Spinocerebellar Ataxia 1

A number sign (#) is used with this entry because spinocerebellar ataxia-1 (SCA1) is caused by an expanded (CAG)n trinucleotide repeat in the ataxin-1 gene (ATXN1; 601556) on chromosome 6p22.

Description

The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias,' (SCAs) even though 'spinocerebellar' is a hybrid term, referring to both clinical signs and neuroanatomical regions (Margolis, 2003). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord, and the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (Schols et al., 2004; Taroni and DiDonato, 2004).

Historically, Harding (1982) proposed a clinical classification for autosomal dominant cerebellar ataxias (ADCAs). ADCA I was characterized by cerebellar ataxia in combination with various associated neurologic features, such as ophthalmoplegia, pyramidal and extrapyramidal signs, peripheral neuropathy, and dementia, among others. ADCA II was characterized by the cerebellar ataxia, associated neurologic features, and the additional findings of macular and retinal degeneration. ADCA III was a pure form of late-onset cerebellar ataxia without additional features. SCA1, SCA2 (183090), and SCA3, or Machado-Joseph disease (109150), are considered to be forms of ADCA I. These 3 disorders are characterized at the molecular level by CAG repeat expansions on 6p24-p23, 12q24.1, and 14q32.1, respectively. SCA7 (607640), caused by a CAG repeat expansion in the ATXN7 gene (607640) on chromosome 3p13-p12, is a form of ADCA II. SCA5 (600224), SCA31 (117210), SCA6 (183086), and SCA11 (600432) are associated with phenotypes most suggestive of ADCA III. However, Schelhaas et al. (2000) noted that there is significant phenotypic overlap between different forms of SCA as well as significant phenotypic variability within each subtype.

Classic reviews of olivopontocerebellar atrophies and of inherited ataxias in general include those of Konigsmark and Weiner (1970), who identified 5 types of olivopontocerebellar atrophy, Berciano (1982), Harding (1993), Schelhaas et al. (2000), and Margolis (2003).

Clinical Features

Symptoms of SCA1 usually begin in the third or fourth decade of life, most often around age 30. In addition to cerebellar signs, there are upper motor neuron signs and extensor plantar responses. Involuntary choreiform movements may occur. Characteristic families with autosomal dominant spinocerebellar ataxia were reported by Menzel (1890), Waggoner et al. (1938), and Destunis (1944).

Both the clinical and the pathologic pictures in the disorder described in a large kindred, known as Vandenberg, by Schut (1950) and by Schut and Haymaker (1951) were variable. Symptoms varied from those of spinocerebellar ataxia to spastic paraplegia. Identification as a form of OPCA was based on the presence of the major pathology in the inferior olivary nucleus and cerebellum with variable pontine involvement. The spinal cord showed variable loss of anterior motor horn cells and changes in the spinocerebellar tracts and posterior funiculus. Involvement of cranial nerves IX, X and XII was another distinguishing feature.

Nino et al. (1980) reported a family in which the mean age of onset was 38.8 years. In addition to ataxia, affected persons showed lower bulbar palsies, hyperreflexia, scanning and explosive speech, incoordination, and, in some, slow motor-nerve conduction. Neuropathologic findings included atrophy of the cerebellum, pons and olives, degeneration of lower cranial nerve nuclei, and atrophy of the dorsal columns and spinocerebellar tracts. Deep tendon reflexes were increased and the Babinski sign was present. Pedersen (1980) reported an extensively affected Danish kindred. Clinical expression was highly variable so that different types of cerebellar ataxia had been diagnosed in individual members of the family. In at least 10, multiple sclerosis had been diagnosed.

Robitaille et al. (1995) compared the neuropathologic features of SCA1 with those reported for SCA2 and SCA3. Unlike the findings in SCA2 and SCA3, brains in SCA1 show almost no neuronal loss from the pars compacta of the substantia nigra or from the locus ceruleus, whereas there is severe atrophy of the dentatorubral pathways. Both SCA1 and SCA2 show severe loss of Purkinje cell and degeneration of the olivocerebellar pathways, which is not seen in SCA3. All 3 disorders share severe atrophy of the nucleus pontis, sparing of the retina and optic nerve, and marked atrophy of Clarke columns and the spinocerebellar tracts. Argyrophilic glial inclusions have not been reported in any of these disorders.

