Spinocerebellar Ataxia Type 8 (SCA8)
Disease characteristics. SCA8 is a slowly progressive ataxia with disease onset typically occurring in adulthood. Onset ranges from age one to 65 years. The progression is typically over decades regardless of the age of onset. Common initial symptoms are scanning dysarthria with a characteristic drawn-out slowness of speech and gait instability. Some individuals present with nystagmus, dysmetric saccades and, rarely, ophthalmoplegia. Tendon reflex hyperreflexity and extensor plantar responses are present in some severely affected individuals. Life span is typically not shortened.
Diagnosis/testing. The diagnosis of SCA8 must be confirmed by the presence of a (CTG)n trinucleotide repeat expansion in the ATXN8OS gene (formerly known as SCA8). The pathogenic (CTG)n repeat is adjacent to a non-pathogenic but highly polymorphic, stably transmitted (CTA)n repeat, which makes it technically difficult to determine the precise number of pathogenic (CTG)n repeats. Therefore, the current reference ranges are based on the total number of both the (CTA)n and (CTG)n repeats. Normal alleles have 15 to 50 repeats. The repeat lengths most often associated with ataxia range from 80 to 250; however, repeat lengths ranging from 71 to more than 1300 have been found in some individuals with ataxia. Although reduced penetrance is observed for alleles of all repeat lengths, it is most often observed with alleles of fewer than 100 repeats. The pathogenesis of the SCA8 phenotype is complex and also involves a (CAG)n repeat in a second overlapping gene, ATXN8.
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. Prevention of secondary complications: vitamin supplements if caloric intake is reduced. Surveillance: routine follow-up with a neurologist. Agents/circumstances to avoid: Alcohol can exacerbate incoordination. Other: Tremor-controlling drugs do not work well.
Genetic counseling. The ATXN8OS (CTA)n(CTG)n composite repeat expansion is transmitted in an autosomal dominant manner with reduced penetrance. To date, all affected individuals whose parents have been evaluated with molecular genetic testing have one parent with an ATXN8OS (CTA)n(CTG)n expansion; de novo mutations have not been reported. The (CTG)n component of the (CTA)n(CTG)n composite repeat is highly unstable and almost always expands upon maternal transmission. In individuals with no apparent family history of SCA8, it is common for the mother to be asymptomatic and to have an (CTA)n(CTG)n expansion with a shorter repeat length than her affected child. When paternally transmitted, the (CTG)n repeat tract almost always contracts in length, usually to a length below 100 combined (CTA)n(CTG)n repeats, a range that is less often associated with ataxia. Each child of an individual with an ATXN8OS expansion has a 50% chance of inheriting the expanded allele. Although the risk of developing ataxia is dependent on the length of the (CTG)n expansion, and probably also on other factors that affect the expression of the mutation, neither family history nor the combined (CTA)n(CTG)n repeat lengths predict whether offspring will develop symptoms of SCA8. Prenatal testing for pregnancies at 50% risk for SCA8 is possible.
SCA8 is suspected [Day et al 2000] in individuals with the following:
Note: Because of the reduced penetrance, a single occurrence in a family is the most common presentation of the disease.
The spinocerebellar ataxias share many clinical symptoms in common and the diagnosis of SCA8 must be confirmed by molecular genetic testing.
Molecular Genetic Testing
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The expansion mutation associated with the SCA8 phenotype is located in both the 3' untranslated region of the ATXN8OS gene and a short polyglutamine ORF in a newly identified overlapping ATXN8 gene [Moseley et al 2006]. The CTG·CAG repeat is adjacent to a CTA·TAG repeat that is highly polymorphic but stable when transmitted from one generation to the next [Koob et al 1999 ; Moseley, Schut, Bird, Koob et al 2000].
· Normal alleles: 15 to 50 combined (CTA·TAG)n(CTG·CAG)n repeats
· Alleles of questionable significance: It is not yet clear whether repeat sizes ranging from 50 to 70 repeats can be pathogenic.
