Spinocerebellar Ataxia Type 8

Clinical characteristics.

SCA8 is a slowly progressive ataxia with onset typically in the third to fifth decade but with a range from before age one year to after age 60 years. Common initial manifestations are scanning dysarthria with a characteristic drawn-out slowness of speech and gait instability. Over the disease course other findings can include eye movement abnormalities (nystagmus, abnormal pursuit and abnormal saccades, and, rarely, ophthalmoplegia); upper motor neuron involvement; extrapyramidal signs; brain stem signs (dysphagia and poor cough reflex); sensory neuropathy; and cognitive impairment (e.g., executive dysfunction, psychomotor slowing and other features of cerebellar cognitive-affective disorder in some). Life span is typically not shortened.

Diagnosis/testing.

The diagnosis of SCA8 is established in a proband with suggestive findings and a heterozygous abnormal (CTG·CAG)_n repeat expansion in the two overlapping genes ATXN8OS/ATXN8 identified by molecular genetic testing.

Management.

Treatment of manifestations: Canes and walkers to help prevent falls; modification of the home (e.g., grab bars, raised toilet seats, ramps for motorized chairs) as needed; speech therapy and communication devices for those with dysarthria; weighted eating utensils and dressing hooks to maintain some independence; feeding evaluations to reduce risk of aspiration from dysphagia; physical activity to maintain muscular and cardiopulmonary conditioning.

Surveillance: Routine follow up by the multidisciplinary care team including neurology to assess disease progression; physiatry and occupational and physical therapy to assess mobility and self-help skills; speech and language specialists to assess need for alternative communication method or speech therapy; feeding team to assess nutrition, aspiration risk, and feeding methods; and mental health professionals.

Agents/circumstances to avoid: Alcohol can exacerbate incoordination.

Genetic counseling.

SCA8 is inherited in an autosomal dominant manner with reduced penetrance. To date, all individuals diagnosed with SCA8 whose parents have been evaluated with molecular genetic testing have one parent with an ATXN8OS/ATXN8 (CTG·CAG)_n repeat expansion. The transmitting parent may or may not have clinical manifestations of SCA8. If a parent of the proband is known to have a (CTG·CAG)_n repeat expansion, the risk to each sib of inheriting the repeat expansion is 50%. The (CTG·CAG)_n repeat expansion is highly unstable and almost always changes in size on transmission: the repeat expansion is more likely to become larger when maternally transmitted and more likely to contract with paternal transmission. Sibs who inherit a (CTG·CAG)_n repeat expansion may or may not develop clinical manifestations of SCA8. Once an SCA8 (CTG·CAG)_n repeat expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Spinocerebellar ataxia type 8 (SCA8) should be suspected in individuals with the following findings.

Clinical findings include slowly progressing cerebellar ataxia with onset typically in the third to fifth decade (age range: <1 to >60 years) AND the following associated clinical features:

• Gait and limb ataxia
• Scanning dysarthria characterized by a drawn-out slowness of speech
• Eye movement abnormalities (e.g., nystagmus, abnormal pursuit and abnormal saccades)
• Often "extracerebellar signs" including:
  • Upper motor neuron findings (e.g., brisk tendon reflexes, spasticity, and Babinski sign)
  • Extrapyramidal signs (e.g., tremor, dystonia and occasionally parkinson-like features)
  • Brain stem signs (e.g., dysphagia and poor cough reflex)
  • Sensory neuropathy (e.g., loss of sensation and loss of tendon reflexes in distal limbs)
  • Cognitive features (e.g., executive dysfunction, psychomotor slowing, and other features of cerebellar cognitive-affective disorder in some)

Family history. SCA8 is an autosomal dominant disorder (i.e., the phenotype can be expressed in heterozygotes); however, because of reduced penetrance, the family history of an affected individual may appear to be consistent with autosomal recessive inheritance (with multiple affected family members in a single generation) or an affected individual may represent a simplex case (i.e., the only affected family member).

The absence of an autosomal dominant family history of disease should not be used to rule out a diagnosis of SCA8.

Note: Affected individuals homozygous for repeat expansions have also been reported in the literature, suggesting that two expansion alleles may further increase risk.

Establishing the Diagnosis

The diagnosis of SCA8 is established in a proband with suggestive findings and a heterozygous abnormal (CTG·CAG)_n repeat expansion in the two overlapping genes ATXN8OS/ATXN8 identified by molecular genetic testing (see Table 1).

