SCA6 Fact Sheet
Ataxia:
SCA6 (Spinocerebellar Ataxia Type 6)
RELATED GENES:
CACNA1A
MUTATION TYPE:
CACNA1A -> CAG expansion mutation
LOCATION:
Chromosome 19 (19p13.2)
HERITAGE:
Autosomal Dominant
LAST UPDATE:
04/08/2025 by Marcio Galvão
Content generated with the support of Generative AI, reviewed by the author.
1. ABOUT SCA6
Spinocerebellar Ataxia Type 6 (SCA6) is a specific type of ataxia within a group of inherited disorders affecting the central nervous system. It is one of the PolyQ (Polyglutamine) disorders , which are characterized by abnormal protein synthesis by genes containing an excessive number of CAG repeats (each CAG repeat encodes one glutamine, a type of amino acid found in proteins) [1, 4] .
More specifically, SCA6 is caused by mutations in the CACNA1A gene, located on chromosome 19. This gene encodes the protein that forms the α1A subunit of voltage-activated calcium channels (Cav2.1). Cav2.1 calcium channels are generally formed by a combination of four protein-based subunits, called alpha, beta, gamma, and delta. The alpha subunit (synthesized by the CACNA1A gene) is primarily responsible for forming the channel pore and selectively conducting calcium ions into the cell. Briefly, these channels open in response to voltage changes across the cell membrane, allowing calcium ions to enter the cell. This process is essential for enabling a variety of cellular processes, including neurotransmitter release. Thus, voltage-activated calcium channels play a crucial role in communication between neurons, involving synaptic transmission and the regulation of neuronal excitability.
A mutation in the CACNA1A gene results in alterations in the protein that makes up calcium channels, impairing the regulation of calcium ion influx into cells. On the one hand, this can impair proper communication between neurons, and on the other, poor calcium regulation can have toxic effects on neurons. These problems affect Purkinje cells in the cerebellum , leading to malfunction, degeneration, or even death of these cells (Figure 1). The resulting progressive cerebellar atrophy is responsible for the symptoms of ataxia.
Note! Although the CACNA1A gene is also present in other brain cells, SCA6 is primarily characterized by the degeneration of cerebellar Purkinje neurons. These neurons have high expression of the Cav2.1 channel, which may explain their vulnerability to functional changes resulting from the mutation.
Figure 1: Diagram generated by the author with the support of Artificial Intelligence.
Effects on signaling
In the cerebellum of a patient without ataxia, Purkinje cells fire (send signals) spontaneously, with a certain frequency and regularity. Research in mouse models reveals that in animals with SCA6, Purkinje cells reduce their firing frequency, and the regularity of these firings is also reduced. In other words, at least in these animal models, SCA6 ataxia interfered with the frequency and regularity of signals emitted by cerebellar Purkinje cells, indicating that their electrical properties were altered. Given that the cerebellum is responsible for coordinating movement, these changes in Purkinje cell signaling may be important in understanding the symptoms of the disease.
BDNF reduction
BDNF ( Brain-derived neurotrophic factor ) - a protein (neurotrophin) that plays a key role in the growth, development, survival, and function of nerve cells (neurons) in the brain - has also been found to be reduced in SCA6 patients. As reported in [7] , scientists have found that exercise helps improve Purkinje cell signaling and also promotes elevated BDNF levels in mice (as do drugs such as 7,8 DHF), and other studies [8] show that specific exercise for motor coordination and balance is also beneficial for human patients with ataxia.
Transcription factor (α1ACT)
As explained in [4] , the CACNA1A gene also encodes another smaller protein, which acts as a transcription factor (α1ACT) in the cell nucleus (a transcription factor is a protein that controls the synthesis of RNA from DNA). This second protein plays a "regulatory" role over some genes, being able to "turn them on" and "off" by activating and deactivating other proteins within the nuclei of Purkinje cells in the cerebellum (and other cells). If there is a mutation in the CACNA1A gene, this α1ACT protein will also be malformed, containing an excessive number of CAG expansions. This may affect the "regulatory" role that the protein plays over other genes, so it is possible that this second mechanism also contributes to the symptoms of SCA6 ataxia.
Figure 2 shows that the CANCA1A gene synthesizes the α1A subunit of the protein that constitutes voltage-activated calcium channels (P/Q in the figure indicates "Purkinje cells"), as well as the α1ACT protein (transcription factor), as demonstrated by research by Du and colleagues.
Figure 2 - Image credit: NAF Webinar "Research and Treatment Development for SCA6", Apr 27, 2023, Dr. Allana Watt [7].
Notes:
1. SCA6 affects only the cerebellum, without compromising other areas of the brain. Therefore, it is considered "pure cerebellar ataxia."
2. Around 1996, it was found [4] that the CACNA1A gene that causes SCA6 ataxia is also involved in two other conditions (same gene, with different mutations). One is one of the subtypes of Familial Hemiplegic Migraine and the other is Episodic Ataxia Type 2 (EA2) .
2. TYPICAL SYMPTOMS
As it is a typically cerebellar ataxia, the symptoms of SCA6 are related to cerebellar functions that can be progressively compromised [6]:
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Gait ataxia (imbalance when walking, with high risk of falls).
