Materials and Methods

The method of literature search was through the MEDLINE database. We obtained articles listed in the references of articles identified by our initial literature search with the keywords “episodic ataxia”, “episodic ataxia type 2”, “CACNA1A mutation”, and “episodic ataxia and nystagmus”. All years were included and searched. We included case reports only if they contributed new information on the presentation, treatment, and associations of episodic ataxia type 2. Non-English articles were included in our literature search and included when they contributed clinically significant information. We included select articles published prior to 2005 but focused our overview on articles from the past two decades.

Disease Entity

EA2, also known as acetazolamide-responsive cerebellar ataxia and hereditary paroxysmal cerebellar ataxia, is a rare autosomal dominant disorder characterized by spells of imbalance, ataxia, and nystagmus [1,2]. H.L. Parker first reported EA2 in 1946 [3], and in 1996 Ophoff et al identified that mutations in the calcium channel gene CACNA1A caused EA2 [2,4]. Although EA2 is uncommon with an estimated incidence of 1 in 100,000, it is the most frequent subtype of the eight episodic ataxias [2,5]. EA2 has high phenotypic variability and there is a recognized clinical overlap with spinocerebellar ataxia type 6 and familial hemiplegic migraine type 1 [1].

Etiology

The most commonly reported cause of EA2 is loss of function mutations in the CACNA1A gene, located at chromosome 19p13 [6]. The CACNA1A gene encodes the ɑ1A subunit of the P/Q type voltage-gated calcium channel Ca_v2.1 in Purkinje cells and granule cells in the cerebellum [7]. The ɑ1A subunit of Ca_v2.1 directs the activity of the multiunit calcium channel [7]. P/Q voltage-gated channels control pace making in Purkinje cells [1]. More than 80 mutations relating to EA2 have been identified, including nonsense, frameshift, and missense mutations [2]. These mutations may lead to a complete loss of function in calcium channels [8]. One potential cause is when a CACNA1A mutation encodes a premature stop codon, forming truncated peptides [3]. CACNA1A mutations in EA2 lead to a decrease in the flow of Ca²⁺ into Ca_v2.1 channels [1].

Pathophysiology

The proposed mechanism of EA2 involves CACNA1A mutations inhibiting the activity of Purkinje cells, leading to motor dysfunction [9]. Such mutations cause improper amino acid sequences in peptides that make up Ca²⁺ channel subunits, resulting in a partial or complete loss of function in Ca²⁺ channels [3-10].The Ca_v2.1 subunit is the predominant channel for Purkinje cells, and P/Q currents in this channel play a crucial role in neurotransmitter release [11,12]. Tara et al. [13] reports CACNA1A mutations in tottering mice models reduce the P/Qtype calcium current of the Ca_v2.1 channel. Reduced calcium flow lowers Purkinje cell coordination and leads to erratic firing, which is linked to motor attacks in mice. Lack of precision in Purkinje cells likely contributes to EA2 symptoms during and in between attacks [1,14]. A lower number of functioning calcium channels corresponding to the cerebellum may also play a role in bouts of ataxia [7]. Since EA2 is an autosomal dominant disorder, wild-type Ca_v2.1 channels may still be expressed. However, it is possible that mutant Ca_v2.1 channels interfere with and decrease the function of wild-type Ca_v2.1 channels, further contributing to EA2 symptoms [15]. While a lower density of calcium channels likely corresponds to ataxia and other symptoms in EA2 patients, no definite mechanism has been identified.

Demographics and Associations

EA2 presents most commonly between the ages of 5 and 20 and has a prevalence of three to five people in 100,000 [4,16]. From the fourteen case reports we analyzed, the mean age at which patients presented symptoms of EA2 was 11.5 years (Table 1). The youngest age a patient presented was 2 years, and the oldest age was 26 years. Nevertheless, there are cases of EA2 presenting in late adulthood [5]. Symptoms of EA2 may continue into or begin in later decades [17]. While there is a typical age at which EA2 presents, there are few known factors other than genetics that predispose one to this disease. Since EA2 is an autosomal dominant disorder, it affects males and females equally, and it remains unknown if certain racial groups are more predisposed to this disease. Studies conducted by Li et al. [18], Niu et al. [19], Rajakulendran et al. [20], and Wong-Spracklen et al. [21] link CACNA1A variations with epilepsy, indicating EA2 patients may be at a greater risk of epilepsy than the general population.

