SCA8 Fact Sheet
Ataxia:
SCA8 (Spinocerebellar Ataxia Type 8)
RELATED GENES:
ATXN8, ATXN8OS
LOCATION:
Chromosome 13. ATXN8 in (13q21), ATXN8OS in (13q21.33)
MUTATION TYPE:
ATXN8, ATXN8OS -> CTG and CAG expansion mutation
HERITAGE:
Autosomal Dominant
LAST UPDATE:
April 21, 2025 by Marcio Galvão
Content generated with the support of Generative AI, reviewed by the author.
1. ABOUT SCA8
Spinocerebellar ataxia type 8 (SCA8) is one of a group of inherited disorders of the central nervous system. Like several other inherited ataxias, SCA8 is the result of genetic defects (mutations) that lead to impairment of specific nerve fibers that carry messages to and from the brain, resulting in degeneration of the cerebellum (the brain's coordination center) [1].
Incomplete penetrance
A striking feature of SCA8 (spinocerebellar ataxia type 8) is its incomplete and highly variable penetrance . Most individuals who carry the genetic mutations that cause SCA8 remain asymptomatic throughout life. In a major study conducted by Barbara A. Perez and colleagues [9] involving multiple families with a confirmed molecular diagnosis of SCA8, it was found that in 82% of the families studied, only one individual presented symptoms of SCA8, although other family members also carried the mutation. In a smaller subset (approximately 5% of families), parents carrying the mutation were asymptomatic, while several children presented the clinical form of the disease.
Difficulties in diagnosis
Low penetrance is one of the most notable aspects of SCA8 and represents a significant diagnostic challenge , especially considering that the disease is inherited in an autosomal dominant manner. For this reason, many symptomatic patients with SCA8 do not report a clear family history of ataxia, which contrasts with the typical pattern of other SCAs and can delay clinical and genetic diagnosis. Furthermore, the risk of intergenerational transmission remains high, as asymptomatic individuals can transmit the expanded mutation to their descendants, who in turn may manifest SCA8 symptoms, possibly due to phenomena such as additional repeat expansion, somatic instability, or interaction with other modifier alleles. For more information, see Section 5. Inheritance .
SCA8 has a very atypical and complex genetic mechanism , involving double transcription (of two genes) located in the same genomic region (on chromosome 13). Let's see which two genes are involved.
Genetic mechanism of SCA8
SCA8 ataxia was initially described in a research article in 1999, having been discovered by a group of researchers led by Dr. Laura Ranum [7] . In most of the spinocerebellar ataxias that had already been identified before SCA8 (the ataxias SCA1, SCA2, SCA3, SCA6 and SCA7) the symptoms were caused by expanded repeats of the nucleotide CAG (which forms the amino acid glutamine) in different genes, that is, all of these were PolyQ diseases, where there is an excessive number of repeated glutamines in the proteins synthesized by the mutated genes.
SCA8 was the first spinocerebellar ataxia to be discovered caused by a different CAG expansion, and involving two different genes , both located on chromosome 13:
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ATXN8OS gene - The ATXN8OS gene is a non-coding gene. It is transcribed into RNA but does not express a functional protein. Its function is likely linked to gene regulation, RNA structure, or epigenetic mechanisms. In SCA8 ataxia, a mutation is found in this gene—an expansion of the CTG (Cytosine, Thymine, Guanine) repeat .
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ATXN8 gene - The ATXN8 gene is a coding gene, meaning its messenger RNA (mRNA) is translated into a protein. In this gene, SCA8 has a different mutation: an expansion of repeats of the nucleotides CAG (Cytosine, Adenine, Guanine).
Thus, to summarize, we say that SCA8 involves "expanded CTG·CAG repeats in the ATXN8OS/ATXN8 genes."
The human DNA structure is composed of two strands of nucleotides twisted into a double helix. Note in Figure 1 that in the DNA double helix, the ATXN80S gene (where the CTG expansion occurs) is on one strand, while the ATXN8 gene (where the CAG expansion occurs) is on the other strand. In other words, both genes overlap in the same region of chromosome 13, but are on different strands. See Figure 1.
Figure 1 credit - NAF webinar Research and Treatment Development for SCA8, Dr. Hannah Shorrock [8] .