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Dizziness.
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Voice changes (dysarthria)
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Vision problems (double vision = diplopia, horizontal or vertical nystagmus)
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Problems with coordination in arms and hands (may drop things, etc.).
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Intention tremors (occur in intentional movements towards a target, such as picking up a glass for example).
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Problems swallowing (dysphagia) solid and liquid foods, in the more advanced stages.
Notes
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In about 10% of cases, dysarthria (lack of clarity in the voice) is the first symptom that manifests in SCA6.
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Double vision (diplopia) or other visual disturbances occur in about 50% of people with SCA6.
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Patients with SCA6 do not report neuropathic pain, restless legs syndrome , muscle stiffness, migraines, or muscle atrophy.
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The severity of symptoms increases during pregnancy, but with no reported effects on fetal viability.
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Just like the age of onset of symptoms, the severity of symptoms can vary considerably, even within the same family.
The progression of SCA6 is generally slow, and the disease does not usually affect life expectancy.
3. ONSET
In general, SCA6 symptoms manifest ( onset ) between 19 and 73 years of age, with a mean age between 43 and 52 years [6] . However, the age of onset of symptoms can vary widely in SCA6, even among affected individuals within the same family. There have been cases of differences of up to 20–30 years in symptom onset between relatives with the same number of CAG repeats, suggesting the influence of epigenetic, environmental, or genetic modifiers.
The Neuromuscular portal [3] suggests that the age of onset of symptoms is inversely correlated with the number of CAG repeats in the CACNA1A gene (symptoms manifest earlier with a higher number of repeats), although this relationship is less pronounced than in other PolyQ diseases such as SCA1 ataxxia or Huntington's disease.
4. ANTICIPATION
Variations in the number of CAG repeats (expansion) in the CACNA1A gene are not normally observed in parent-to-child transmission (vertical transmission). Therefore, genetic anticipation has not been observed in SCA6 so far [6] . The Neuromuscular portal mentions the clinical observation of anticipation of symptoms, but apparently without an increase in CAG repeats [3] , so that the genetic anticipation of SCA6 symptoms, if it indeed occurs, may have causes other than increased CAG expansion.
5. INHERITANCE
SCA6 is an autosomal dominant disease. This means that individuals of both sexes have the same chance of inheriting the gene and becoming carriers of the mutation . A child of a person with SCA6 has a 50% chance of inheriting a copy (allele) of the altered gene (assuming only the biological mother or father carries the mutation).
CAG Expansion ranges for SCA6
Each person has two copies (alleles) of the CACNA1A gene, one inherited from the mother and one from the father. One of the inherited alleles might have, for example, 12 CAG repeats, which is normal and does not cause disease, while the other allele (the other copy of the same gene) might have, for example, 26 repeats—in which case the person will develop the disease sooner or later.
The CAG repeat thresholds for genetic diagnosis of SCA6 are indicated below [6] :
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Normal Range (does not develop the disease): From 4 to 18 CAG repeats
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Intermediate Range: In the case of 19 CAG repeats, whether or not SCA6 occurs is still unclear.
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Pathological Range (the disease manifests itself): From 20 to 33 CAG repeats
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
Epidemiological studies suggest that the average global prevalence of SCA6 is 1 to 2 cases per 100,000 population, varying according to the population studied. In Japan, for example, the prevalence may be higher (2 to 5 cases per 100,000) due to genetic factors or the "founder effect."
7. ADDITIONAL INFORMATION
SCA6 ataxia is one of the "polyglutamine (PolyQ) diseases." It occurs when the allele (copy) of the CACNA1A gene inherited from one parent contains a mutation with an abnormal number of CAG (Cytosine, Adenine, Guanine) trinucleotide repeats, which code for the amino acid glutamine (Q) in the protein created by the gene.
Additional notes on PolyQ disorders: (Adapted from "Pathogenesis of SCA3 and implications for other polyglutamine diseases". Hayley S. McLoughlin et al, 2020).
1. Currently, nine PolyQ disorders are known, including Huntington's disease (HD), Dentato-Rubro-Pallido-Louisiana Atrophy (DRPLA), Bulbospinal Muscular Atrophy (SBMA), and six different types of spinocerebellar ataxias (SCAs), including SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17. All of these diseases result from expanded CAG repeats in the coding regions of their respective genes and share other common features. For example, all PolyQ diseases are inherited in an autosomal dominant fashion (with the exception of SBMA, which is X-linked), primarily affect the CNS (Central Nervous System), although peripheral nerves and muscles can also be affected, and have a progressive course over years. Furthermore, in all PolyQ diseases there is an inverse correlation between the size of the mutation (number of CAG repeats) and the age of onset of symptoms and their severity, and the phenomenon of anticipation as already mentioned may occur.
