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Episodic Ataxia Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
13383 ACO2 81479,81479 Order Options and Pricing
ARSA 81405,81479
ATP1A2 81406,81479
ATP1A3 81479,81479
ATP5MK 81479,81479
BCKDHA 81405,81479
BCKDHB 81406,81479
CACNA1A 81185,81479
CACNB4 81479,81479
CEP290 81408,81479
COL4A1 81408,81479
COL4A2 81479,81479
DARS2 81479,81479
DBT 81406,81405
ETHE1 81479,81479
FGF14 81479,81479
GALC 81479,81479
ITPR1 81479,81479
KCNA1 81479,81479
KCNA2 81479,81479
KCND3 81479,81479
OTC 81405,81479
PNKD 81406,81479
SCN1A 81407,81479
SCN2A 81479,81479
SETX 81406,81479
SLC1A3 81479,81479
SLC2A1 81405,81479
SPTBN2 81479,81479
TBC1D24 81479,81479
TGM6 81479,81479
TPK1 81479,81479
TRPC3 81479,81479
TTBK2 81479,81479
UBE3A 81406,81479
UBR4 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
13383Genes x (36)81479 81185(x1), 81405(x5), 81406(x6), 81407(x1), 81408(x2), 81479(x57) $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Erin Sybouts, PhD

Clinical Features and Genetics

Clinical Features

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. 

Genetics

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.  

Clinical Sensitivity - Sequencing with CNV PGxome

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).

Testing Strategy

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).

Indications for Test

Candidates for this test include children and adults that experience recurrent episodes of ataxia with or without additional neurologic symptoms. 

Diseases

Name Inheritance OMIM ID
Alternating Hemiplegia Of Childhood AD 104290
Alternating Hemiplegia of Childhood 2 AD 614820
Amyotrophic Lateral Sclerosis Type 4 AD 602433
Angelman Syndrome AD 105830
Angiopathy, Hereditary, With Nephropathy, Aneurysms, And Muscle Cramps AD 611773
Aniridia, Cerebellar Ataxia, And Mental Retardation AD 206700
Bardet-Biedl Syndrome 14 AR 615991
Benign Familial Neonatal-Infantile Seizures AD 607745
Brugada Syndrome 9 AD 616399
CAPOS syndrome AD 601338
Deafness , autosomal recessive 86 AR 614617
Deafness, autosomal dominant 65 AD 616044
DOOR syndrome AR 220500
Dystonia 12 AD 128235
Dystonia 9 AD 601042
Epilepsy, Idiopathic Generalized 9 AD 607682
Epilepsy, Idiopathic Generalized, Suscpetibility to, 12 AD 614847
Epilepsy, rolandic, with proxysmal exercise-induce dystonia and writer's cramp AR 608105
Epileptic Encephalopathy, Early Infantile, 11 AD 613721
Epileptic Encephalopathy, Early Infantile, 16 AR 615338
Epileptic Encephalopathy, Early Infantile, 32 AD 616366
Epileptic Encephalopathy, Early Infantile, 42 AD 617106
Episodic Ataxia Type 1 AD 160120
Episodic Ataxia Type 2 AD 108500
Episodic Ataxia, Type 5 AD 613855
Episodic Ataxia, Type 6 AD 612656
Episodic ataxia, type 9 AD 618924
Ethylmalonic Encephalopathy AR 602473
Familial Hemiplegic Migraine Type 1 AD 141500
Familial Hemiplegic Migraine Type 2 AD 602481
Familial Hemiplegic Migraine Type 3 AD 609634
Galactosylceramide Beta-Galactosidase Deficiency AR 245200
Generalized Epilepsy With Febrile Seizures Plus, Type 2 AD 604403
Glut1 Deficiency Syndrome 1 AD 606777
Glut1 Deficiency Syndrome 2 AD 612126
Infantile cerebellar-retinal degeneration AR 614559
Joubert Syndrome 5 AR 610188
Leber Congenital Amaurosis 10 611755
Leukoencephalopathy With Brainstem And Spinal Cord Involvement And Lactate Elevation AR 611105
Maple Syrup Urine Disease AR 248600
Meckel Syndrome 4 AR 611134
Metachromatic Leukodystrophy AR 250100
Microangiopathy and leukoencephalopathy, pontine, autosomal dominant AD 618564
Myoclonic Epilepsy, Familial Infantile AR 605021
Optic atrophy 9 AR 616289
Ornithine Carbamoyltransferase Deficiency XL 311250
Paroxysmal Choreoathetosis AD 118800
Porencephaly 1 AD 175780
Porencephaly 2 AD 614483
Retinal arteries, tortuosity of AD 180000
Senior-Loken Syndrome 6 AR 610189
Severe Myoclonic Epilepsy In Infancy AD 607208
Spinocerebellar Ataxia 11 AD 604432
Spinocerebellar Ataxia 15 AD 606658
Spinocerebellar ataxia 19 AD 607346
Spinocerebellar Ataxia 27 AD 609307
Spinocerebellar ataxia 29, congenital nonprogressive AD 117360
Spinocerebellar Ataxia 35 AD 613908
Spinocerebellar ataxia 41 AD 616410
Spinocerebellar Ataxia 5 AD 600224
Spinocerebellar Ataxia 6 AD 183086
Spinocerebellar Ataxia Autosomal Recessive 1 AR 606002
Spinocerebellar ataxia, autosomal recessive 14 AR 615386
Stomatin-deficient cryohydrocytosis with neurologic defects AD 608885
Stroke, hemorrhagic 614519
Thiamine Metabolism Dysfunction Syndrome 5 (Episodic Encephalopathy Type) AR 614458

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Citations

Ordering/Specimens

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Specimen Types

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PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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STAT and Prenatal Test Options are not available with Patient Plus.

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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