· Reduced penetrance allele size: Reduced penetrance is found for (CTA·TAG)n(CTG·CAG)n repeats of all sizes [Ranum et al 1999]. Although the length of the repeat tract does not correlate with the age of onset, severity, symptoms, or disease progression, within the 75 to 250 repeat range, affected individuals tend to have longer repeat tracts than asymptomatic individuals. Individuals with (CTA·TAG)n(CTG·CAG)n repeat sizes ranging from 71 to 80 repeats have been reported to have ataxia; however, in some families this range appears to be less likely to be associated with ataxia than repeat sizes of over 100 repeats.
· Higher penetrance allele size: 80 to 250 (CTA·TAG)n(CTG·CAG)n repeats are most often seen in individuals with ataxia; however, repeat sizes ranging from 71 to more than 1300 repeats have been found both in individuals who develop ataxia and in those who do not.
· Targeted mutation analysis. Although it is the (CTG·CAG)n portion of the repeat tract that expands in affected individuals, the current method of detection measures the combined (CTA·TAG)n(CTG·CAG)n repeat total. For smaller allele sizes (expansions <200 repeats), the mutation can be detected by PCR. For larger expansions (>200 combined (CTA·TAG)n(CTG·CAG)n CAG repeats), Southern analysis is needed to reliably detect expansions.
If PCR analysis fails to detect an expansion and if the PCR results appear to indicate that the individual has two alleles of the same size, Southern analysis should be performed to determine if an expansion that failed to be amplified by PCR is present.
Genetically Related (Allelic) Disorders
SCA8 is a slowly progressive ataxia with disease onset typically in adulthood. Onset has been reported from age one to 65 years [Day et al 2000 , Juvonen et al 2000 , Silveira et al 2000 , Felling & Barron 2005]. The progression is typically over decades regardless of the age of onset. Common initial symptoms reported are dysarthria and gait instability [Day et al 2000 , Juvonen et al 2000]. The clinical presentation is fairly consistent among most families regardless of the pathogenic threshold, and life span is typically not shortened.
Clinical symptoms observed in most individuals with the SCA8 form of ataxia are dysarthria and clumsiness of gait and limb movements [Day et al 2000 ; Ikeda, Shizuka et al 2000 ; Juvonen et al 2000 ; Cellini et al 2001 ; Brusco et al 2002 ; Tazon et al 2002 ; Topisirovic et al 2002 ; Mosemiller et al 2003 ; Schols et al 2003 ; Zeman et al 2004 ; Lilja et al 2005]. One distinguishing feature of SCA8 is scanning dysarthria with a characteristic drawn-out slowness of speech. At an early stage, speech can be disproportionately affected relative to other cerebellar signs. Ataxic symptoms of the lower extremities appear to be more pronounced than those of upper extremities. Severe truncal titubation that advances with disease progression is characteristic. Some individuals with SCA8 present with nystagmus, dysmetric saccades and, rarely, ophthalmoplegia. Tendon reflex hyperactivity and extensor plantar responses are present in some severely affected individuals [Day et al 2000 ; Ikeda, Shizuka et al 2000 ; Juvonen et al 2000].
Cognitive impairment, found in 40% of affected individuals of Finnish heritage, has not been observed in other populations [Juvonen et al 2000 , Stone et al 2001 , Zeman et al 2004 , Baba et al 2005 , Lilja et al 2005].
Atypical clinical features identified in individuals heterozygous for an ATXN8OS/ATXN8 expansion include Parkinsonism, multiple system atrophy, and severe childhood onset [Baba et al 2005 , Factor et al 2005 , Felling & Barron 2005 , Munhoz et al 2006]. The causative relationship between the ATXN8OS/ATXN8 expansion and these other conditions remains unknown, given the relatively high frequency of the ATXN8OS/ATXN8 expansion in the general population and the reduced penetrance of the disease.
