Episodic Ataxias
Ataxia:
Episodic ataxias (EA1, EA2, EA3, EA4, EA5, EA6, EA7, EA8)
RELATED GENES:
KCNA1 (EA1), CACNA1A (EA2), CACNB4 (EA5) and others
MUTATION TYPE:
Pathogenic variants
LOCATION:
Various
HERITAGE:
Autosomal dominant
LAST UPDATE:
09/22/2025 by Marcio Galvão
Content generated with the support of Generative AI, reviewed by the author.
1. ABOUT EPISODIC ATAXIAS
Primary episodic ataxias (EA) are a group of rare hereditary disorders that cause cerebellar dysfunction, producing symptoms of ataxia during attacks (episodes), affecting the coordination of body movements. As the name suggests, an episodic ataxia is clinically characterized by temporary episodes (crises, attacks) of ataxia. The symptoms, duration of episodes, severity, and “triggers” that can cause the episodes may vary depending on the type of ataxia. Normally, the individual remains without ataxia symptoms between these episodes, but some other neurological symptoms may manifest [12].
So far, eight different types of primary episodic ataxias have been recognized, each potentially presenting some distinct symptoms [1]. The most common types are EA1 and EA2, while the others are extremely rare (in some cases affecting only a single family). For some types, the causative gene has already been identified (EA1, EA2, EA5, and EA6), while for others it has not yet been determined.
EA1 – Episodic Ataxia Type 1 – KCNA1 gene, chromosome 12 (location 12p13.32)
EA2 – Episodic Ataxia Type 2 – CACNA1A gene, chromosome 19 (location 19p13.13)
EA3 – Episodic Ataxia Type 3 – (gene unknown)
EA4 – Episodic Ataxia Type 4 – (gene unknown)
EA5 – Episodic Ataxia Type 5 – CACNB4 gene (proposed), chromosome 2 (2q23.3)
EA6 – Episodic Ataxia Type 6 – SLC1A3 gene, chromosome 5 (location 5p13.2)
EA7 – Episodic Ataxia Type 7 – (gene unknown)
EA8 – Episodic Ataxia Type 8 – (gene not yet identified; described in a single family)
For more information on the most common types (EA1 and EA2), see Section 7. Additional Information.
In addition to the eight types of primary episodic ataxias of genetic origin listed above, there are also secondary or acquired episodic ataxias, or episodic ataxia attacks caused by a variety of other non-genetic neurological disorders that may affect the cerebellum, such as Multiple Sclerosis, strokes, autoimmune or metabolic diseases, etc. (Figure 1). While primary EAs tend to manifest earlier (in childhood) and show a more clearly defined pattern of episodes or attacks with family history, in secondary or acquired EAs a family history is unlikely to be found, and symptom onset may occur at any age (from childhood to old age), depending on the factor that caused the ataxia [12].
Figure 1 – Image generated by the author with the support of Artificial Intelligence
2. TYPICAL SYMPTOMS
Symptoms of Primary Episodic Ataxias (of Genetic Origin)
The symptoms of primary episodic ataxias (such as EA1) can vary considerably from family to family, and even among individuals within the same family, including identical twins. In other words, carriers of the same mutation may present different symptoms, suggesting that other genetic or environmental modifiers may influence the condition [12].
The most common symptoms include typical episodes of ataxia (balance and coordination difficulties) and unclear or slurred speech (dysarthria), with attacks interspersed with periods of normal or near-normal neurological functioning. The episodes are usually triggered by stimuli such as physical exertion, emotional excitement, sudden changes in posture, or, in some cases, a high-carbohydrate meal. Depending on the type of ataxia, additional symptoms reported during episodes may include nausea, vomiting, migraines, and ringing in the ears (tinnitus). Some individuals may experience several attacks per day, while others may have only one or two episodes per year ([3, 4]).
EA1 Ataxia
In EA1, episodes are typically associated with ataxia (lack of coordination and balance) and vertigo, and are usually brief, lasting only seconds or minutes (rarely hours or days). Triggers for EA1 episodes include psychological stress, exercise, emotions, heat, fever, menstruation, caffeine, and alcohol. Frequency ranges from several brief daily episodes to a single episode per month. Other symptoms may include double vision (diplopia), slurred speech (dysarthria), nausea, headaches, muscle stiffness, abnormal posturing, and cramps. Myokymia may also occur between attacks. Typically, there are no ataxia symptoms between episodes, and brain MRI is normal. However, over time, especially after a long disease course, imaging may reveal cerebellar atrophy. There may also be a connection between EA1 and epilepsy, as well as cognitive issues and hearing loss [12].
EA2 Ataxia
In EA2, attacks last longer, ranging from 30 minutes to six hours. Symptoms usually include muscle weakness, trunk instability, and possibly dizziness and fatigue. Involuntary eye movements (nystagmus) are common between episodes. Muscle contractions typically do not occur in EA2, but rigidity and dystonia may be present. EA2 is the most common subtype of episodic ataxia.