In 19 (70%) of 27 patients with confirmed SCA type 1, 2, 3, 6, or 7, van de Warrenburg et al. (2004) found electrophysiologic evidence of peripheral nerve involvement. Eight patients (30%) had findings compatible with a dying-back axonopathy, whereas 11 patients (40%) had findings consistent with a primary neuronopathy involving dorsal root ganglion and/or anterior horn cells; the 2 types were clinically almost indistinguishable. Four of 5 patients with SCA1 had a neuronopathy and 1 had a sensorimotor axonopathy.

Biochemical Features

In autopsied brain from 2 patients with autosomal dominant OPCA, Perry et al. (1977) found markedly reduced aspartic acid and markedly elevated taurine content. The patients were from the family reported by Currier et al. (1972), in which linkage to HLA was discovered by Jackson et al. (1977).

Plaitakis et al. (1980) found deficiency of glutamate dehydrogenase (GLUD1; 138130) in 3 patients with a 'spinocerebellar syndrome.' One was a 19-year-old male with juvenile onset of spinocerebellar and extrapyramidal manifestations. The others were 2 sibs, aged 64 and 71, with adult onset of spinocerebellar symptoms. The authors were led to this work by the fact that the nicotinamide antagonist 3-acetylpyridine produces ataxia in rats and CNS changes like those of OPCA IV. Four nicotinamide-adenine dinucleotide phosphate-requiring enzymes were measured. GDH may have an important role in metabolism of glutamate, a putative neurotransmitter in cerebellum, brainstem and spinal cord.

Sorbi et al. (1986) found a 50 to 60% reduction in platelet GLUD activity in 3 patients out of 4 with a so-called nondominant, i.e., sporadic or recessive, form of adult-onset OPCA and in father and son with a dominant form of OPCA. In another family, affected members (but not unaffected members), despite normal GDH activity, showed lack of activation of GDH by ADP in either the presence or the absence of Triton.

Diagnosis

Lucotte et al. (2001) demonstrated the feasibility of presymptomatic diagnosis in spinocerebellar ataxia-1. They studied a family in which the mean age of onset of the disorder was 38 years. Hitherto, presymptomatic testing for late-onset autosomal dominant disorders had largely been confined to Huntington disease, which is a genetically homogeneous entity. The same protocol could be applied to dominantly inherited ataxias, with the additional requirement that the SCA type of the disorder must be determined in the family at risk.

Mapping

Jackson et al. (1977) concluded that a form of spinocerebellar atrophy is linked with HLA on chromosome 6; the lod score was 3.15 for a recombination fraction of about 12. Moller et al. (1978) found further evidence in support of this linkage. In an extensively affected Prussian family, Nino et al. (1980) also found linkage to HLA. The maximum lod score was 1.97 at a male recombination fraction of 0.18 and a female recombination fraction of 0.36. When combined with data from other families, these results yielded a lod score of 4.681 at a recombination frequency of 0.22. Morton et al. (1980) reviewed linkage data on 13 kindreds. For linkage with HLA, they found a lod score of 5.53 at recombination rates of 0.223 in males and 0.327 in females. Nine of the 13 pedigrees, which appeared to have typical OPCA I, showed recombination rates of 0.150 in males and 0.300 in females. The remaining 4 pedigrees were clinically atypical or included discrepant data and gave no evidence of linkage. They suggested that linkage evidence may be decisive in delineation of the confused category of ataxias. In addition to the typical OPCA I of Menzel, other allelic forms of ataxia may exist, e.g., that in the Danish pedigree with pyramidal lesions and dementia (Pedersen et al., 1980).