DNA is made up of two complementary strands. In the example in Figure 1, we have a sequence of CTG repeats on one strand (where the ATXN8OS gene is located) and a sequence of CAG repeats on the other strand (the ATXN8 gene):
Tape 1: CTG CTG CTG ... - (ATXN8OS)
Tape 2: GAC GAC GAC... - (ATXN8)
The CTG repeat in the sense strand (ATXN8OS) is complementary to the CAG repeat in the antisense strand (ATXN8). That is, the same expansion appears in both strands . Thus, if there are (for example) 100 CTG repeats in the ATXN8OS gene, then there will be 100 CAG repeats in the ATXN8 gene. Thus, two mutations of "the same size" occur but in two different genes, generating two different mechanisms that are toxic to nerve cells , contributing to the pathogenesis of SCA8. This duality explains why SCA8 is considered a "dual pathology" disease.
Pathogenesis of SCA8
It is believed that mutations in both genes contribute to disease pathology, but through distinct mechanisms:
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The CAG expansion in ATXN8 (a coding gene) may lead to the production of abnormal proteins with expanded polyglutamine tracts, which aggregate and damage neurons — a mechanism commonly seen in other ataxias such as SCA1 and SCA3.
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The CTG expansion in ATXN8OS (a non-coding gene) contributes to the pathogenesis of SCA8 by producing toxic RNA and through RAN translation effects.
Although the ATXN8 gene has coding potential — with a CAG sequence that could theoretically produce a polyglutamine (PolyQ) protein — its role in SCA8 is likely secondary. The primary cause of symptoms appears to be the toxic RNA and RAN proteins resulting from the mutation in the ATXN8OS gene.
Toxic RNA
The excessive number of CTG repeats caused by the ATXN8OS gene mutation leads to the production of expanded toxic RNA, which disrupts several cellular processes [7]:
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Formation of nuclear RNA foci that sequester regulatory proteins
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Disruption of gene transcription (transcription is the process by which genetic information in DNA is copied to form RNA)
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Autophagy dysfunction
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Impairment of the ubiquitin-proteasome system, which is responsible for degrading misfolded proteins
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Disruption of synaptic transmission and cellular homeostasis
Toxicity from RAN Proteins
There is also evidence of non-canonical translation of the expanded RNA via a mechanism known as Repeat-Associated Non-AUG (RAN) translation, which can generate toxic proteins ("RAN proteins") even in the absence of a traditional start codon. These RAN proteins include polyLeucine, polyAlanine, and polySerine. They are high molecular weight proteins with hundreds of amino acids and can form insoluble aggregates in the cytoplasm or nucleus, interfering with critical cellular processes and contributing to the neurotoxicity observed in SCA8, ultimately leading to neuron death in the cerebellum. Neuronal loss in the cerebellum is typically observed via imaging exams that reveal cerebellar atrophy, which is the primary cause of ataxia symptoms.
CCG·CGG Interruptions
In addition to the presence of the CTG·CAG expansion, the risk of developing SCA8 symptoms is increased by CCG·CGG interruptions within the expanded CTG·CAG repeat sequence. These interruptions may alter the stability of the repeat, modulate RNA toxicity, and influence the efficiency of RAN translation (see Section 7: Additional Information).
Figure 2 (generated by the author with support from Artificial Intelligence) provides a simplified illustration of the pathogenesis of SCA8.
2. TYPICAL SYMPTOMS
Typical symptoms of SCA8 include slowly progressive cerebellar ataxia, usually beginning between the third and fifth decades of life, and may also involve extracerebellar manifestations [5]:
Typical cerebellar manifestations:
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Gait Ataxia: Unsteady walking, often with a widened base of support.
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Limb Ataxia: Impaired precision of movements (e.g., dysmetria, dysdiadochokinesia).
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Dysarthria, characterized by slow, hesitant, and sometimes explosive speech.
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Oculomotor abnormalities (e.g., nystagmus, abnormal pursuit, and abnormal saccades).
Extracerebellar manifestations (commonly seen in more advanced stages):
Upper motor neuron involvement:
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Hyperreflexia (increased deep tendon reflexes);
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Spasticity;
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Positive Babinski sign.