Other Types of Episodic Ataxia
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EA3 – Symptoms are similar to EA1, except for the presence of tinnitus.
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EA4 – Symptoms are similar to EA2, but nystagmus is absent.
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EA5 – Seizures may occur.
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EA6 – Typical symptoms include seizures, hemiplegia (paralysis on one side of the body), and migraine.
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EA7 – Symptoms resemble EA2, except for nystagmus.
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EA8 – Symptoms involve myokymia and persistent intention tremors.
For more detailed information on symptoms, please see reference [10].
Episodic Ataxia with Proximal Chorea (Paroxysmal Choreoathetosis) and Spasticity
In this form, attacks generally last around 20 minutes and involve loss of balance, uncoordinated muscle movements, dystonia in the arms, legs, and/or fingers, and a burning sensation in the legs and around the mouth.
Double vision (diplopia) and headaches are also possible in episodic ataxias. In some cases, involuntary muscle contractions and temporary paralysis of the lower body and legs may persist between episodes.
In addition to stress, emotional excitement, and exertion, attacks may also be triggered by alcohol or fatigue.
3. ONSET
Symptoms of primary episodic ataxias typically begin ( onset ) from childhood to early adulthood, with the most likely age range varying with the type of ataxia. For example,
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In EA1, symptoms generally appear in childhood, around 8 years of age on average [12].
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In EA4, symptoms generally appear between 30 and 60 years of age.
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In EA7, symptoms also tend to manifest in adulthood.
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In EA8, symptoms can appear in childhood.
Notes
1. Although there is still no cure for episodic ataxias, in some cases, symptoms may reduce or even disappear later in life, sometimes in early adulthood. In other cases, symptoms persist into old age.
2. The condition does not shorten lifespan, and symptoms can in some cases be reduced or eliminated with medication. See Section 9. Treatments .
4. ANTICIPATION
Genetic anticipation is a phenomenon in which the severity of a genetic disorder tends to increase or symptoms tend to appear at an earlier age in successive generations within a family. This phenomenon is commonly associated with trinucleotide expansion disorders such as Huntington's disease, the spinocerebellar ataxias SCA1 , SCA2 , SCA3 , SCA6 , SCA7 , and SCA17, Dentato-Rubro-Pallido-Louisiana ataxia (DRPLA) , and X-associated spinal and bulbar muscular atrophy (SMAX1/SBMA).
In the case of episodic ataxias such as EA1 and EA2, which are rare genetic disorders with autosomal dominant inheritance, there is limited evidence suggesting genetic anticipation. Although some studies have suggested that symptoms may present at an earlier age in subsequent generations, the evidence is not as robust as for other disorders with trinucleotide expansions.
Overall, more research is needed to determine whether genetic anticipation occurs in episodic ataxias such as EA1 and EA2 and to understand the underlying genetic mechanisms involved.
5. INHERITANCE
Primary episodic ataxias are autosomal dominant diseases. This means that individuals of both sexes have the same chance of inheriting the gene and developing the disease, and that it passes directly from one generation to the next without skipping generations. A child of a person with episodic ataxia has a 50% chance of inheriting the altered gene.
In the case of EA1 ataxia, inheritance is typically autosomal dominant, but "de novo" mutations may also occur, that is, non-hereditary cases (without family history) [12] .
Note: "Autosomal" means that the gene is located on any chromosome except the X and Y sex chromosomes. Genes, like chromosomes, normally exist in pairs (we have a pair of each gene, one copy of the gene is inherited from the mother, the other from the father). "Dominant" means that just one copy of the responsible gene (an allele) inherited from either the father is enough to pass on a physical characteristic (such as dimpled cheeks) or a genetic disease (such as hereditary ataxia) from one generation (parents) to the next (children).
Figure 3 - Source: MedlinePlus, US National Library of Medicine .
6. PREVALENCE
The estimated prevalence for EA2 (the most common of the primary episodic ataxias) is 1 case per 100,000 inhabitants [12] . For the other types of EA, the prevalence is not known, but they are much rarer than EA2, and as already mentioned, in some cases only a single family is affected.
7. ADDITIONAL INFORMATION
About EA1
The first clinical description of EA1 (Episodic Ataxia type 1) emerged in 1975.
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A family was described with episodes of ataxia and vertigo lasting from seconds to a few minutes. Triggers for these episodes included strong emotions or physical exertion (exercise).
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Eyelid myokymia (eye tremors) could be present between attacks.