In connection with other studies of a large family, the Schut-Swier kindred (Schut, 1950), Haines et al. (1984) concluded that there was linkage with HLA (maximum lod score = 3.71 at theta = 0.18). Haines and Trofatter (1986) placed ATXN1 telomeric to HLA-A. Using a DNA marker (D6S7) to study the Schut-Swier kindred, Rich et al. (1987) demonstrated linkage between the SCA locus and HLA-A. The observed linkage indicated that the position of the gene was about 15 cM telomeric of HLA-A on 6p. Rich and Orr (1989) and Orr and Rich (1989) studied the linkage of SCA1 in 2 '7-generation kindreds' (the Schut-Swier kindred) with the conclusion that the locus is distal to HLA and proximal to F13A. Three-point linkage analysis on the 2 kindreds combined favored the gene order HLAA--ATXN1--F13A--6pter over the second most likely order ATXN1--HLAA--F13A by odds of 9 million to 1.

Zoghbi et al. (1987) demonstrated HLA linkage in a large black kindred with variable age of onset. Although the mean age of onset was 34 years, in 6 of 41 affected individuals onset was under 15 years of age and was accompanied by the unique clinical features of mental retardation and rapid progression of disease. Linkage to HLA showed a lod score of 5.83 at a recombination fraction of 0.12. Linkage to HLA-DR and HLA-DQ showed lod scores of 3.39 and 2.51 at recombination fractions of 0.15 and 0.17, respectively. This suggested that the SCA1 locus is distal to the MHC region. However, Zoghbi et al. (1988, 1989), by multilocus linkage analysis, obtained results indicating that the SCA1 gene locus is centromeric to HLA-DP, with odds of 46:1 favoring this most likely location over the second most likely location, i.e., telomeric to the HLA complex but proximal to F13A (134570). This appears to indicate localization in the 6p21.3-p21.2 region.

Wakisaka et al. (1989) and Shrimpton et al. (1989) described linkage studies in families with autosomal dominant ataxia. In 2 large Italian pedigrees with HLA-linked spinocerebellar ataxia, Frontali et al. (1991) excluded linkage with F13A at less than 5% recombination and with GLO1 at less than 10% recombination. The results favored the view that ATXN1 is distal to HLA. Thus, they favored the order cen--GLO1--HLA--ATXN1--tel.

Studies of 2 large kindreds led Ranum et al. (1991) to conclude that ATXN1 is unequivocally located distal to HLA and proximal to F13A. Furthermore, ATXN1 was found to lie centromeric and genetically very close to the highly informative D6S89 marker. In the 2 kindreds, 1 recombinant was observed between D6S89 and ATXN1, resulting in a recombination fraction of 0.014. Linkage analysis in the Schut-Swier kindred led Wilkie et al. (1991) likewise to conclude that ATXN1 is telomeric to HLA-A and lies between HLA-A and F13A. The maximum pairwise lod score for linkage between ATXN1 and HLA-A was 8.52; male theta = 0.10, female theta = 0.22. In a 5-generation American black family, Keats et al. (1991) excluded close linkage between the SCA1 locus and both HLA and F13A1; lod scores for all locations of the disease locus between these 2 loci were less than -1.4. However, the disease locus was found to be closely linked to a microsatellite polymorphism, D6S89, which is situated between HLA and F13A1; maximum lod = 4.90 at theta = 0.0, both in males and in females. The findings indicated that exclusion of close linkage to HLA and F13A1 in a kindred with spinocerebellar ataxia does not rule out the possibility that the disease locus is in fact on 6p. Accordingly, all families segregating a dominantly inherited ataxia should be evaluated for linkage to D6S89.

Zoghbi et al. (1991) tested for linkage with 2 highly informative dinucleotide repeat sequences in 3 large kindreds, 1 in Houston, Texas, and 2 in Calabria. Pairwise linkage analysis of ATXN1 and D6S89 revealed a maximum lod score of 5.86 in the Houston kindred and of 8.08 in the Calabrian kindreds, at recombination fractions of 0.050 and 0.022, respectively. A maximum pairwise lod score of 4.54 at recombination frequency of 0.100 was obtained for ATXN1 and TCTE1 (186975) in the Houston pedigree but no evidence of linkage was detected between these loci in the case of the Calabrian kindreds. Multilocus linkage analysis supported strongly localization of ATXN1 telomeric to HLA. Volz et al. (1992) studied D6S89 in mutant cell lines with cytogenetically detectable interstitial 6p deletions to map the marker to 6p24.2-p23.05. This would place ATXN1 in the 6p24-p23 segment. In 4 of 10 French families with autosomal dominant cerebellar ataxia type 1, Khati et al. (1993) found very close linkage of the neurologic disorder to the D6S89 marker, with no evidence of recombination. Linkage to D6S89 was excluded in the other 6. After the cloning of the ataxin-1 gene (601556), Volz et al. (1994) reported that it was mapped to 6p23 by in situ hybridization.

