification of Dystonia

Biase

Santo

Caminiti

et al. 2022

Life

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Dystonia is a hyperkinetic movement disorder characterized by abnormal movement or posture caused by excessive muscle contraction. Because of its wide clinical spectrum, dystonia is often underdiagnosed or misdiagnosed. In clinical practice, dystonia could often present in association with other movement disorders. An accurate physical examination is essential to describe the correct phenomenology. To help clinicians reaching the proper diagnosis, several classifications of dystonia have been proposed. The current classification consists of axis I, clinical characteristics, and axis II, etiology. Through the application of this classification system, movement disorder specialists could attempt to correctly characterize dystonia and guide patients to the most effective treatment. The aim of this article is to describe the phenomenological spectrum of dystonia, the last approved dystonia classification, and new emerging knowledge.

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Section: Autosomal Dominantmentioning

confidence: 99%

Classification of Dystonia

Biase

Santo

Caminiti

et al. 2022

Life

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“…With increasing use of DBS (most commonly targeting the globus pallidus pars internus – GPi), there have been multiple observations that DBS is more effective in children with monogenic forms of dystonia or dyskinesia (particularly TOR1A [67], GNAO1 [68] and KMT2B [69]). In addition, there is emerging evidence for a positive response to GPi DBS in an evolving number of other rare childhood-onset movement disorders ( ACTB [70], ADCY5 [71], ANO3 [72], EIF2AK2 [73], PANK2 [74], SGCE [75], TAF1 [76], THAP1 [77], UBA5 [78]). Independent of cause, an important application of DBS is in the setting of status dystonicus and refractory status dystonicus [79 ▪▪ ,80,81].…”

Section: Deep Brain Stimulationmentioning

confidence: 99%

Emerging therapies for childhood-onset movement disorders

Vogt,

Quiroz,

Ebrahimi-Fakhari

2024

Current Opinion in Pediatrics

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Purpose of review We highlight novel and emerging therapies in the treatment of childhood-onset movement disorders. We structured this review by therapeutic entity (small molecule drugs, RNA-targeted therapeutics, gene replacement therapy, and neuromodulation), recognizing that there are two main approaches to treatment: symptomatic (based on phenomenology) and molecular mechanism-based therapy or ‘precision medicine’ (which is disease-modifying). Recent findings We highlight reports of new small molecule drugs for Tourette syndrome, Friedreich's ataxia and Rett syndrome. We also discuss developments in gene therapy for aromatic l-amino acid decarboxylase deficiency and hereditary spastic paraplegia, as well as current work exploring optimization of deep brain stimulation and lesioning with focused ultrasound. Summary Childhood-onset movement disorders have traditionally been treated symptomatically based on phenomenology, but focus has recently shifted toward targeted molecular mechanism-based therapeutics. The development of precision therapies is driven by increasing capabilities for genetic testing and a better delineation of the underlying disease mechanisms. We highlight novel and exciting approaches to the treatment of genetic childhood-onset movement disorders while also discussing general challenges in therapy development for rare diseases. We provide a framework for molecular mechanism-based treatment approaches, a summary of specific treatments for various movement disorders, and a clinical trial readiness framework.

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“…Of note, EIF2AK2 activity is regulated by the interferon-inducible double-stranded RNA-dependent protein kinase activator A, whose mutations cause a rare form of young onset parkinsonism-dystonia [49,50]. To further support the molecular link with stress response, fever-induced decompensation has recently been described in a patient carrying an EIF2AK2 novel variant [51,52].…”

Section: Quality Control Machinery and Traffickingmentioning

confidence: 99%

The apparent paradox of phenotypic diversity and shared mechanisms across dystonia syndromes

Fonzo

Albanese

Jinnah

2022

Current Opinion in Neurology

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Purpose of reviewWe describe here how such mechanisms shared by different genetic forms can give rise to motor performance dysfunctions with a clinical aspect of dystonia.Recent findingsThe continuing discoveries of genetic causes for dystonia syndromes are transforming our view of these disorders. They share unexpectedly common underlying mechanisms, including dysregulation in neurotransmitter signaling, gene transcription, and quality control machinery. The field has further expanded to include forms recently associated with endolysosomal dysfunction.SummaryThe discovery of biological pathways shared between different monogenic dystonias is an important conceptual advance in the understanding of the underlying mechanisms, with a significant impact on the pathophysiological understanding of clinical phenomenology. The functional relationship between dystonia genes could revolutionize current dystonia classification systems, classifying patients with different monogenic forms based on common pathways. The most promising effect of these advances is on future mechanism-based therapeutic approaches.

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Heterozygous EIF2AK2 Variant Causes Adolescence‐Onset Generalized Dystonia Partially Responsive to DBS

Cited by 10 publications

References 11 publications

Classification of Dystonia

Classification of Dystonia

Emerging therapies for childhood-onset movement disorders

The apparent paradox of phenotypic diversity and shared mechanisms across dystonia syndromes

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