*Patients related to each other, familial EA2 **Patients related to each other, familial EA2

CACNA1A mutations also cause the disorders familial hemiplegic migraine-1 (FHM1) and spinocerebellar ataxia type 6 (SCA6), and like EA2, are associated with progressive ataxia [4]. Further similarities lie in early-stage symptoms. Both EA2 and SCA6 patients experience imbalance, loss of coordination, and stumbling. Symptoms of FHM1 may include seizures, nystagmus, and ataxia, like EA2 [22]. Nardello et al reports different phenotypes corresponding to these three disorders from a common CACNA1A mutation [23]. FHM1 is characterized by severe migraines with aura [24]. Symptoms of aura include temporary loss of sensation, vision, and motor control. A notable symptom during the aura phase is hemiparesis [25]. The effects of hemiplegic migraine are typically temporary, but cases such as those reported by T.J. Schwedt et al. [26] and Obendorfer et al. [27] involve patients who experience permanent symptoms. Medications such as sodium valproate and acetazolamide have been prescribed as treatment for FHM1, often reducing attack duration and frequency [28]. Thus, while FHM1 is not a fatal disorder, patients may experience lifelong effects that may be mitigated with medication and lifestyle changes. SCA6 is distinguishable from its allelic disorders in that it has an adult age of onset, whereas EA2 typically involves a childhood onset [5,29]. SCA6 is characterized by late onset progressive ataxia. Patients with SCA6 may display EA2 symptoms such as nystagmus and dysarthria due to the similarity of the disorders [29]. SCA6 is not typically a fatal disorder, but quality of life may be hindered by severity of symptoms. Symptoms of SCA6 may be managed through medications such as rovatirelin and acetazolamide, as well as physical therapy [30].

Management

Symptoms

The symptoms of EA2 can have a wide range between patients. Table 1 illustrates the symptoms that have been reported in various case reports of EA2 patients. Symptoms include gaze-evoked nystagmus, rebound nystagmus, primary position downbeat nystagmus, headaches, vertigo, and imbalance [1,17]. Episodes of ataxia may be triggered by bouts of emotional or physical stress, exercise, and alcohol, with duration varying from seconds to days [31]. The frequency of these spells varies from several times a week to once or twice a year [32,33]. Patients are generally asymptomatic between attacks, although they may develop constant nystagmus, progressive ataxia, and cerebellar atrophy [4]. While it is an autosomal dominant disorder, individuals may not report a family history of either EA2 or FHM1 [8]. EA2’s effect on Purkinje cell activity may influence the behavior the cerebellum regulates, including motor function, problem-solving, and emotion regulation [34]. EA2-induced cerebellar atrophy may cause cognitive deficiencies [34]. These include impairments of verbal fluency, figural memory, visuoconstructive abilities, and psychomotor delays and are common in these patients during childhood. Many adult EA2 patients have deficiencies in attention, memory, visuoconstructive abilities, and cognitive control [35].