Neuroimaging. MRI and CT have consistently shown cerebellar atrophy, specifically in the cerebellar hemisphere and vermis in individuals with SCA8 [Day et al 2000 ; Ikeda, Shizuka et al 2000 ; Juvonen et al 2000 ; Cellini et al 2001 ; Brusco et al 2002 ; Tazon et al 2002 ; Topisirovic et al 2002 ; Schols et al 2003 ; Zeman et al 2004 ; Lilja et al 2005]. In one individual in whom serial MRI scans were performed nine years apart, little progression was seen in the cerebellar atrophy [Day et al 2000]. Mild cerebellar atrophy was observed in a 71-year-old asymptomatic male with an ATXN8OS/ATXN8 expansion [Ikeda, Shizuka-Ikeda et al 2000].
Although there is a correlation between repeat number and penetrance, longer alleles in the size range from 50 to 250 CTA/CTG repeats are more often found in affected individuals than in unaffected relatives (p<0.001).
The clinical presentation in the two individuals from the MN-A family homozygous for the ATXN8OS/ATXN8 expansion did not differ in severity from the clinical presentation in siblings heterozygous for the ATXN8OS/ATXN8 expansion. It is important to note that only one of the expanded alleles in each of these homozygous individuals in the MN-A appears to be in the pathogenic range [Day et al 2000].
Individuals homozygous for the ATXN8OS/ATXN8 expansion have been reported more frequently than for other forms of spinocerebellar ataxia caused by similar expansion mutations [Koob et al 1999 , Day et al 2000 , Stevanin et al 2000 , Tazon et al 2002 , Izumi et al 2003 , Schols et al 2003 , Brusco et al 2004 , Corral et al 2005 , Juvonen et al 2005]. The ages at onset in most individuals homozygous for an ATXN8OS/ATXN8 expansion were not obviously accelerated compared to the ages of onset of individuals heterozygous for an ATXN8OS/ATXN8 expansion.
In the large family (MN-A) originally reported to have SCA8 (Lod 6.8 at :0.00), affected individuals have longer CTG·CAG repeat tracts (mean: 117) than the 21 asymptomatic individuals with a CTG·CAG repeat expansion (mean: 92; p<10-6). These results indicate that repeat length plays a role in disease penetrance [Koob et al 1999 , Day et al 2000]. Further analysis of other families showed that the pathogenic range can vary among families and that a positive test for an ATXN8OS/ATXN8 expansion, regardless of the repeat size, cannot be used to predict whether an asymptomatic individual will develop ataxia [Ranum et al 1999 ; Moseley, Schut, Bird, Koob et al 2000 ; Worth et al 2000 , Ikeda et al 2004].
· The polymorphic CTA·TAG repeat. The CTA·TAG repeat, which is adjacent to the CTG·CAG repeat, remains stable during transmission; however, the CTA·TAG repeat varies among families, ranging in size from one to 21 repeats [Koob et al 1999 ; Moseley, Schut, Bird, Koob et al 2000 ; Stevanin et al 2000]. Because the PCR assay measures the length of both repeats, the polymorphic CTA·TAG may account for some of the apparent interfamilial differences in affected allele size ranges and reduced penetrance of the mutation.
· Interruptions within the CTG·CAG expansion. Interruptions within the CTG·CAG expansion by one or more CCG·CGG, CTA·TAG, CTC·GAG, CCA·TGG, or CTT·AAG trinucleotides have also been observed in full penetrance alleles [Moseley, Schut, Bird, Koob et al 2000]. Surprisingly, these interruptions can duplicate when transmitted from one generation to the next. Individuals with the SCA8 form of ataxia have been shown to have both pure CTG·CAG tracts and tracts with interruptions. Most normal-length alleles do not have interrupted CTG·CAG repeat tracts, although one normal allele (23 combined repeats) with an interruption in the CTG·CAG portion of the repeat tract has been reported [Sobrido et al 2001]. The potential influence of the interruptions on the development of ataxia is not yet clear [Moseley, Schut, Bird, Koob et al 2000 ; Mosemiller et al 2003].