Note: Pathogenic (CTG·CAG)_n repeat expansions in ATXN8OS/ATXN8 cannot be detected by sequence-based multigene panels, exome sequencing, or genome sequencing.

Molecular Genetic Testing

Molecular genetic testing relies on targeted analysis to characterize the number of ATXN8OS/ATXN8 (CTA·TAG)_n(CTG·CAG)_n repeats (see Table 7).

Table 1.

Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 8

Clinical Description

SCA8 is a slowly progressive ataxia with onset typically in adulthood (range: neonatal period to age 73 years) [Day et al 2000, Ikeda et al 2000, Juvonen et al 2000, Silveira et al 2000, Felling & Barron 2005, Maschke et al 2005, Whaley et al 2011]. Disease progression is typically over decades regardless of the age of onset. Common initial manifestations are dysarthria and gait instability; life span is typically not shortened [Day et al 2000, Juvonen et al 2000].

Persons with adult onset typically exhibit cerebellar signs (e.g., nystagmus, abnormal pursuit and saccadic eye movement) and gait and limb ataxia indicated by a broad-based gait and abnormal finger-to-nose, finger-chase, and heel-to-shin maneuvers. These are often associated with additional neurologic signs [unpublished data and Gupta & Jankovic 2009].

Dysphagia can be a significant complication [Zeman et al 2004, Kim et al 2013].

Table 2.

Select Features of Spinocerebellar Ataxia Type 8

Although a number of atypical findings have been reported in individuals with (CTG·CAG)_n repeat expansions in ATXN8OS/ATXN8, the causative relationship between the (CTG·CAG)_n repeat expansion and these other findings remains unknown, given the relatively high frequency of the (CTG·CAG)_n repeat expansion in the general population and the reduced penetrance of the disease. These atypical findings can include the following:

• Parkinson-like features [Wu et al 2004, Baba et al 2005, Wu et al 2009, Kim et al 2013]
• Multiple-system atrophy [Factor et al 2005, Munhoz et al 2009, Smetcoren & Weckhuysen 2016]
• Severe childhood onset (<20 years) including neonatal onset with cognitive difficulties associated with ataxia and cerebellar atrophy on brain imaging observed in a proportion of individuals without other identified disorders [Felling & Barron 2005]
• Amyotrophic lateral sclerosis [Baba et al 2005, Kim et al 2013]
• Oromandibular and lingual dystonia (in 1 individual). Persons with oromandibular or lingual dystonia may have increased chewing and swallowing problems.
• Respiratory muscle weakness (uncommon) [Kim et al 2013]
• Seizure-like episodes (highly unusual; reported in 1 individual) [Swaminathan 2019]

Neuroimaging. Brain MRI and CT consistently show cerebellar atrophy, specifically in the cerebellar hemisphere and vermis [Gupta & Jankovic 2009]. Occasionally the imaging studies do not show an abnormality in the presence of clinical ataxia.

In one individual in whom serial MRI scans were performed nine years apart, little progression in the cerebellar atrophy was observed [Day et al 2000].

Mild cerebellar atrophy was observed in an asymptomatic male age 71 years with a (CTG·CAG)_n repeat expansion [Ikeda et al 2000].

Genotype-Phenotype Correlations

Expansion repeat size. No correlation between the combined (CTA·TAG)_n(CTG·CAG)_n repeat length and age of onset or disease severity has been observed [Day et al 2000; Gupta & Jankovic 2009; Authors, unpublished data].

Homozygosity for the repeat expansion. Individuals homozygous for the (CTG·CAG)_n repeat expansion have been reported more frequently than for other forms of spinocerebellar ataxia caused by nucleotide repeat expansions [Koob et al 1999; Day et al 2000; Stevanin et al 2000; Tazón et al 2002; Izumi et al 2003; Schöls et al 2003; Brusco et al 2004; Corral et al 2005; Juvonen et al 2005; Authors, unpublished data].

Compared to the ages of onset of individuals heterozygous for a (CTG·CAG)_n repeat expansion, the ages at onset in most individuals homozygous for (CTG·CAG)_n repeat expansions were not obviously accelerated even within a sibship [Day et al 2000].