Kwiatkowski et al. (1993) reported a new marker, AM10GA, that demonstrated no recombination with ATXN1; maximum lod = 42.14 at theta = 0. Linkage analysis and analysis of recombination events confirmed that ATXN1 maps centromeric to D6S89 (which showed a maximum lod score of 67.58 at a maximum recombination fraction of 0.004 with ATXN1). They cited multipoint linkage analysis indicating that ATXN1 is telomeric to HLA.

In 7 families from a Siberian founder population with autosomal dominant SCA, Lunkes et al. (1994) demonstrated allelic association of the disease with polymorphisms known to flank the SCA1 locus on 6p. The association was absolute in the case of microsatellite D6S274, whereas an allele switch was observed for D6S89 in 2 families, suggesting a historic recombinant.

Heterogeneity

Genetic Heterogeneity

Koeppen et al. (1980) found no evidence of linkage to chromosome 6 markers in 5 families with 'dominant ataxia' and 3 with 'recessive ataxia' (Friedreich disease). Kumar et al. (1986) found negative lod scores for linkage to HLA in all of 5 families in which at least 3 generations were affected with autosomal dominant SCA.

By linkage studies in families with Machado-Joseph disease (MJD; 109150), Carson et al. (1992) demonstrated conclusively that MJD cannot be allelic to SCA1. A clinically indistinguishable form of spinocerebellar ataxia, SCA2, occurs in high frequency in Cuba. Lunkes et al. (1993) excluded linkage to 6p in a 5-generation Danish family.

Pathogenesis

Orr et al. (1993) demonstrated that the basic genetic defect in spinocerebellar ataxia-1 consists of expansion of a trinucleotide CAG repeat. They showed that the repeat is present not only in genomic DNA but also in a 10-kb mRNA transcript. Banfi et al. (1994) identified the gene, termed ataxin-1. This was the fifth example of a pathologic state resulting from expansion of an unstable trinucleotide repeat. The others, in chronologic order of discovery, were the fragile X syndrome (300624), myotonic dystrophy (160900), Kennedy spinal and bulbar muscular atrophy (313200), and Huntington disease (143100).

After the lesion in SCA1 was found to involve an expanded trinucleotide repeat, this lesion was demonstrated in affected members of the Schut-Swier kindred, thus proving that it was, in fact, SCA1 (Wexler, 1993).

By immunoblot analysis, Servadio et al. (1995) demonstrated that a mutant protein that varies in its electrophoretic migration properties according to the size of the CAG repeat is detected in cultured cells and tissues from SCA1 individuals along with the wildtype protein. The ataxin-1 protein has a nuclear localization in all normal and SCA1 brain regions examined, but a cytoplasmic localization of ataxin-1 was also observed in cerebellar Purkinje cells, leading to progressive degeneration of Purkinje cells. The data showed that the expanded ATXN1 alleles are also translated into proteins of apparently normal stability and distribution.

Orr and Zoghbi (1996) reviewed the work elucidating polyglutamine-induced neurologic disease in SCA1.

Cummings et al. (1998) found colocalization of the 20S proteasome (see 602175) and chaperone HSJ2 (602837), a member of the Hsp40 family, with large nuclear inclusions of ataxin-1 in brain neurons of patients with SCA1 and in mice transgenic for a mutant ATXN1 allele containing 82 glutamines. In these nuclear inclusions, there was also faint staining for Hsc70 (HSPA8; 600816), a member of the Hsp70 chaperone family. Similar colocalization was seen in HeLa cells transfected with ataxin-1. In the transfected HeLa cells, unlike in the brains, there was apparent induction of Hsc70 chaperone. Overexpression of HSJ2 in these cells reduced aggregation of ataxin-1, suggesting a possible therapeutic strategy.