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The gene responsible for EA1 was initially mapped in 1994 to a specific region of chromosome 12 (OMIM [6] cites the locus as 12p13.32, while source [12] cites 12q13). It was later identified as the KCNA1 gene, which encodes the proteins forming the alpha subunits of voltage-gated potassium channels Kv1.1. These channels play a critical regulatory role in neuron-to-neuron communication [12, 15], both in the central nervous system and the peripheral nervous system.
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Because of this, pathogenic mutations in KCNA1 can cause different neurological disorders classified as potassium channelopathies (i.e., disorders involving potassium channels).
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Kv1.1 potassium channels are highly expressed at the nerve terminals of a specific type of cerebellar cell called basket cells, where they limit the release of the inhibitory neurotransmitter GABA onto Purkinje cells.
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Due to genetic mutations, this regulatory action may be disrupted, causing excessive GABA release onto Purkinje cells, which—because of GABA’s inhibitory action—reduces the output from Purkinje cells leaving the cerebellum. This leads to impaired motor coordination in the patient [13].
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It’s important to note that there are multiple mutations in the KCNA1 gene that can cause EA1 and other neurological disorders. At least 63 pathogenic variants in KCNA1 have been identified that can lead to EA1 ataxia, with or without epilepsy, depending on the specific mutation.
Sources: [12, 13]
About EA2
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EA2 (Episodic Ataxia type 2) is caused by mutations in the CACNA1A gene, which encodes voltage-gated calcium channels (Cav2.1) that control synaptic communication between neurons.
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As with EA1, EA2 symptoms tend to manifest during childhood.
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The ataxia episodes in EA2 are usually longer than those in EA1, lasting from several minutes to hours, and are generally associated with dysarthria, vertigo, nausea, vomiting, and headaches. Some patients may experience daily attacks.
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Episodes are typically triggered by physical or emotional stress, exercise, alcohol, and caffeine.
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Nearly all EA2 patients experience nystagmus, which consists of involuntary, rhythmic eye movements, in addition to ataxia.
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Over 100 different mutations in the CACNA1A gene have been reported. Many of these mutations cause the voltage-gated calcium channels to malfunction, impairing communication between neurons. This dysfunction underlies several neurological disorders. See following note for details.
Source: [13]
Note: A different mutation in the CACNA1A gene that causes episodic ataxia type 2 (EA2), located on chromosome 19, is responsible for spinocerebellar ataxia type 6 (SCA6). The symptoms of EA2 and SCA6 may be similar, especially in the early stages of SCA6. The same gene (with yet another alteration) can also cause Familial Hemiplegic Migraine type 1 (FHM1) [10].
Clinical evaluation of EA1 for diagnosis
When consulting a neurologist in search of a diagnosis, the patient should expect a detailed assessment of family history, questions about the attacks (symptoms, duration, triggers, etc.), as well as neurological and laboratory tests such as brain MRI and electromyography. If EA1 is suspected, confirmation of the diagnosis requires molecular genetic testing (DNA analysis) to detect mutations (pathogenic variants) in the KCNA1 gene. If the neurologist suspects some form of episodic ataxia but is unsure which type, there is also the option of performing a panel test that screens for multiple genes associated with different types of episodic ataxias. Finally, if tests for the KCNA1 gene and EA panels return negative, it is possible to conduct whole genome sequencing to search for DNA mutations—although this type of test is considerably more expensive [12].
8. THERAPIES AND MEDICINES BEING TRIALED FOR THESE ATAXIAS
There are medications for various symptoms of episodic ataxias, which must be prescribed by doctors.
In a pilot study of an experimental clinical trial, the drug 4-Aminopyridine (4-AP) (a potassium channel blocker) was shown to be effective in reducing the frequency of AS2 episodes and improving patient well-being. Several drugs have also been tested for AS1, with mixed results (e.g., antiepileptics such as carbamazepine and lamotrigine) [10] . More information is available in Section 9. Treatments .
9. TREATMENTS
There is still no cure for episodic ataxias, but its symptoms can be treated.
Treatments for EA1 ataxia:
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Anticonvulsant medications (in case of epilepsy symptoms) such as Carbamazepine, Phenytoin and Lamotrigine, and in certain cases, Acetalozamide and Benzodiazepine [12] .
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The response to medications is variable, and there are patients who do not respond to these medications.
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On the other hand, there are patients whose episodes are very brief and not so frequent and who do not need medication.
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If episodes of ataxia are more frequent, the patient is recommended neurofunctional physiotherapy and, in certain cases, occupational physiotherapy and speech therapy (in cases of dysarthria, for example).
Treatments for EA2 ataxia.
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Acetalozamide is the treatment normally used in EA2.
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The drug 4-AP (4-aminopyridine) which acts as a potassium channel blocker may also be effective.
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The response to medication is quite variable and some patients may not respond to treatment [13].
See information about medications for ataxia symptoms .
See information about treatments and care for patients .
See information about those who have recently been diagnosed .
See information about Support Groups for patients and caregivers.