Penetrance

The true penetrance of the combined (CTA·TAG)_n(CTG·CAG)_n repeat lengths is not understood, as interfamilial differences in penetrance for the same size repeat expansion can be seen. Nevertheless, the following have been observed:

• A number of independent studies have shown that greater than 90 combined (CTA·TAG)_n(CTG·CAG)_n repeats are more often found in individuals with ataxia than in unaffected controls [Izumi et al 2003, Ikeda et al 2004, Zeman et al 2004].
• In a large family (MN-A [Day et al 2000]) with SCA8, individuals with ataxia had longer combined (CTA·TAG)_n(CTG·CAG)_n repeat lengths (mean size: 117) compared to 21 asymptomatic relatives with shorter combined repeat lengths (mean size: 92), demonstrating that repeat length plays a role in disease penetrance [Koob et al 1999, Day et al 2000].

Analysis of additional families showed that the pathogenic repeat expansion range varied substantially among families, and that repeat length could not be used to predict whether an asymptomatic individual would subsequently develop disease manifestations [Ikeda et al 2004; Ikeda et al 2008; Authors, unpublished data].

Anticipation

Maternal transmission. The (CTG·CAG)_n portion of the repeat tract is more likely to become larger with maternal transmission [Moseley et al 2000].

Paternal transmission. The (CTG·CAG)_n portion of the repeat tract is more likely to contract with paternal transmission, usually resulting in smaller repeats that may fall into the reduced penetrance range [Moseley et al 2000].

Prevalence

There are no epidemiologic studies of the frequency of (CTA·TAG)_n(CTG·CAG)_n repeat expansions; however, estimates suggest that the prevalence of expansions greater than 50 (CTA·TAG)_n(CTG·CAG) repeats is approximately 1:100 to 1:1200 chromosomes in various populations [Koob et al 1999; Ikeda et al 2000; Juvonen et al 2000; Vincent et al 2000; Ikeda et al 2004; Sułek et al 2004; Zeman et al 2004; Authors, unpublished data] (see Molecular Genetics).

SCA8 is thought to account for 2%-5% of autosomal dominant inherited ataxia. Because of reduced penetrance, the prevalence of SCA8 is far lower than expected based on observed frequency of (CTA·TAG)_n(CTG·CAG)_n repeat expansions.

The frequency of expansions greater than ~90 repeats is higher in persons with ataxia than in the general population [Izumi et al 2003, Ikeda et al 2004, Zeman et al 2004].

The prevalence of a (CTG·CAG)_n repeat expansion and SCA8 may be especially high in Finland [Juvonen et al 2000, Juvonen et al 2002, Juvonen et al 2005].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 8 (SCA8) the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 8

Treatment of Manifestations

There is no specific treatment for SCA8. The goals of treatment are to maximize function and reduce complications.

It is recommended that affected individuals be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech and language therapists, and psychologists depending on the clinical manifestations.

Table 4.

Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 8

Surveillance

Table 5.

Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 8

Agents/Circumstances to Avoid

Alcohol should be avoided because it can exacerbate problems with incoordination.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Troriluzole is in a Phase III clinical trial (NCT03701399) for a number of SCAs including SCA8.

Ongoing preclinical studies are being performed in SCA8 animal models to assess possible benefits of therapies that target the pathogenic (CTA·TAG)_n(CTG·CAG)_n repeat expansions or the RNA or proteins produced from the pathogenic repeat expansion.

Because it is possible that therapeutic strategies successful for one spinocerebellar ataxia caused by an abnormal nucleotide repeat expansion could apply to other SCAs, it is important to prepare for eventual clinical trial studies by establishing key outcome measures for affected individuals.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Spinocerebellar ataxia type 8 (SCA8) is inherited in an autosomal dominant manner.

Note: Because the penetrance of SCA8 is reduced, it is common for a proband to represent a simplex case (i.e., the only affected family member) or, alternatively, the family history of a proband may appear to be consistent with autosomal recessive inheritance because of multiple affected sibs in a single generation.