Lam et al. (2006) examined soluble protein complexes from mouse cerebellum and found that the majority of wildtype and expanded Atxn1 assembles into large stable complexes containing the transcriptional repressor Capicua (CIC; 612082). Atxn1 directly bound Cic and modulated Cic repressor activity in Drosophila and mammalian cells, and its loss decreased the steady state level of Cic. Interestingly, the S776A mutation, which abrogates the neurotoxicity of expanded Atxn1 (Emamian et al., 2003), substantially reduced the association of mutant Atxn1 with Cic in vivo. Lam et al. (2006) concluded that their data provided insight into the function of Atxn1 and suggested that the neuropathology of SCA1, caused by expansion of the ATXN1 polyglutamine tract, depends on native, not novel, protein interactions. Lam et al. (2006) found that the majority of CIC associates with ATXN1 in vivo and that ATXN1 binds CIC through an 8-amino-acid sequence conserved across species.

Lim et al. (2008) demonstrated that the expanded polyglutamine tract of ATXN1 differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favors the formation of a particular protein complex containing RBM17 (606935), contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. Lim et al. (2008) concluded that their model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.

Jain and Vale (2017) showed that repeat expansions create templates for multivalent basepairing, which causes purified RNA to undergo a sol-gel transition in vitro at a similar critical repeat number as observed in Huntington disease, spinocerebellar ataxia, myotonic dystrophy, and FTDALS1 (105550). In human cells, RNA foci form by phase separation of the repeat-containing RNA and can be dissolved by agents that disrupt RNA gelation in vitro. Jain and Vale (2017) concluded that, analogous to protein aggregation disorders, their results suggested that the sequence-specific gelation of RNAs could be a contributing factor to neurologic disease.

Molecular Genetics

Banfi et al. (1994) determined that the CAG trinucleotide repeat identified by Orr et al. (1993) in SCA1 occurs in the ataxin-1 gene (601556.0001).

Genetic Anticipation

Chung et al. (1993) found that 63% of paternal transmissions show an increase in repeat number, whereas 69% of maternal transmissions show no change or a decrease in repeat number. Sequence analysis showed that 98% of unexpanded alleles had an interrupted repeat configuration, whereas a contiguous repeat (CAG)n was found in expanded alleles. This indicated that the repeat instability in ATXN1 is more complex than a simple variation in repeat number and that the loss of an interruption predisposes the ATXN1 (CAG)n to expansion. Matilla et al. (1993) studied the expansion of the ATXN1 gene CAG repeat in a large family in which spinocerebellar ataxia showed the phenomenon of anticipation. There were 41 affected members with no juvenile cases of SCA1, the mean age of onset being 36 years. The family also showed the phenomenon of parental male bias; i.e., the age of onset was younger and the duration of illness before death was shorter in the members of the family who inherited the disorder from the father. In this large Spanish kindred, Matilla et al. (1993) found 9 clinically unaffected persons between ages 18 and 40 years who had expansions of the CAG repeat within the pathogenetic range. In 22 other genetically 'at risk' individuals, they found that the number of CAG repeats in the ATXN1 gene was within the normal range.

Ranum et al. (1994) examined the frequency and variability of the ATXN1 repeat expansion in 87 kindreds with diverse ethnic backgrounds and dominantly inherited ataxia. All 9 families for which linkage to the ATXN1 region of 6p had previously been established showed repeat expansion, while 3 of the remaining 78 showed a similar abnormality. For 113 patients from the families with repeat expansion, inverse correlations between CAG repeat size and both age at onset and disease duration were observed. Repeat size accounted for 66% of the variation in age at onset in these patients. After correction for repeat size, interfamilial differences in age at onset remained significant, suggesting that additional genetic factors affect the expression of the ATXN1 gene product.