Extrapyramidal signs:
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Rest or action tremor;
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Focal dystonia: Sustained muscle contractions (e.g., neck, hands);
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Parkinsonian features in rare cases (bradykinesia, rigidity).
Brainstem signs:
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Dysphagia: Difficulty swallowing (moderate to advanced stages);
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Ineffective cough: Increased risk of aspiration pneumonia.
Peripheral sensory neuropathy:
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Loss of vibratory and proprioceptive sensation, more common in the lower limbs;
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Absent deep tendon reflexes in the lower limbs.
Cognitive and affective symptoms:
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Psychomotor slowing;
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Attention and working memory deficits;
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Mild executive dysfunction;
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In some cases, a clinical picture consistent with cerebellar cognitive-affective syndrome.
The progression of SCA8 is slow, typically unfolding over several decades. Life expectancy is not affected. However, complications such as severe dysphagia may impact quality of life in the later stages [5].
3. ONSET
Symptom onset typically occurs in adulthood (usually between the third and fifth decades of life), although juvenile and late-onset cases have been documented [5] . The exact age of symptom onset can vary from person to person, even within a family.
4. ANTICIPATION
Source [5] reports that no correlation was observed between the number of CTG·CAG repeats and the age of onset of symptoms, or the severity of the disease.
It is worth noting that although in SCA8 the number of CTG·CAG repeats in the ATXN8OS/ATXN8 genes alone does not appear to affect the age at onset of symptoms, patients with CCG or CGG interruptions within the expanded CTG·CAG repeat have a higher risk of developing the disease. (higher penetrance), and there is also a greater likelihood of earlier onset of symptoms. As mentioned, the presence of these interruptions makes the mutation more toxic to cells. In this case, the age at onset of symptoms is inversely correlated with the number of CCG•CGG interruptions (the more interruptions, the earlier symptoms appear), and not with the number of CTG·CAG repeats.
5. INHERITANCE
SCA8 is an autosomal dominant disorder. This means that individuals of any sex have the same likelihood of inheriting a copy (allele) of the mutated gene and becoming carriers of the mutation. A child of a person with SCA8 has a 50% chance of inheriting the altered gene copy (assuming that only one parent carries the mutation — either the biological mother or father). In the case of SCA8, the mutation is inherited as a single genetic block — if the individual inherits the expanded allele, they will inherit mutations in both the ATXN8 and ATXN8OS genes, since they represent the same physical expansion in the same region of DNA, just in opposite directions.
Dominant, but sometimes mistaken for recessive or even sporadic.
As discussed, SCA8 is genetically more complex than other SCAs in two main ways. First, it involves mutations in two different genes (ATXN8 and ATXN8OS) with repeat expansions of the CTG and CAG nucleotides. Furthermore, SCA8 has low penetrance, meaning not everyone who inherits the mutated gene will develop the disease. There are reports of individuals diagnosed with SCA8 despite having no family history (no other affected relatives in the same or previous generations). Because of this, SCA8 can be misinterpreted as a sporadic or even recessive ataxia, especially during the diagnostic process. (See Section 7: Additional Information).
Expansion Ranges for SCA8
One of the challenges in reproducing the expansion ranges that can cause SCA8 is that different sources report different thresholds. As a reminder:
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The expanded CTG repeats occur in the ATXN8OS gene
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The expanded CAG repeats occur in the ATXN8 gene
In a webinar presented by Dr. Hannah Shorrock [8], the following expansion ranges were shared to support SCA8 diagnosis (see Figure 1):
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Normal: 15 to 34 repeats
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Intermediate: 34 to 89 repeats
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Expanded: 89 to 250 repeats
The (CTG·CAG)ⁿ expansion is highly unstable and almost always changes in size during transmission. The expansion tends to increase during maternal transmission and contract (shrink) during paternal transmission [5]. Therefore, unlike other spinocerebellar ataxias (SCAs), in SCA8 the disease penetrance tends to be higher with maternal inheritance [7].
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
It is estimated that the occurrence of SCA8 is less than 1 case per 100,000 individuals , characterizing it as a rare condition.
The source [5] cites that SCA8 may represent between 2% and 5% of cases of ataxias with autosomal dominant inheritance. Global epidemiological studies are limited, but SCA8 is known to be less common than other SCAs, such as SCA1, SCA2, SCA3 (the most prevalent), and SCA6.
