Spinocerebellar Ataxia 8

A number sign (#) is used with this entry because evidence suggests that spinocerebellar ataxia-8 (SCA8) is caused by bidirectional transcription at the SCA8 locus on chromosome 13q21 involving both an expanded CTG trinucleotide repeat in the ATXN8OS gene (603680.0001) and the complementary CAG repeat in the ATXN8 gene (613289.0001). These variations result in expression of a CUG expansion mRNA transcript and a polyglutamine protein, respectively, suggesting a toxic gain of function at both the protein and RNA levels. The molecular defect is often referred to as the 'CTG*CAG' repeat expansion, referring to the complementary basepairs of the ATXN8OS and ATXN8 genes, reading 5-prime to 3-prime (review by Ikeda et al., 2008).

Normal alleles contain 15 to 50 repeats, whereas pathogenic alleles contain 71 to 1,300 repeats (Todd and Paulson, 2010).

For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Clinical Features

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.

Mapping

By PCR analysis of a large 7-generation kindred with SCA and expanded repeats of the SCA8 CTG allele, Koob et al. (1999) found linkage to the SCA8 gene on chromosome 13q21 (maximum lod score of 6.8).

Molecular Genetics

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.

Pathogenesis

Daughters et al. (2009) presented evidence that the expanded CTG repeat in the ATXN8OS gene (603680.0001) is transcribed into an mRNA with an expanded CUG repeat, conferring a toxic gain of function that plays a role in the SCA8 phenotype. In brain tissue from humans and mice with SCA8, ATXN8OS mRNA containing the expanded repeat was found to accumulate as ribonuclear inclusions, or RNA foci, that colocalized with the RNA-binding protein MBNL1 (606516) in selected cerebellar cortical neurons in the brain. In Sca8 mice, genetic loss of Mbnl1 enhanced motor deficits, suggesting that loss of MBNL1 plays a role in SCA8 pathogenesis. In Sca8 mice and SCA8 human brains, sequestration of MBNL1 in RNA foci resulted in the dysregulation of downstream splicing patterns normally regulated by the CUGBP1 (601074)/MBNL1 pathway, including that of mouse GABA transporter-4 (GAT4, or SLC6A11; 607952). These changes in Gat4 were associated with loss of GABAergic inhibition in the granular cell layer. These data indicated that expanded CUG ATXN8OS mRNA transcripts can dysregulate gene pathways in the brain, similar to the mechanism involved in myotonic dystrophy (DM1; 160900), which is caused by a CTG repeat expansion in the 3-prime UTR of the DMPK gene (605377) on chromosome 19q13. Daughters et al. (2009) also suggested that the findings may have relevance for other mainly CAG repeat expansion disorders in which an expanded CTG repeat on the opposite stand may also have toxic effects.