· Intergenerational size changes. The ATXN8OS/ATXN8 expansion is unstable and almost always changes in size when transmitted from generation to generation. A maternal penetrance bias for disease transmission that occurs in some families appears to be related to the maternal expansion bias of the CTG·CAG repeat tract (-11 to +900) [Koob et al 1999 , Ranum et al 1999 , Day et al 2000 , Corral et al 2005]. In contrast, a bias for contraction (-86 to +7) of the CTG·CAG repeat is observed with paternal transmission [Koob et al 1999 , Ranum et al 1999]. In sperm from males with SCA8, nearly all of the expanded alleles contract, resulting in tracts that usually contain fewer than 100 combined repeats [Moseley, Schut, Bird, Koob et al 2000]. It is likely that these dramatic repeat contractions in sperm play a role in the reduced penetrance of paternal transmissions. In summary, intergenerational changes in repeat size appear to play a role in the reduced penetrance of SCA8, with ataxia more likely to result from the larger maternally transmitted repeat tracts than from smaller paternally transmitted expansions.
Maternal transmission. The CTG·CAG expansion is more likely to become larger when maternally transmitted. Therefore, individuals who inherit the expansion from their mothers are at a greater risk of developing ataxia because their allele sizes tend to be large and, at least in some families, in a more penetrant size range.
Paternal transmission. The CTG·CAG expansion is more likely to contract with paternal transmission, usually resulting in smaller, less penetrant allele sizes. Therefore, individuals who inherit the expansion from their fathers, at least in some families, are at a lower risk of developing ataxia.
Epidemiologic studies of the frequency of the ATXN8OS/ATXN8 expansion have not been performed, but estimates of the prevalence of ATXN8OS/ATXN8 expansions in various control groups suggest that the prevalence of ATXN8OS/ATXN8 expansions larger than 50 combined repeats ranges from approximately 1:100 to 1:1200 chromosomes in various ethnic populations [Koob et al 1999 ; Ikeda, Shizuka et al 2000 ; Juvonen et al 2000 ; Vincent, Neves-Pereira et al 2000 ; Sulek et al 2004 ; Zeman et al 2004]. (See Molecular Genetics).
The SCA8 form of ataxia is thought to account for 2%-5% of autosomal dominant forms of inherited ataxia. The prevalence of the disease is far lower than the prevalence of expansions because of the reduced penetrance of this mutation. Most of the expansions found in control groups are either in repeat ranges that are less penetrant or at the lower end of the expansion range (50-100 combined repeats), or are very large expansions (>500 repeats) [Ikeda et al 2004].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Ataxia. SCA8 is similar to other SCAs in that it affects coordination, with oculomotor and bulbar involvement and limb and gait ataxia (see Ataxia Overview). Some distinctions exist between SCA8 and other SCAs:
· SCA5, SCA6 . In contrast to the mainly cerebellar presentations of SCA5 and SCA6, severely affected individuals with SCA8 have spastic dysarthria, tendon reflex hyperactivity, and extensor plantar responses [Ranum et al 1994 , Zhuchenko et al 1997].
· SCA12 . Although cognitive decline has been reported in some families with SCA8 [Zeman et al 2004 , Baba et al 2005 , Lilja et al 2005], it occurs less commonly than in SCA12 [Rasmussen et al 2001].
Psychiatric symptoms. The ATXN8OS/ATXN8 expansion has been found in individuals with psychiatric conditions, as well as various control populations [Pato et al 2000 ; Vincent, Neves-Pereira et al 2000 ; Vincent, Yuan et al 2000]. The frequency of ATXN8OS/ATXN8 expansions is not significantly higher among individuals under psychiatric care than in controls and therefore the ATXN8OS/ATXN8 expansion is unlikely to play a role in psychiatric disorders.
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 8 (SCA8):
Treatment of Manifestations
Use of canes and walkers helps prevent falls.
Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.
Speech therapy, communication devices such as writing pads, and computer-based devices may benefit those with dysarthria.
Weighted eating utensils and dressing hooks help maintain some degree of independence.
When dysphagia becomes troublesome, a video esophagram can identify the consistency of food least likely to trigger aspiration.