Jodice et al. (1994) found trinucleotide repeat expansion in 64 subjects from 19 families: 57 patients with SCA1 and 7 subjects predicted, by haplotype analysis, to carry the mutation. Comparison with a large set of normal chromosomes showed 2 distinct distributions with a much wider variation among expanded chromosomes. The sex of the transmitting parent played a major role in the size distribution of expanded alleles, those with more than 54 repeats being transmitted by affected fathers exclusively. Alleles with 46 to 54 repeats were transmitted by affected fathers and mothers in equal proportions. On the other hand, the sex ratio of offspring receiving either more than 54 or less than 54 repeats approached the expected 50:50. If a steady-state distribution of repeat numbers is assumed to persist through the generations, this raises the question as to why affected females transmitting alleles with more than 54 repeats are lacking, while females receiving more than 54 repeats exist. This may be explained, at least in part, by reduced biologic fitness. Detailed clinical follow-up of a subset of patients by Jodice et al. (1994) demonstrated significant relationships between increasing repeat number on expanded chromosomes and earlier age at onset, faster progression of the disease, and earlier age at death.

Koefoed et al. (1998) performed single sperm analysis of (CAG)n stretches in SCA1 patients and asymptomatic carriers. A pronounced variation in the size of the expanded allele was found in sperm cells and in peripheral blood leukocytes, with a higher degree of instability in sperm cells, where an allele with 50 repeat units was contracted in 11.8%, further expanded in 63.5%, and unchanged in 24.6% of the single sperm analyzed. They also found a low instability of the normal alleles; the normal alleles from the individuals carrying a CAG repeat expansion was significantly more unstable than the normal alleles from control individuals (P less than 0.001), indicating an interallelic interaction between the expanded and the normal alleles.

Matsuyama et al. (1999) studied 17 patients with SCA1. In one of these patients the expanded ATXN1 allele was interrupted by a CAT trinucleotide. The total number of CAG repeats was 58, predicting an age at onset of 22.0 years, in contrast to the actual age at onset of 50 years. In addition, brainstem atrophy was mild compared to that of a patient with 52 CAG repeats. Sequence analysis showed the repeat portion of the ATXN1 allele contained 45 uninterrupted CAG repeats with 2 interspersed CAT repeats in the subsequent 12 trinucleotides. Matsuyama et al. (1999) concluded that the age at onset of SCA1 is not determined by the total number of CAG repeats, but rather by the total number of uninterrupted CAG repeats.

Zuhlke et al. (2002) performed genotype-phenotype correlation in intermediate alleles from 36 to 43 CAG repeats in the ATXN1 gene with respect to the presence of interrupting CAT trinucleotides. Alleles with 36 to 38 triplets were present in individuals with ataxia but without additional characteristic features of SCA1. SCA1 phenotypes were found for patients with 41 and 43 triplets. The 39 triplet allele missing CAT interruptions was associated with symptoms characteristic for SCA1 in 4 patients, whereas the interrupted allele with 39 triplets did not cause characteristic SCA1 features in 1 individual. These findings suggested a change from normal to pathologic alleles at 39 triplets depending on the presence of CAT interruptions in the CAG repeat. Stable inheritance of the uninterrupted 39 triplet allele was observed in 1 familial case of SCA1.

Van de Warrenburg et al. (2005) applied statistical analysis to examine the relationship between age at onset and number of expanded triplet repeats from a Dutch-French cohort of 802 patients with SCA1 (138 patients), SCA2 (166 patients), SCA3 (342 patients), SCA6 (53 patients), and SCA7 (103 patients). The size of the expanded repeat explained 66 to 75% of the variance in age at onset for SCA1, SCA2, and SCA7, but less than 50% for SCA3 and SCA6. The relation between age at onset and CAG repeat was similar for all groups except for SCA2, suggesting that the polyglutamine repeat in the ataxin-2 protein exerts its pathologic effect in a different way. A contribution of the nonexpanded allele to age at onset was observed for only SCA1 and SCA6. Van de Warrenburg et al. (2005) acknowledged that their results were purely mathematical, but suggested that they reflected biologic variations among the diseases.

Associations Pending Confirmation

For discussion of a possible association between autosomal dominant SCA and variation in the ZFYVE27 gene, see 610243.0002.

For discussion of a possible association between autosomal dominant SCA and variation in the KIF26B gene, see 614026.0001.

For discussion of a possible association between autosomal dominant SCA and variation in the EP300 gene, see 602700.