2. While in other PolyQ diseases, misfolded proteins form toxic aggregates in the cytoplasm or nucleus of nerve cells, in SCA6 the mutation primarily causes calcium channel dysfunction. This dysfunction affects synaptic communication and neuronal survival, with a preferential impact on Purkinje cells, resulting in cerebellar atrophy and the clinical symptoms of ataxia (see Figure 4). Thus, in SCA6, neuronal death is more closely linked to calcium excitotoxicity and neurotransmission failure than to nuclear aggregate formation. This distinction makes SCA6 unique among PolyQ diseases, reinforcing the importance of therapies targeting calcium regulation and synaptic protection.
Diagnosis - SCA6 can be diagnosed with molecular genetic testing (DNA testing) to detect mutations in the CACNA1A gene, which is especially recommended if someone in the family already has a confirmed diagnosis (a positive family history of SCA6). Before ordering genetic testing, the neurologist typically performs clinical neurological examinations to analyze symptoms, reflexes, ocular abnormalities, and assess family history. It is common for them to order imaging tests to check for cerebellar atrophy, for example.
Note: Although diagnosis by genetic testing can be difficult, time-consuming and expensive, it is important because it allows for better genetic counseling for family members (risk of transmitting the mutation to future generations in the family), better management of the disease, which will be well determined, and also allows the patient to participate in clinical trials for medications for specific ataxias.
In the MRI image below, C shows an individual without SCA6, and 10.5, 17.5, and 22 show individuals with SCA6. Cerebellar atrophy caused by the loss of Purkinje cells can be seen.
Figure 4 - Image Credit: NAF Webinar "All About SCA6" on 10-04-2023, Dr. Anoopum Gupta [4] .
8. THERAPIES AND DRUGS BEING TRIALED FOR THIS ATAXIA
View NAF Treatment Pipeline for SCA6
See also
NAF Webinar " Research and Treatment Development for SCA6 ", Apr 27, 2023, Dr. Allana Watt [7] .
9. TREATMENTS
Spinocerebellar Ataxia Type 6 (SCA6) currently has no cure, but it is possible to treat symptoms to improve quality of life and provide continuous support to the patient. It is important for individuals with SCA6 to be followed by a neurologist and a specialized multidisciplinary medical team, gradually including additional healthcare professionals as symptoms evolve (geneticist, neuro-ophthalmologist, neurofunctional physiotherapist, occupational therapist, speech therapist, nutritionist, etc.).
Below are some general recommendations for symptom management in SCA6:
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Neurofunctional physiotherapy, exercise (especially stationary cycling), and other regular physical activities (Yoga, Pilates, water aerobics, etc.) are recommended (within each individual’s possibilities).
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To reduce the risk of falls due to balance difficulties while walking, canes, walkers, or wheelchairs may be used depending on the stage of the disease.
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Occupational therapy and some home and daily habit adaptations may help (e.g., installing grab bars in hallways and bathrooms, shower chairs, night lights, rearranging furniture to facilitate mobility, removing rugs to prevent tripping, using cups with lids and straws, wearing shoes with non-slip soles that are easy to put on, etc.).
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Rest whenever needed, and ensure good-quality nighttime sleep. In case of sleep difficulties, consult a doctor, as there are medications that may help (for example, cannabidiol oil).
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Maintain a healthy diet and proper hydration.
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Supplements and vitamins may be recommended (consult a doctor to assess the need — do not take vitamins or supplements without medical supervision).
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Weight control is advisable to avoid further mobility challenges.
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For diplopia (double vision) caused by ataxia, prism lenses in glasses may help. For nystagmus, there are medications that may help — consult a neuro-ophthalmologist if these symptoms appear.
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For tremors, consult a neurologist to evaluate the most appropriate medication.
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For dizziness and vertigo, consult a neurologist to determine the best management strategies.
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For dysarthria, if this symptom occurs, specialized speech therapy is recommended. Depending on the stage, the use of assistive communication devices (available for smartphones, computers, iPads, etc.) may be considered.
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For dysphagia, which may occur in later stages of the disease, consultation with a speech therapist is also recommended — there are exercises that can aid swallowing and reduce the risk of aspiration that could lead to pneumonia.
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Avoid stress as much as possible, as it generally worsens ataxia symptoms.
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If necessary, medications are available for managing anxiety and depression. Consult a physician to determine the most appropriate options.
Note: Some patients with various cerebellar ataxias report benefits and symptom improvement after neuromodulation sessions or non-invasive cerebellar stimulation, such as transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS) performed by certified physiotherapists. It should be noted that although these therapies are already commercially available, they have not yet been approved by the FDA in the United States (or by ANVISA in Brazil) for the treatment of ataxias (i.e., these are experimental treatments without guarantees).
See information about medications for ataxia symptoms.
See information about treatments and care for patients.
See information about those with a recent diagnosis.
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:
Language:
English
Date:
Updated February 2016 - NAF—01/2019
Ref #4
Source:
Language:
English. You can enable subtitles and configure automatic translation of subtitles into other languages.
Date:
Apr 11, 2023
Ref #5
Source:
Language:
English
Date:
Edit History: carol: 12/20/2023
Ref #7
Source:
Language:
English. You can enable subtitles and configure automatic translation of subtitles into other languages.
Date:
Apr 27, 2023
Ref #8
Source:
Language:
English
Date:
2014