Although neither exercise nor physical therapy has been shown to stem the progression of incoordination, individuals with SCA8 should try to remain active in order to maintain their muscular and cardiopulmonary conditioning.
Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.
Prevention of Primary Manifestations
Management of affected individuals remains supportive, as there is no known therapy to delay or halt the progression of the disease.
Prevention of Secondary Complications
No dietary factor has been shown to curtail symptoms; however, vitamin supplements are recommended, particularly if caloric intake is reduced.
Affected individuals should regularly visit a neurologist familiar with the ataxia syndromes to identify potential complications that develop over time and to manage clinical challenges associated with decreased mobility and exercise or difficulties with speech and swallowing.
Agents/Circumstances to Avoid
Alcohol should be avoided because it can exacerbate problems with incoordination.
Affected individuals should get plenty of rest; symptoms are often aggravated by fatigue.
Testing of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Tremor-controlling drugs do not work well for cerebellar tremors.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.
Mode of Inheritance
Risk to Family Members
Parents of a proband
Note: Because all individuals diagnosed with SCA8 have a parent with an ATXN8OS/ATXN8 gene expansion, in the absence of molecular genetic testing, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, reduced penetrance, or late onset of the disease in the affected parent.
Mother of a proband
Father of a proband
Sibs of a proband
Offspring of a proband
o Maternal transmission. The CTG·CAG expansion is more likely to become larger when maternally transmitted. In some families, individuals who inherit the expansion from their mothers are at a greater risk of developing ataxia, because their allele sizes tend to be large and thus in a more penetrant size range.
o Paternal transmission. The CTG·CAG expansion is more likely to contract with paternal transmission, usually resulting in smaller allele sizes, which in some families are less penetrant. Therefore, in some families, individuals who inherit the expansion from their father are at a lower risk of developing ataxia.
Other family members of a proband
Related Genetic Counseling Issues
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.
Reduced penetrance. The presence of the (CTA·TAG)n(CTG·CAG)n ATXN8OS/ATXN8 expansion is not always associated with ataxia. Therefore, some individuals with an ATXN8OS/ATXN8 expansion may remain asymptomatic for ataxia throughout their lives.
Maternal vs. paternal penetrance bias. Physicians and genetic counselors should be aware of the differences in male versus female transmission of the (CTA·TAG)n(CTG·CAG)n ATXN8OS/ATXN8 expansion (see Parents of a proband and Offspring of a proband) when providing genetic risk information to family members.
Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults is possible using the same techniques described in Molecular Genetic Testing . Predictive testing can determine whether an individual has a (CTA·TAG)n(CTG·CAG)n ATXN8OS/ATXN8 expanded allele and thus whether that individual is at risk of developing the disease. Because of reduced penetrance, an individual with an ATXN8OS/ATXN8 expansion is at risk for developing ataxia, but repeat size cannot be used to predict whether ataxia will occur or what the age of onset, severity, or progression of the symptoms will be. An affected family member should be tested prior to offering testing to at-risk family members to confirm the presence of an ATXN8OS/ATXN8 expansion in the family. Predictive testing should be accompanied by genetic counseling to assure that individuals are aware of the limitations of the molecular genetic test and the possible risks associated with predictive testing.
Testing of at-risk individuals during childhood. Testing of asymptomatic at-risk individuals during childhood is not recommended for adult-onset conditions for which there is no known effective treatment to prevent the disease or improve the outcome. Individuals younger than age 18 years who are symptomatic usually benefit from having a specific diagnosis established. (See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents.)
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See DNA Banking for a list of laboratories offering this service.
Prenatal testing for pregnancies at 50% risk for SCA8 is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for typically adult-onset conditions such as SCA8 are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.
Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.
Normal allelic variants: Normal alleles are 15-50 combined (CTA·TAG)n(CTG·CAG)n repeats in length. Not all expanded alleles (>50 repeats) are pathogenic. The prevalence of ATXN8OS/ATXN8 expansions larger than 70 repeats was 0.4% in 2626 control chromosomes [Ikeda et al 2004].