Clinical Diagnosis

Physicians may diagnose EA2 through physical examination, assessment of family history, and neurological examination, including analysis of coordination, motor function, and sensory function [5]. Tests such as computed tomography and magnetic resonance imaging provide insight into any cerebellar atrophy [8]. In our review of case reports on EA2, 42% of patients who underwent brain imaging had some form of cerebellar atrophy (Table 2). Cerebellar atrophy may aid in the diagnosis of EA2 but is not present in all patients. Between EA2 attacks, the brain often functions normally, but atrophy of the cerebellum may occur as a long-term effect of the disease [5]. Genetic testing is necessary when diagnosing EA2 in a patient, as it may identify mutations in the CACNA1A gene. Whole exome sequencing and next generation sequencing are often used to diagnose ataxic disorders [5]. Mutation in the CACNA1A gene may signify EA2, but it may also indicate SCA6 or FHM1 [2,4]. Therefore, a referral to both genetics and neurology is needed. A full history of the condition of the patient should be established, including onset age, duration and frequency of attacks, cognitive impairments, events that affected childhood development, and family history of the past three generations [5]. A video of the patient’s attacks and symptoms between episodes may provide insight into the telltale signs of ataxia and nystagmus [5]. EA2 may be overlooked due to its wide range of phenotypes and genetic variability. Misdiagnoses include migraine, vestibular disorders, seizures, transient ischemic attack, and anxiety [5].

Prognosis

EA2 is a lifelong condition that does not have a cure, yet symptoms can be mitigated with the use of medications and lifestyle changes. In some cases, symptoms cease entirely in patients who have been treated with medication [15,36]. It does not shorten lifespan and can be managed with treatments such as 4-aminopyridine or acetazolamide [24].These medications can be used as long as patients experience EA2 episodes, which can occur for the entirety of one’s life [14].

*Patients related to each other, familial EA2 **Patients related to each other, familial EA2

Treatment

4-aminopyridine (4-AP) and acetazolamide (AZM) are mainstays in the treatment of this condition. They may reduce the duration and frequency of attacks in patients [34]. 4-AP operates by blocking potassium channels, mainly the Kv1.5 subunit, increasing and extending action potential [14,37]. This has demonstrated improvement in the precision of pace making in Purkinje cells in tottering mice, which in turn increases the motor function of the animals [38]. Typical doses of 4-AP are between 10 to 20 mg/day [38,39]. Reported side effects of 4-AP include paresthesia, fatigue, dizziness, and insomnia [39,40]. AZM functions by inhibiting carbonic anhydrase, lowering lactate and pyruvate levels in the brain and decreasing pH. Lower pH reduces potassium flow, resetting firing potential of Purkinje cells [19]. The typical dosage of AZM is 250 to 1000 mg/day [41]. Reported side effects include kidney stones, nephrocalcinosis, paresthesia, dysgeusia, fatigue, hyperhidrosis, and gastrointestinal disturbances [41,42]. 4-AP and AZM have demonstrated their abilities to mitigate symptoms in EA2 attacks through numerous studies, including a doubleblind crossover trial with 30 EA2 patients. Concluding the 12- week period of the study, 4-AP reduced the number of attacks to 63%, while AZM reduced attack frequency to 52% [39]. Levetiracetam is another medication that may reduce symptoms in EA2 patients. Levetiracetam likely functions by intracellularly inhibiting presynaptic calcium channels. This may prevent the release of neurotransmitters and potentially mitigate ataxic episodes [43]. Combined treatment of levetiracetam and AZM has worked to reduce severity of symptoms in specifi cases. Patients who have previously been treated with AZM and experienced little to no change or an eventual increase in attacks have responded well to taking both medications [44]. To best manage EA2, one may make lifestyle changes to avoid triggers such as stress or lack of sleep. Maintaining one’s health through exercise, a balanced diet, and stress-relieving or managing practices may aid in reducing EA2 attacks. Several studies have demonstrated that patients with degenerative ataxia improved motor skills with consistent physical therapy [41,45]. While EA2 is not typically degenerative, patients may still experience improvements in gait and coordination with consistent physical therapy [46-49].

Conclusion

EA2 involves interictal nystagmus and possibly triggerinduced episodes of ataxia and vertigo. The frequency of attacks ranges widely between patients but typically present in childhood and persist into late adulthood. EA2 may be managed through the administration of 4-aminopyridine, AZM, or levetiracetam, and the avoidance of triggers. Potential areas of future study include further research into the mechanism between CACNA1A mutations and ataxic episodes, long-term effects of medications used to treat EA2, and risk factors to EA2.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest..

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