Risk to Family Members

Parents of a proband

• To date, all individuals diagnosed with SCA8 whose parents have been evaluated with molecular genetic testing have one parent with an ATXN8OS/ATXN8 (CTG·CAG)_n repeat expansion.
• The transmitting parent may or may not have clinical manifestations of SCA8 depending on the size of the combined (CTA·TAG)_n(CTG·CAG)_n repeat tract and other factors that affect the penetrance of the expanded repeat [Day et al 2000, Juvonen et al 2002, Ikeda et al 2004].
• If neither of the parents of the proband is known to have SCA8, recommendations for the evaluation of parents include targeted analysis for the SCA8 (CTA·TAG)_n(CTG·CAG)_n repeat.
• The family history of some individuals diagnosed with SCA8 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the (CTG·CAG)_n repeat expansion.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the parents:

• If a parent of the proband is known to have a (CTG·CAG)_n repeat expansion, the risk to each sib of inheriting the repeat expansion is 50%.
• Sibs who inherit a (CTG·CAG)_n repeat expansion may or may not develop clinical manifestations of SCA8. The true penetrance of combined (CTA·TAG)_n(CTG·CAG)_n repeat sizes is not understood, as interfamilial differences in penetrance for the same size repeat expansion can be seen (see Penetrance).
• The (CTG·CAG)_n portion of the repeat expansion is highly unstable and almost always changes in size when transmitted from one generation to the next: the repeat expansion is more likely to become larger when maternally transmitted and more likely to contract with paternal transmission (see Anticipation).

Offspring of a proband

• Each child of an individual with a (CTG·CAG)_n repeat expansion has a 50% chance of inheriting the repeat expansion. Offspring who inherit a (CTG·CAG)_n repeat expansion may or may not develop clinical manifestations of SCA8. The true penetrance of combined (CTG·CAG)_n repeat expansion sizes is not understood, as interfamilial differences in penetrance for the same size repeat expansion can be seen (see Penetrance).
• If the proband is female, the (CTG·CAG)_n repeat expansion is more likely to become larger when transmitted; if the proband is male, the repeat expansion is more likely to contract when transmitted (see Anticipation).

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected and/or has the (CTG·CAG)_n repeat expansion, the parent's family members are at risk.

Related Genetic Counseling Issues

Note: If neither parent of a proband with SCA8 has a (CTG·CAG)_n repeat expansion, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Because of reduced penetrance and disease complexity, the combined (CTA·TAG)_n(CTG·CAG)_n repeat length cannot be used to predict whether or not an individual will develop disease. However, a family history with multiple affected relatives appears to increase the likelihood that an asymptomatic individual with a (CTG·CAG)_n repeat expansion will develop ataxia [Author, personal observation].

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once molecular genetic testing has identified a (CTG·CAG)_n repeat expansion in an affected family member:
  • If a (CTG·CAG)_n repeat expansion is not detected, the individual is not at risk of developing SCA8.
  • If a (CTG·CAG)_n repeat expansion is detected, the individual is at risk for SCA8; however, the test result cannot be used to predict whether an asymptomatic individual will subsequently develop disease manifestations or what the age of onset will be. In addition, the test result cannot be used to predict the severity, features, or rate of progression of SCA8 in individuals who develop disease manifestations.
  • The true penetrance of the combined (CTA·TAG)_n(CTG·CAG)_n repeat length is not understood, as interfamilial differences in penetrance for the same size repeat expansion can be seen (see Penetrance). However, one or more (CCG·CGG) interruptions within the expanded (CTG·CAG)_n portion of the repeat have been found more frequently in probands with multiple affected family members compared to probands who represent simplex cases (i.e., a single affected family member). These data suggest that asymptomatic individuals with CCG·CGG interruptions within the (CTG·CAG)_n repeat expansion may be at higher risk of developing ataxia [Authors, unpublished data].
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of SCA8, it is appropriate to consider testing of symptomatic individuals regardless of age.

Prenatal Testing and Preimplantation Genetic Testing

Once the ATXN8OS/ATXN8 (CTG·CAG)_n repeat expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. (Note: The prenatal finding of a (CTG·CAG)_n repeat expansion cannot be used to accurately predict if a heterozygous family member will develop manifestations of SCA8.)

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors position statement on prenatal testing for adult-onset conditions.

Molecular Pathogenesis

The role of (CTG·CAG)_n repeat expansions in ATXN8OS/ATXN8 in disease pathogenesis is supported by findings in families of various backgrounds with ataxia and in mouse models [Ikeda et al 2004; Moseley et al 2006; Daughters et al 2009; Zu et al 2011; Authors, unpublished data].

