Pearls &amp; Oy-sters: Episodic ataxia type 2

Guterman, Elan L.; Yurgionas, Brian; Nelson, Alexandra

doi:10.1212/wnl.0000000000002743

Cited by 23 publications

(12 citation statements)

References 11 publications

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“…7 ). Together these data in EA2 mice are in agreement with EA2 patient studies that show memory deficits and anxiety disorders ( 11 , 13 , 14 , 26 ).…”

Section: Discussionsupporting

confidence: 90%

Cognitive deficits in episodic ataxia type 2 mouse models

Bohne

Mourabit

Josten

et al. 2021

Human Molecular Genetics

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Episodic ataxia type 2 (EA2) is a rare autosomal dominant disorder characterized by motor incoordination, paroxysmal dystonia, vertigo, nystagmus and more recently cognitive deficits. To date over 100 mutations in the CACNA1A gene have been identified in EA2 patients leading to a loss of P/Q-type channel activity, dysfunction of cerebellar Purkinje cells (PC) and motor incoordination. To determine if the cerebellum is contributing to these cognitive deficits, we examined 2 different EA2 mouse models for cognition impairments where CACNA1A was removed specifically from cerebellar Purkinje or granule cells postnatally. Both mutant mouse models showed anxiolytic behavior to lighted, open areas in the open field and light/dark place preference tests but enhanced anxiousness in the novel suppressed feeding test. However, EA2 mice continued to show augmented latencies in the light/dark preference test and when the arena was divided into 2 dark zones in the dark/dark preference test. Moreover, increased latencies were also displayed in the novel object recognition test, indicating that EA2 mice are indecisive and anxious to explore new territories and objects and may have memory recognition deficits. Exposure to a foreign mouse led to deficiencies in attention and sniffing as well as social and genital sniffing were observed. These data suggest that postnatal removal of the P/Q type calcium channel from the cerebellum regulates neuronal activity involved in anxiety, memory, decision making and social interactions. Our EA2 mice will provide a model to identify the mechanisms and therapeutic agents underlying cognitive and psychiatric disorders seen in EA2 patients.

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“…7 ). Together these data in EA2 mice are in agreement with EA2 patient studies that show memory deficits and anxiety disorders ( 11 , 13 , 14 , 26 ).…”

Section: Discussionsupporting

confidence: 90%

Cognitive deficits in episodic ataxia type 2 mouse models

Bohne

Mourabit

Josten

et al. 2021

Human Molecular Genetics

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“…Acetazolamide and 4-aminopyridine are reported to decrease severity and frequency of spells in EA2, 27 and represent two valid and generally safe treatment options. A clinical trial focusing on the comparison of acetazolamide and 4-aminopyridine therapy in EA2 patients is ongoing in Munich (EAT2TREAT study).…”

Section: Discussionmentioning

confidence: 99%

Therapy of episodic ataxias: case report and review of the literature

Orsucci¹,

Raglione²,

Mazzoni³

et al. 2019

DIC

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Episodic ataxias (EAs) are characterized by recurrent, discrete episodes of vertigo and ataxia. EA1 and EA2 are the two most common forms. In the interictal interval, myokymia is typically present in EA1, whereas EA2 patients present with interictal nystagmus. Specific pharmacological therapies are available for EA1 and especially EA2. We briefly discuss the case of an Italian young man with EA2, with a novel de novo CACNA1A mutation, who in our opinion is particularly illustrative for introducing the therapeutic approach. Acetazolamide could fully suppress EA episodes in our patient. We also provide a perspective review of the topic. 4-Aminopyridine is another valid treatment option. For EA1 (and for rarer EAs), the therapeutic possibilities are more limited. Carbamazepine is probably the treatment of choice for EA1, but the optimal treatment plan is unknown. A better understanding of the molecular processes involved in the mediation of EAs will lead to more specific and efficacious therapies for this still elusive group of disorders.

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“…Clinical This is the most common hereditary episodic ataxia. The classical description, first published in 1946, is intermittent spells of ataxia and dysarthria lasting several hours, possibly up to 2-3 days [2,22]. There is interictal nystagmus between attacks, a useful clinical clue.…”

Section: Ea2mentioning

confidence: 99%

Episodic Ataxias: Primary and Secondary Etiologies, Treatment, and Classification Approaches

Hassan¹

2023

Tremor and Other Hyperkinetic Movements

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Background: Episodic ataxia (EA), characterized by recurrent attacks of cerebellar dysfunc tion, is the manifestation of a group of rare autosomal dominant inherited disorders. EA1 and EA2 are most frequently encountered, caused by mutations in KCNA1 and CACNA1A. EA3-8 are reported in rare families. Advances in genetic testing have broadened the KCNA1 and CACNA1A phenotypes, and detected EA as an unusual presentation of several other genetic disorders. Additionally, there are various secondary causes of EA and mimicking disorders. Together, these can pose diagnostic challenges for neurologists.Methods: A systematic literature review was performed in October 2022 for 'episodic ataxia' and 'paroxysmal ataxia', restricted to publications in the last 10 years to focus on recent clinical advances. Clinical, genetic, and treatment characteristics were summarized.Results: EA1 and EA2 phenotypes have further broadened. In particular, EA2 may be accom panied by other paroxysmal disorders of childhood with chronic neuropsychiatric features. New treatments for EA2 include dalfampridine and fampridine, in addition to 4aminopyridine and acetazolamide. There are recent proposals for EA9-10. EA may also be caused by gene mutations associated with chronic ataxias (SCA-14, SCA-27, SCA-42, AOA2, CAPOS), epilepsy syndromes (KCNA2, SCN2A, PRRT2), GLUT1, mitochondrial disorders (PDHA1, PDHX, ACO2), metabolic disorders (Maple syrup urine disease, Hartnup disease, type I citrullinemia, thiamine and biotin metabolism defects), and others. Secondary causes of EA are more commonly encountered than primary EA (vascular, inflammatory, toxicmetabolic). EA can be misdiagnosed as migraine, peripheral vestibular disorders, anxiety, and functional symptoms. Primary and secondary EA are frequently treatable which should prompt a search for the cause.Discussion: EA may be overlooked or misdiagnosed for a variety of reasons, including phenotypegenotype variability and clinical overlap between primary and secondary causes. EA is highly treatable, so it is important to consider in the differential diagnosis of paroxysmal disorders. Classical EA1 and EA2 phenotypes prompt single gene test and treatment pathways. For atypical phenotypes, next generation genetic testing can aid diagnosis and guide treatment. Updated classification systems for EA are discussed which may assist diagnosis and management.

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Pearls & Oy-sters: Episodic ataxia type 2

Cited by 23 publications

References 11 publications

Cognitive deficits in episodic ataxia type 2 mouse models

Cognitive deficits in episodic ataxia type 2 mouse models

Therapy of episodic ataxias: case report and review of the literature

Episodic Ataxias: Primary and Secondary Etiologies, Treatment, and Classification Approaches

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