Genotype/Phenotype Correlations

Schols et al. (1997) compared clinical, electrophysiologic, and magnetic resonance imaging (MRI) findings to identify phenotypic characteristics of genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and action tremor suggested SCA2. SCA3 patients frequently developed diplopia, severe spasticity or pronounced peripheral neuropathy, and impaired temperature discrimination, apart from ataxia. SCA6 presented with a predominantly cerebellar syndrome, and patients often had onset after 55 years of age. SCA1 was characterized by markedly prolonged peripheral and central motor conduction times in motor evoked potentials. MRI scans showed pontine and cerebellar atrophy in SCA1 and SCA2. In SCA3, enlargement of the fourth ventricle was the main sequel of atrophy. SCA6 presented with pure cerebellar atrophy on MRI. Overlap between the 4 SCA subtypes was broad, however.

Among 65 patients with SCA1, SCA2, or SCA3, Burk et al. (1996) found reduced saccade velocity in 56%, 100%, and 30% of patients, respectively. MRI showed severe olivopontocerebellar atrophy in SCA2, similar but milder changes in SCA1, and very mild atrophy with sparing of the olives in SCA3. Careful examination of 3 major criteria of eye movements, saccade amplitude, saccade velocity, and presence of gaze-evoked nystagmus, permitted Rivaud-Pechoux et al. (1998) to assign over 90% of patients with SCA1, SCA2, or SCA3 to their genetically confirmed patient group. In SCA1, saccade amplitude was significantly increased, resulting in hypermetria. In SCA2, saccade velocity was markedly decreased. In SCA3, the most characteristic finding was the presence of gaze-evoked nystagmus.

In an investigation of oculomotor function, Buttner et al. (1998) found that all 3 patients with SCA1, all 7 patients with SCA3, and all 5 patients with SCA6 had gaze-evoked nystagmus. Three of 5 patients with SCA2 did not have gaze-evoked nystagmus, perhaps because they could not generate corrective fast components. Rebound nystagmus occurred in all SCA3 patients, 33% of SCA1 patients, 40% of SCA6 patients, and none of SCA2. Spontaneous downbeat nystagmus only occurred in SCA6. Peak saccade velocity was decreased in 100% of patients with SCA2, 1 patient with SCA1, and no patients with SCA3 or SCA6. Saccade hypermetria was found in all types, but was most common in SCA3. Burk et al. (1999) found that gaze-evoked nystagmus was not associated with SCA2. However, severe saccade slowing was highly characteristic of SCA2. Saccade velocity in SCA3 was normal to mildly reduced. The gain in vestibuloocular reflex was significantly impaired in SCA3 and SCA1. Eye movement disorders of SCA1 overlapped with both SCA2 and SCA3.

The reticulotegmental nucleus of the pons (RTTG), also known as the nucleus of Bechterew, is a precerebellar nucleus important in the premotor oculomotor circuits crucial for the accuracy of horizontal saccades and the generation of horizontal smooth pursuit. By postmortem examination, Rub et al. (2004) identified neuronal loss and astrogliosis in the RTTG in 1 of 2 SCA1 patients, 2 of 4 SCA2 patients, and 4 of 4 SCA3 patients that correlated with clinical findings of hypometric saccades and slowed and saccadic smooth pursuits. The 3 patients without these specific oculomotor findings had intact RTTG regions. The authors concluded that the neurodegeneration associated with SCA1, SCA2, and SCA3 affects premotor networks in addition to motor nuclei in a subset of patients.

Using an analysis of covariance and multivariate models to examine symptom severity in 526 patients with SCA1, SCA2, SCA3, or SCA6, Schmitz-Hubsch et al. (2008) found that repeat length of the expanded allele, age at onset, and disease duration explained 60.4% of the ataxia score in SCA1, 45.4% in SCA2, 46.8% in SCA3. However, only age at onset and disease duration appeared to explain 33.7% of the score in SCA6. Similar findings were obtained for nonataxic symptoms. The study suggested that SCA1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors.