This repeat sequence is located in both the 3' untranslated region of ATXN8OS (CTG orientation) and as part of a short polyglutamine open reading frame in the overlapping gene ATXN8 (CAG orientation) [Moseley et al 2006]. CTG·CAG and CTA·TAG refer to the forward and reverse sequences, respectively, of two adjacent repeat tracts containing three base pairs of repeat sequences. The CTA·TAG repeat varies modestly in length between families but it is the CTG·CAG portion of the repeat that expands in SCA8.

The CTG·CAG repeat is unstable when transmitted from one generation to the next (see Anticipation). In contrast, the highly polymorphic CTA·TAG repeat adjacent to the CTG·CAG repeat is stable when transmitted from generation to generation [Koob et al 1999, Moseley et al 2000, Ikeda et al 2004, Moseley et al 2006].

Mechanism of disease causation. SCA8 occurs through both toxic RNA and toxic protein gain-of-function mechanisms:

• CUG expansion transcripts (ATXN8OS) cause RNA gain-of-function effects [Daughters et al 2009] similar to those found in myotonic dystrophy type 1 and myotonic dystrophy type 2 [Ranum & Cooper 2006]. CUG RNA foci were detected in Purkinje cells, molecular layer interneurons, and Bergmann glia [Daughters et al 2009].
• CAG expansion transcripts (ATXN8) express ATG-initiated polyGln protein that accumulates in nuclear aggregates in Purkinje cells [Moseley et al 2006] as well as frontal cortex, pons, and hippocampus [Ayhan et al 2018].
• CAG expansion transcripts (ATXN8) have also been shown to express polyalanine [Zu et al 2011] and polyserine [Ayhan et al 2018] expansion proteins, by repeat-associated non-AUG translation. These proteins accumulate in SCA8-affected human and mouse brains [Zu et al 2011, Ayhan et al 2018], with polyserine accumulating in white matter regions that show demyelination and axonal degeneration [Ayhan et al 2018].

Table 6.

ATXN8OS/ATXN8 Technical Considerations

Methods to characterize ATXN8OS/ATXN8 (CTA·TAG)_n(CTG·CAG)_n repeats. Because of the technical challenges of detecting and sizing (CTA·TAG)_n(CTG·CAG)_n repeats within ATXN8OS/ATXN8, multiple methods may be needed to rule out or detect an expanded repeat (see Table 7). Repeats in the normal range (15-50 combined (CTA·TAG)_n(CTG·CAG)_n repeats) may be detected by traditional PCR; however, because detection of an apparent homozygous normal (CTA·TAG)_n(CTG·CAG)_n repeat length does not rule out the presence of an expanded (CTA·TAG)_n(CTG·CAG)_n allele, testing by RP-PCR or Southern blotting is required.

Table 7.

Methods to Characterize ATXN8OS/ATXN8 (CTA·TAG)_n(CTG·CAG)_n Repeats

Author Notes

University of Florida Center for NeuroGenetics: neurogenetics.med.ufl.edu

SH Subramony's web page: neurology.ufl.edu/profile/subramony-sub

Laura PW Ranum's web page: neurogenetics.med.ufl.edu/profile/ranum-laura

John Douglas Cleary's web page: neurogenetics.med.ufl.edu/profile/cleary-john

Acknowledgments

We would like to acknowledge all the SCA8 families who have donated time, materials, or knowledge to our work over the years. We would also like to acknowledge previous authors, trainees, and colleagues who have contributed to the understanding of this disorder. Our work has been funded and/or supported by the National Ataxia Foundation, National Institutes of Health, the University of Florida Foundation, and many private donors.

Author History

Fatma Ayhan, BS; University of Florida (2014-2021)
John Douglas Cleary, PhD (2021-present)
Joline C Dalton, MS; University of Minnesota (2001-2021)
John W Day, MD, PhD; Stanford University (2001-2021)
Yoshio Ikeda, MD, PhD; Gunma University Graduate School of Medicine (2001-2021)
Laura PW Ranum, PhD (2001-present)
SH Subramony, MD, PhD (2021-present)

Revision History

• 22 April 2021 (bp) Comprehensive update posted live
• 3 April 2014 (me) Comprehensive update posted live
• 7 February 2007 (me) Comprehensive update posted live
• 15 March 2004 (me) Comprehensive update posted live
• 27 November 2001 (me) Review posted live
• 15 February 2001 (jd) Original submission

Published Guidelines / Consensus Statements

• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 6-10-22.

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