Pathologic allelic variants: Expanded alleles ranging in size from 71 to more than 800 combined (CTA·TAG)n(CTG·CAG)n repeats have been found in ataxic individuals. The ATXN8OS/ATXN8 expansion shows reduced penetrance and the molecular mechanisms for pathogenesis are not well understood.
It has been suggested that the CTG·CAG expansion is not involved in the spinocerebellar ataxia type 8 (SCA8) disease process and is simply a non-pathogenic polymorphism in linkage disequilibrium with another mutation that causes the ataxia [Stevanin et al 2000 , Worth et al 2000]. The linkage data and biologic relationship between repeat length and disease status in the MN-A family have supported the hypothesis that this CTG·CAG expansion is directly associated with ataxia. Haplotype analysis from 37 families with SCA8 showed a common haplotype and, thus common ancestral origin, among most Caucasian families; two other distinct haplotypes were present in non-Caucasian families. The identification of independently arising ATXN8OS/ATXN8 expansions among families of ataxia with various ethnic backgrounds further supports the direct role of the CTG·CAG expansion in disease pathogenesis [Ikeda et al 2004]. Additionally, the recent development of a BAC transgenic mouse model of SCA8 demonstrates that the ATXN8OS/ATXN8 expansion is pathogenic and can cause a progressive neurologic phenotype, cerebellar deficits, and intranuclear polyglutamine inclusions in Purkinje cells which parallel the human disease [Moseley et al 2006].
While it is now clear that the ATXN8OS/ATXN8 mutation can cause ataxia, a number of issues, including reduced penetrance, gender effects, and normal and pathogenic expansion ranges, require further investigation [Koob et al 1999 ; Ikeda, Shizuka et al 2000 ; Moseley, Jacobsen et al 2000 ; Moseley, Schut, Bird, Day et al 2000 ; Ikeda et al 2004].
Normal gene product: The genomic organization of the ATXN8OS/ATXN8 locus differs between humans and mice. In humans, three genes are in close proximity: ATXN8OS, ATXN8, and KLHL1. The expansion mutation is located within both of the overlapping ATXN8OS and ATXN8 genes. In contrast, the KLHL1 and ATXN8OS genes overlap at their respective 5' ends, a location approximately 35 kb upstream of the repeat. In mouse, the region containing the repeat is not conserved. While there is a mouse homolog of KLHL1 (Klhl1) and there is a much shorter version of the human ATXN8OS gene (Klhl1as), the mouse Klhl1as gene is much simpler, with a single exon and conservation only to the 5' end of the human ATXN8OS which overlaps KLHL1. Conservation of this short version of the ATXN8OS gene in mouse (Klhl1as) has led to the proposal that ATXN8OS transcripts may regulate KLHL1 [Nemes et al 2000 , Benzow & Koob 2002]. At this point, however, no functional studies substantiating this hypothesis have been published. A conditional knockout of the murine Klhl1 gene was recently reported to result in a mild atrophy of the molecular layer of the cerebellum, indicating that KLHL1 plays a normal role in cerebellar function. Because it is not known if KLHL1 transcripts are downregulated in persons with SCA8 or if the ATXN8OS/ATXN8 expansion mutation affects KLHL1 regulation, it is not yet clear whether KLHL1 plays a role in SCA8 pathogenesis [He et al 2006].
Abnormal gene product: Both RNA gain-of-function mechanism involving CUG expansion RNAs and polyglutamine expansion proteins are known to contribute to the pathology of other repeat expansion disorders [Ranum & Cooper 2006]. While the pathogenic effects of the ATXN8OS/ATXN8 CTG·CAG expansion are not yet understood, ATXN8OS transcripts containing elongated CUG expansions may cause a gain of toxic function of the RNA as has been demonstrated for myotonic dystrophy type 1 and myotonic dystrophy type 2 [Philips et al 1998 , Mankodi et al 2000 , Liquori et al 2001]. Additionally, the polyglutamine expansion protein expressed from the overlapping ATXN8 gene is also likely to contribute to the disease through toxic effects of the polyglutamine expansion protein [Moseley et al 2006].
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