Koob et al. (1999) reported a large kindred with autosomal dominant spinocerebellar ataxia. Onset of symptoms ranged from age 18 to 65, with a mean of 39 years. Dysarthria, mild aspiration, and gait instability were commonly the initial ... Koob et al. (1999) reported a large kindred with autosomal dominant spinocerebellar ataxia. Onset of symptoms ranged from age 18 to 65, with a mean of 39 years. Dysarthria, mild aspiration, and gait instability were commonly the initial symptoms. Clinical findings included spastic and ataxic dysarthria, nystagmus, limb and gait ataxia, limb spasticity, and diminished vibration perception. Progression was generally fairly slow, but severely affected family members were nonambulatory by the fourth to fifth decades. MRI showed cerebellar atrophy. Disease severity appeared to correlate with repeat length and age. Ikeda et al. (2000) reported 6 patients with expanded CTG repeat alleles in the ATXN8OS gene. The expanded alleles from the patients ranged from 89 to 155 repeats, and those from normal elderly subjects (over age 79 years) ranged from 15 to 34 repeats. The mean age at onset in the SCA8 cases was 53.8 years, ranging from 20 to 72 years. One father and daughter from an SCA8 family showed remarkable paternal anticipation: the number increase from father to daughter was +16 CTG repeats, with a 31-year acceleration of onset. In general, the SCA8 patients showed trunk and limb incoordination, ataxic dysarthria, impaired smooth pursuit and horizontal nystagmus, and significant atrophy of the cerebellar vermis and hemispheres on MRI. Ikeda et al. (2000) noted that the SCA8 phenotype corresponded to autosomal dominant cerebellar ataxia type III (ADCA III). Factor et al. (2005) reported a patient with onset of dysarthria and impairment of balance and coordination at age 53 years that rapidly progressed to include gait and postural instability, urinary incontinence, impotence, and depression. MRI showed cerebellar and pontine atrophy. Molecular analysis identified an expansion of 145 CTA/CTG repeats in one allele and 28 repeats in the other allele, which was consistent with SCA8. However, postmortem examination showed findings consistent with multiple system atrophy. Factor et al. (2005) noted that the association between the SCA8 repeat expansion and ataxia is controversial, and suggested that testing sporadic cases with late-onset ataxia may lead to misdiagnosis, as in their case. Ito et al. (2006) reported a Japanese father and son with heterozygous expanded SCA8 CAG repeats of 240 and 221, respectively. The father developed progressive gait unsteadiness at age 41 years. Other features included ataxic dysarthria, limb and trunk ataxia, limited upward gaze, and later onset of bradykinesia, rigidity, and difficulty swallowing. The son presented at age 14 with dysarthria and later developed cerebellar ataxia, facial grimacing, hyperreflexia, rigidity, spasticity, dystonia, and bradykinesia. His verbal IQ was 63. The father died suddenly at age 45 from accidental suffocation by sputum while hiking. Postmortem examination showed cerebellar atrophy, depigmentation of the substantia nigra, and severe atrophy or loss of Purkinje cells. The sites of Purkinje cell loss had been replaced by fibrillary accumulations resembling afferent axons. Some residual Purkinje cells had somatic sprouts and contained clusters of granular material. The inferior olives also showed neuronal loss, but the dentate nucleus was preserved. There was extensive gliosis in the periaqueductal gray matter.
In 8 pedigrees with autosomal dominant spinocerebellar ataxia, Koob et al. (1999) identified a CTG repeat expansion in the ATXN8OS gene (603680.0001), which was found to be transcribed into an mRNA with an expanded CUG repeat in its ... In 8 pedigrees with autosomal dominant spinocerebellar ataxia, Koob et al. (1999) identified a CTG repeat expansion in the ATXN8OS gene (603680.0001), which was found to be transcribed into an mRNA with an expanded CUG repeat in its 3-prime UTR. The corresponding CAG repeat expansion in the 5-prime-to-3-prime orientation of the ATXN8 (613289) template strand was determined not to be translated into a polyglutamine-containing protein. In the largest pedigree, which included affected members spanning at least 4 generations, repeat length ranged from 107 to 127 CTG repeats. However, 20 unaffected individuals also carried expanded repeats. Daughters et al. (2009) presented evidence that the expanded CTG repeat in the ATXN8OS gene is transcribed into an mRNA with an expanded CUG repeat, conferring a toxic gain of function that plays a role in the SCA8 phenotype. Moseley et al. (2006) identified IC2-immunoreactive intranuclear inclusions, detecting polyglutamine expansions, in brain tissue from patients with SCA8, but not in normal controls. The polyglutamine protein was determined to be encoded by an expanded CAG repeat in the ATXN8 gene (613289.0001). This CAG repeat was complementary to the expanded CTG repeat in the ATXN8OS gene on the opposite strand. The findings of Moseley et al. (2006) indicated that bidirectional transcription at the SCA8 locus results in expression of both a polyglutamine protein and a CUG expansion transcript, which may represent a toxic gain of function at both the protein and RNA levels.
