Episodic Ataxia Panel

Episodic ataxia is a rare neurological condition characterized by periods of incoordination and loss of balance. The major feature is bouts of ataxia lasting minutes to hours, sometimes days, with distinct onset and resolution of symptoms. The frequency of ataxic attacks varies; some individuals may have several a day, while others have several a year (Garone et al. 2020. PubMed ID: 32443735). 

Minor features vary between episodic ataxias of different genetic origins but frequently include myokymia, weakness, nystagmus, dysarthria, vertigo, double vision, and tinnitus. Episodic ataxia can be variably associated with other neurologic phenotypes as well, such as epilepsy, dystonia, hemiplegic migraine, headache, hemiplegia, myasthenia, tremor, and intermittent coma (Jen et al. 2007. PubMed ID: 17575281; Garone et al. 2020. PubMed ID: 32443735). These additional features vary among patients, and some individuals may not have any other symptoms other than ataxia. 

Most known episodic ataxias have an age of onset (age of first attack) within the first two decades of life; however, adult onset has also been described (Garone et al. 2020. PubMed ID: 32443735). Episodic ataxia is estimated to occur in less than 1 in 100,000 individuals, though this estimate may not be fully accurate due to the limited understanding of episodic ataxia (Choi and Choi. 2016. PubMed ID: 27667184). 

Other ataxia syndromes, such as spinocerebellar ataxia 6, may demonstrate fluctuations in baseline ataxia, thus misguiding diagnosis (Jen et al. 2007. PubMed ID: 17575281). Genetic testing can help guide treatment for ataxia patients, as management of episodic ataxia can be aided with medications such as aminopyridines and acetazolamide (Ilg et al. 2014. PubMed ID: 24222635). 

Genes known to cause episodic ataxia have also been associated with other disorders with different neurological phenotypes, predominantly epilepsy (Choi and Choi. 2016. PubMed ID: 27667184). In addition, pathogenic variants in CACNA1A are associated with developmental and epileptic encephalopathy, familial hemiplegic migraine, and spinocerebellar ataxia type 6 in addition to episodic ataxia type 2. 

Currently, eight episodic ataxia (EA) syndromes are described in OMIM (EA1-8), five of which have a known genetic cause (EA 1,2,5,6, and 8). All these disorders demonstrate autosomal dominant inheritance and familial as well as de novo cases have been reported in the literature.

The best characterized genes associated with episodic ataxia are KCNA1 and CACNA1A, which cause the most common episodic ataxias, types 1 and 2, respectively. KCNA1 encodes a potassium gated ion channel and CACNA1A encodes the α1 subunit of the P/Q-type voltage-gated calcium ion channel (Choi and Choi. 2016. PubMed ID: 27667184); these ion channels are expressed throughout the nervous system and are highly expressed within the cerebellum (Jen et al. 2007. PubMed ID: 17575281). 

Most pathogenic variants reported in KCNA1 are missense variants that disrupt channel function, though nonsense variants resulting in premature protein termination have also been described (Tomlinson et al. 2009. PubMed ID: 19734086). The disease-causing variants in KCNA1 affect residues within the transmembrane segments S1-S6 or the C-terminus (Paulhus et al. 2020. PubMed ID: 32316562). 

Pathogenic variants in CACNA1A have been associated with multiple disorders (developmental and epileptic encephalopathy, familial hemiplegic migraine, spinocerebellar ataxia type 6, and episodic ataxia type 2), and the type and location of the variant is likely what determines the clinical phenotype observed. Variants that result in EA2 are often those that disrupt the reading frame or result in premature protein termination, though missense variants have been reported as well, particularly in the pore region, for severe progressive ataxia with episodic features (Jen et al. 2007. PubMed ID: 17575281). Of note, the only copy number variants (primarily deletions) known to cause episodic ataxia include the CACNA1A gene (Labrum et al. 2009. PubMed ID: 19586927). 

CACNB4 encodes the calcium channel β4 subunit of the P/Q-type voltage-gated calcium ion channel and interacts directly with the protein product of CACNA1A (Choi and Choi. 2016. PubMed ID: 27667184). Pathogenic variants in CACNB4 are associated with EA5 and have been reported in a family with epilepsy without ataxia (Garone et al. 2020. PubMed ID: 32443735). 

EA6 is caused by pathogenic variants in SLC1A3, which encodes the excitatory amino acid transporter 1 (EAAT1). EAAT1 is a glutamate transporter present in astrocytes. Only missense variants that affect highly conserved amino acid residues have been reported to be causative for EA6. These variants disrupt the glutamate reuptake activity of EAAT1 (Jen et al. 2007. PubMed ID: 17575281; de Vries et al. 2009. PubMed ID: 19139306). 

Pathogenic variants in UBR4 are associated with episodic ataxia type 8. Unlike the other known EA genes, UBR4 encodes a ubiquitin ligase. UBR4 protein interacts with calmodulin, a calcium ion binding protein, and co-localizes with ITPR1, a calcium release channel (Conroy et al. 2014. PubMed ID: 23982692). Although not directly affecting cellular calcium ions, the molecular pathogenesis of EA8 likely still relates to disrupted ion homeostasis within neurons.

A ninth episodic ataxia has recently been proposed and attributed to pathogenic variants in FGF14 (Piarroux et al. 2020. PubMed ID: 32162847). The growth factor encoded by FGF14 is highly expressed in Purkinje cells and regulates neuronal excitability through voltage-gated sodium ion channels. 

In addition, this test includes candidate episodic ataxia genes such as ATP1A2, SCN1A, TTBK2, TGM6, and KCND3 (Choi et al. 2017. PubMed ID: 29062094). Genes associated with paroxysmal movement disorders with ataxic characteristics, such as SLC2A1, ATP1A3, TBC1D24, BCKDHA, and BCKDHB are also included (Garone et al. 2020. PubMed ID: 32443735). 

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.  

Due to the genetic heterogeneity and the limited number of known genetic causes of episodic ataxia, the clinical sensitivity of this test is difficult to estimate. Clinical sensitivity for episodic ataxia 2 (CACNA1A) has been reported to range from 13 to 40% (Mantuano et al. 2010. PubMed ID: 20129625; Denier et al. 1999. PubMed ID: 10371528; Eunson et al. 2005. PubMed ID: 16043807). In a Korean episodic ataxia cohort study by Choi et al., 28% of patients had a pathogenic variant in one of the five known EA genes (KCNA1, CACNA1A, CACNB4, SLC1A3, and UBR4; Choi et al. 2017. PubMed ID: 29062094).

This test is performed using Next-Generation Sequencing with additional Sanger sequencing as necessary. 

This panel typically provides 99.9% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).