10. REFERENCES
The references below include academic sources and specialized organizations that supported the information in this fact sheet, including peer-reviewed articles, genetic repositories (OMIM), literature summaries (GeneReviews), and informational materials from ataxia foundations. For more information, see the ataxia.info References list .
Ref #1
Source:
NAF (National Ataxia Foundation)
Copyright © National Ataxia Foundation
Language:
English
Date:
NAF-01/2019
Ref #2
Source:
diziness-and-balance.com 2024 Copyright: Timothy C. Hain, MD
Language:
English
Date:
Nov 7, 2023
Ref #3
Source:
GARD - Genetic and Rare Diseases Information Center.
Copyright © National Center for Advancing Translational Sciences - National Institutes of Health (NIH).
Language:
English
Date:
Last Updated: February 2025
Ref #4
Source:
GARD - Genetic and Rare Diseases Information Center.
Copyright © National Center for Advancing Translational Sciences - National Institutes of Health (NIH).
Language:
English
Date:
Last Updated: February 2025
Ref #5
Source:
NEUROMUSCULAR DISEASE CENTER (Alan Pestronk, MD)
Washington University, St. Louis, MO - USA
Language:
English
Date:
Last Updated: Please see https://neuromuscular.wustl.edu/rev.htm
Ref #6
Source:
OMIM ® - An Online Catalog of Human Genes and Genetic Disorders.
Copyright © Johns Hopkins University.
Language:
English
Date:
Edit History: alopez: 07/08/2020
Ref #7
Source:
OMIM ® - An Online Catalog of Human Genes and Genetic Disorders.
Copyright © Johns Hopkins University.
Language:
English
Date:
Edit History: carol: 05/30/2023
Ref #8
Source:
OMIM ® - An Online Catalog of Human Genes and Genetic Disorders.
Copyright © Johns Hopkins University.
Language:
English
Date:
Edit History: carol: 02/12/2016
Ref #9
Source:
OMIM ® - An Online Catalog of Human Genes and Genetic Disorders.
Copyright © Johns Hopkins University.
Language:
English
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Edit History: carol: 09/15/2016
Ref #10
Source:
Paola Giunti, Elide Mantuano, and Marina Frontali
PubMed ® PMID: 32899446
Language:
English
Date:
Published online 2020 Sep 5
Ref #11
Source:
Kwang-Dong Choi and Jae-Hwan Choi
PubMed ® PMID: 27667184
Language:
English
Date:
Published online 2016 Sep 21
Ref #12
Source:
Presented by: Dr. Anhar Hassan
YouTube - Copyright © National Ataxia Foundation (NAF)
Language:
English. You can enable subtitles and configure automatic translation of subtitles into other languages.
Date:
Jan 19, 2024
Ref #13
Source:
Presented by: Dr. Lorenzi Cingolani
YouTube - Copyright © National Ataxia Foundation (NAF)
Language:
English. You can enable subtitles and configure automatic translation of subtitles into other languages.
Date:
Jan 31, 2024
Ref #14
Source:
Sonia M Hasan, PhD and Maria Cristina D'Adamo, PhD
Copyright © GeneReviews. GeneReviews ® is a registered trademark of the University of Washington, Seattle.
Language:
English.
Date:
Last Revision: November 1, 2018.
Ref #15
Source:
Kelsey Paulhus, Lauren Ammerman, and Edward Glasscock
PubMed ® PMID: 3231656
Language:
English.
Date:
Published online 2020 Apr 17
Ref #16
Fonte:
GARD - Genetic and Rare Diseases Information Center.
Copyright © National Center for Advancing Translational Sciences - National Institutes of Health (NIH).
Language:
English.
Date:
Last Update: Feb 2025
Ref #17
Source:
GARD - Genetic and Rare Diseases Information Center.
Copyright © National Center for Advancing Translational Sciences - National Institutes of Health (NIH).
Language:
English.
Date:
Last Update: Feb 2025
Ref #19
Source:
GARD - Genetic and Rare Diseases Information Center.
Copyright © National Center for Advancing Translational Sciences - National Institutes of Health (NIH).
Language:
English.
Date:
Last Update: Feb 2025
Ref #19
Fonte:
GARD - Genetic and Rare Diseases Information Center.
Copyright © National Center for Advancing Translational Sciences - National Institutes of Health (NIH).
Language:
English.
Date:
Last Update: Feb 2025
Ref #20
Source:
GARD - Genetic and Rare Diseases Information Center.
Copyright © National Center for Advancing Translational Sciences - National Institutes of Health (NIH).
Language:
English.
Date:
Last Update: Feb 2025
Ref #21
Fonte:
GARD - Genetic and Rare Diseases Information Center.
Copyright © National Center for Advancing Translational Sciences - National Institutes of Health (NIH).
Language:
English.
Date:
Last Update: Feb 2025