SCA8 is suspected [Day et al 2000] in individuals with the following: ...
DiagnosisClinical DiagnosisSCA8 is suspected [Day et al 2000] in individuals with the following: Principally cerebellar ataxia Slowly progressing ataxia Scanning dysarthria characterized by a drawn-out slowness of speech Marked truncal instability Hyperactive tendon reflexes Family history of ataxia consistent with single occurrence in the family or either an autosomal recessive or autosomal dominant pattern of inheritance. 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 TestingGene. The expansion mutation associated with the SCA8 phenotype involves two overlapping genes [Moseley et al 2006]: In the CTG direction, ATXN8OS (formerly known as SCA8) expresses transcripts containing the CUG expansion. In the CAG direction, ATXN8 expresses the mutation and encodes a nearly pure polyglutamine expansion protein. The expansion mutation associated with the SCA8 phenotype is located in both the 3' untranslated region of ATXN8OS and a short polyglutamine ORF in an overlapping gene, ATXN8 [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 et al 2000c].The reduced penetrance of this mutation and the presence of the polymorphic CTA·TAG repeat have made it difficult to determine the pathogenic size range of the CTG·CAG repeat.Allele sizes 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. Clinical testing 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. Table 1. Summary of Molecular Genetic Testing Used in SCA8View in own windowTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityPCR, Southern blot analysisTrinucleotide repeat expansion located within two overlapping genes: an untranslated portion of ATXN8OS and a short ORF for ATXN8 ~100%Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated geneTesting StrategyIf 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. Clinical uses Diagnosis Presymptomatic diagnosis Prenatal testing Genetically Related (Allelic) DisordersNo other phenotypes have been shown to be associated with mutations in ATXN8OS or ATXN8.
Spinocerebellar ataxia type 8 (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....
Natural HistorySpinocerebellar ataxia type 8 (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 et al 2000a, 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 et al 2000a, 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 et al 2000a, 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 et al 2000b].
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). ...
Genotype-Phenotype CorrelationsAlthough 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). No correlation between the size of the expansion and age of onset or disease severity was observed [Day et al 2000, Ikeda et al 2000a, Juvonen et al 2000].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.
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: ...
Differential DiagnosisAtaxia. 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: SCA1. SCA8 disease progression is much slower, with less bulbar involvement than SCA1 [Schut 1950, Day et al 2000]. SCA2. Saccadic eye movements in SCA8 are not dramatically slowed, in contrast to SCA2 [Orozco Diaz et al 1990]. SCA3. Unlike SCA3, SCA8 does not show marked signs or symptoms suggestive of involvement of either lower motor neurons or extrapyramidal neurons [Barbeau et al 1984]. SCA4. Although sensory nerves are affected, SCA8 does not result in the complete loss of sensory nerve function seen in SCA4 [Flanigan et al 1996]. 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]. SCA7. Unlike SCA7, SCA8 does not feature retinal degeneration [Gouw et al 1995]. SCA10. Seizures are not common in individuals with SCA8, distinguishing it from SCA10 [Matsuura et al 2000]. 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 et al 2000a, Vincent et al 2000b]. 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.
To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 8 (SCA8), the following are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 8 (SCA8), the following are recommended:Neurologic assessment, including neuroimaging (brain MRI or CT) Assessment of the family pedigree and the disease course in other affected family members to aid in establishing a clinical prognosis Treatment of ManifestationsUse 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 ManifestationsManagement of affected individuals remains supportive, as there is no known therapy to delay or halt the progression of the disease.Prevention of Secondary ComplicationsNo dietary factor has been shown to curtail symptoms; however, vitamin supplements are recommended, particularly if caloric intake is reduced. SurveillanceAffected 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 AvoidAlcohol should be avoided because it can exacerbate problems with incoordination.Affected individuals should get plenty of rest; symptoms are often aggravated by fatigue. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.OtherTremor-controlling drugs do not work well for cerebellar tremors.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Spinocerebellar Ataxia Type 8: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameHGMDATXN8OS13q21.33UnknownATXN8OSATXN813q21Ataxin-8ATXN8Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Spinocerebellar Ataxia Type 8 (View All in OMIM) View in own window 603680ATAXIN 8 OPPOSITE STRAND; ATXN8OS 608768SPINOCEREBELLAR ATAXIA 8; SCA8 613289ATAXIN 8; ATXN8Normal 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 families of northern European origin; two other distinct haplotypes were present in non-northern European 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 et al 2000a, Moseley et al 2000a, Moseley et al 2000b, 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. In contrast, KLHL1 and ATXN8OS 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 human ATXN8OS (Klhl1as), mouse Klhl1as 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 ATXN8OS 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 murine Klhl1 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 overlapping ATXN8 is also likely to contribute to the disease through toxic effects of the polyglutamine expansion protein [Moseley et al 2006].