The following information on the prevalence of SCA8 is also available [4] :
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SCA8 is particularly prevalent in the Finnish population, being the main cause of dominant hereditary ataxia in the country.
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India, Mexico, and Japan: In these countries, SCA8 is considered rare, with a significantly lower frequency compared to other forms of ataxia.
7. ADDITIONAL INFORMATION
As we have seen, SCA8 ataxia is quite complex as it involves two genes and two types of trinucleotide expansions (excessive repeats), in this case, CTG and CAG expansions. Additionally, sources [9, 10] explain that some patients may experience interruptions within the sequence that repeats itself , and that these interruptions act as a genetic modifier that can increase the carrier's risk of developing symptoms . Let's see what this means.
Interruptions within expansions
Within a series of trinucleotide repeats in a gene, breaks or sequence variations can occur. These breaks can be of various types, including the presence of different trinucleotides. For example, when a CCG sequence occurs within a sequence of CAG repeats (as in CAG-CAG-CAG- CCG -CAG-CAG), we say there is a "CCG break in the CAG expansion." These breaks can influence gene expression and the severity of the associated disease.
In SCA8 ataxia, interruptions of the CCG, CTA, CTC, CCA, and CTT types have been reported within the expanded CTG repeat. Research [9] has revealed that the occurrence of CCG or CGG interruptions within the expanded CTG CAG repeat has a more toxic effect on cells than the simple existence of expanded CTG CAG repeats without such interruptions (Figure 2). In other words, these interruptions increase the penetrance of the disease , and in this case, the likelihood of symptoms also increases earlier. (see Section 4. Anticipation ).
The role of CGG interrupts
Now we can better understand why individuals have CGG interruptions within the expanded CAG repeat in the ATXN8 gene, for example, have a greater risk of developing SCA8 symptoms - these interruptions result in a greater number of RAN translation errors that generate "RAN proteins", which are toxic to cells [8] as illustrated in Figure 4. In individuals who present CGG interruptions within the expansion, more RAN proteins are generated, which increases toxicity (contributing to neuron death), thus increasing the penetrance of the disease in these individuals.
Figure 4 credit - NAF webinar Research and Treatment Development for SCA8, Dr. Hannah Shorrock [8] .
In summary:
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A CTG•CAG expansion in the ATXN8OS/ATXN8 genes is sufficient to put an individual at risk for developing SCA8 ataxia. However, penetrance is low, and many carriers of the expansion do not experience symptoms.
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For carriers of the mutation that causes SCA8, the risk of developing ataxia symptoms is increased by the presence of CCG•CGG interruptions within the expanded CTG·CAG repeat. In this case, the risk of generating toxic RAN proteins is greater, contributing to the greater penetrance of SCA8 ataxia in these individuals (symptom manifestation) and also a greater likelihood of early symptom onset.
Diagnosis - SCA8 can be diagnosed with molecular genetic testing (DNA testing) to detect mutations in the ATXN8 and ATXN8OS genes (with CTG and CAG repeat expansions). Genetic testing is especially recommended if someone in the family has a confirmed diagnosis (positive family history of SCA8). Before ordering genetic testing, the neurologist typically performs clinical neurological examinations to analyze symptoms that may manifest in SCA8, in addition to evaluating family history.
Note that diagnosis can be difficult . Given the low penetrance of SCA8 ataxia, it is not certain that symptoms will manifest even in individuals who carry the mutation. Parents who remain asymptomatic may pass the mutated genes to future generations. In some of these transmissions, the mutation may spread due to its instability, potentially becoming pathological and causing symptoms. Thus, the child may have symptoms without a family history of the disease . Therefore, the physician should not rule out the possibility of SCA8 simply because the patient has no family history or because neither parent has presented symptoms.
Information to aid in the differential diagnosis of SCA8 (in relation to other types of spinocerebellar ataxias) can be found in the Differential Diagnosis section of the source [5] .
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.
8. THERAPIES AND DRUGS IN TRIALS FOR SCA8
9. TREATMENTS
SCA8 ataxia currently has no cure, but it is possible to treat symptoms to improve quality of life and provide ongoing support to the patient. It is important for patients with SCA8 to be followed by a neurologist and a specialized multidisciplinary medical team, with the gradual inclusion of new healthcare professionals as needed based on symptoms (such as a geneticist, neuro-ophthalmologist, neurofunctional physical therapist, occupational therapist, speech-language pathologist, nutritionist, etc.).
Below are some general recommendations for symptom management in SCA8:
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Neurofunctional physiotherapy, exercise (especially stationary biking), and other regular physical activities (such as yoga, Pilates, water aerobics, etc.) are recommended, within each individual’s capacity.
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To reduce the risk of falls due to balance difficulties while walking, assistive devices like canes, walkers, or wheelchairs may be adopted depending on the stage of the disease.
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Occupational therapy and certain home and daily habit adaptations can help (e.g., installing support bars in hallways and bathrooms, using a shower chair, adding night lights, rearranging furniture to improve mobility, removing rugs to prevent tripping, using lidded cups with straws, wearing slip-resistant and easy-to-wear shoes, etc.).
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Rest whenever necessary, and maintaining good quality sleep at night is important. In case of sleep difficulties, consult a physician, as certain medications (e.g., cannabidiol oil) may help.
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Maintain a healthy diet and stay well hydrated.
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Supplements and vitamins may be recommended (consult a physician to assess the need—do not take vitamins or supplements without medical supervision).
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It is advisable to manage weight to avoid further mobility issues.
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In the case of nystagmus, some medications may help. A neuro-ophthalmologist should be consulted if this symptom appears.
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In the case of spasticity, consult a neurologist, as there are medications that can help (e.g., Baclofen).
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For dysarthria, if this symptom occurs, specialized speech therapy is recommended. Depending on the stage, assistive communication devices (available for smartphones, computers, tablets, etc.) can be considered.
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For dysphagia, which may occur in more advanced stages, a consultation with a speech-language pathologist is also recommended—there are exercises that can help with swallowing and reduce the risk of choking that could lead to aspiration pneumonia.
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Avoid stress as much as possible, as it tends to worsen ataxia symptoms.
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If necessary, medications to manage anxiety and depression are available. Consult a physician to evaluate the most appropriate options.
Note: Some patients with various cerebellar ataxias report benefits and symptom improvement after sessions of neuromodulation or non-invasive cerebellar stimulation, such as transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS) with certified physical therapists. However, it is important to note that although this therapy is already being commercially offered, it has not yet been approved by the FDA in the United States (or by ANVISA in Brazil) for the treatment of ataxias—meaning it is still considered an experimental treatment with no guaranteed outcomes.
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:
NAF (National Ataxia Foundation)
© Copyright National Ataxia Foundation
Language:
English
Date:
Revised 01/2018
Ref #2
Source:
NAF (National Ataxia Foundation)
© Copyright National Ataxia Foundation
Language:
English
Date:
Not available
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: November 2023
Ref #4
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 #5
Source:
John Douglas Cleary, PhD, SH Subramony, MD, and Laura PW Ranum, PhD.NLM - GeneReviews © 1993-2019.
Copyright © GeneReviews is a registered trademark of the University of Washington, Seattle.
Language:
English
Date:
Last Update: April 22, 2021
Ref #6
Source:
OMIM® - An Online Catalog of Human Genes and Genetic Disorders.
Copyright © Johns Hopkins University.
Language:
English
Date:
Edit History: terry: 12/22/2010
Ref #7
Source:
Presented by: Dr. Odinachi Oguh
YouTube - Copyright ® National Ataxia Foundation (NAF)
Language:
English. You can enable subtitles and configure automatic translation of subtitles into other languages.
Date:
Aug 18, 2023
Ref #8
Source:
Presented by: Dr. Hannah Shorrock
YouTube - Copyright ® National Ataxia Foundation (NAF)
Language:
English. You can enable subtitles and configure automatic translation of subtitles into other languages.
Date:
Aug 24, 2023
Ref #9
CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity
Source:
Barbara A. Perez et al.
Copyright ® EMBO Molecular Medicine 13: e14095
Language:
English
Date:
Published online 11 October 2021
Ref #10
Source:
Written by Dr. Hannah K Shorrock - Edited by Dr. Larissa Nitschke
Copyright ® National Ataxia Foundation (NAF)
Language:
English
Date:
Not available