Population Genetics

Giunti et al. (1994) examined members of 73 families who were affected with a variety of autosomal dominant late-onset cerebellar ataxias for the trinucleotide repeat expansion associated with the SCA1 locus. The mutation was found in 19 of 38 kindreds with the SCA1 phenotype. However, it was not found in any of 8 families with olivopontocerebellar atrophy with maculopathy (164500), or in 24 kindreds with pure adult-onset cerebellar ataxia (SCA31; 117210), or in 12 patients with sporadic degenerative ataxia. The patients with the expansion were Italian, British, Malaysian, Bangladeshi, and Jamaican.

Ranum et al. (1995) made use of the fact that the genes involved in 2 forms of autosomal dominant ataxia, that for Machado-Joseph disease (109150) and that for SCA1, have been isolated to assess the frequency of trinucleotide repeat expansions among individuals diagnosed with ataxia. They collected and analyzed DNA from individuals with both disorders. In both cases, the genes responsible for the disorder were found to have an expansion of an unstable CAG trinucleotide repeat. These individuals represented 311 families with adult-onset ataxia of unknown etiology, of which 149 families had dominantly inherited ataxia. Ranum et al. (1995) found that of these, 3% had SCA1 trinucleotide repeat expansions, whereas 21% were positive for the MJD trinucleotide expansion. For the 57 patients with MJD trinucleotide repeat expansions, strong inverse correlation between CAG repeat size and age at onset was observed (r = -0.838). Among the MJD patients, the normal and affected ranges of CAG repeat size were 14 to 40 and 68 to 82 repeats, respectively. For SCA1, the normal and affected ranges were much closer, namely 19 to 38 and 40 to 81 CAG repeats, respectively.

In a nationwide survey of Japanese patients, Hirayama et al. (1994) found an estimated prevalence of the various forms of spinocerebellar degeneration to be 4.53 per 100,000. Of these, 12.6% were thought to have the Menzel type of spinocerebellar atrophy (SCA1). However, it was not clear how they distinguished this disorder from the other forms of OPCA. In Japan, Suzuki et al. (1995) found that all affected and presymptomatic individuals in 12 pedigrees with SCA1 (determined by haplotype per segregation analyses) carried an abnormally expanded allele with a range of 39 to 63 repeat units. This repeat size inversely correlated with the age of onset. However, contrary to previous reports, the size of the repeat did not correlate with gender of the transmitting parent. CAG triplet repeat instability on paternal transmission was not observed.

Wakisaka et al. (1995) determined the haplotype cosegregating with SCA1 in 12 Japanese pedigrees. Although the alleles of the ATXN1 haplotype varied from pedigree to pedigree depending on the distance from the SCA1 locus, the affected and presymptomatic subjects carried the same alleles at 2 loci, D6S288 and D6S274. All the families with SCA1 had migrated from either the Miyagi or Yamagata Prefectures, neighboring areas in the Tokohu District, the northern part of Honshu, which is the main island of Japan. The findings suggested to the authors that SCA1 in the Japanese, at least those residing in Hokkaido, derived from a single common ancestry. Goldfarb et al. (1996) studied 78 SCA1 patients from a large Siberian kindred which included 1,484 individuals, 225 of whom are known to be affected and 656 of whom were at risk. Normal alleles had 25 to 37 trinucleotide repeats, whereas expanded alleles contained 40 to 55 repeats. The disease was not fully penetrant inasmuch as there was one 66-year-old woman with 44 CAG repeats who was asymptomatic. Of her 7 children, 4 were affected, including a homozygous daughter and another child with 44 repeats. Two symptomatic individuals who had expansions on both chromosomes demonstrated clinical manifestations that corresponded to the size of the larger allele.

In Catalonia, Genis et al. (1995) found a large kindred traced to a common ancestor born in 1735 that segregated spinocerebellar ataxia-1. Affected individuals all had 1 allele with between 41 in 59 repeats, whereas asymptomatic individuals for the most part fell in the range of 6 to 39 repeats. Two asymptomatic individuals, an 18-year-old female and a 25-year-old male, had 41 repeats.

Klockgether et al. (1994) analyzed DNA from 19 German families with autosomal dominant cerebellar ataxia and 61 unrelated individuals with idiopathic cerebellar ataxia with a mean age of onset of 53.6 years. Heterozygosity for the ATXN1 triplet repeat expansion was diagnosed in 5 out of 19 of the autosomal dominant kindreds. In contrast, none of the 61 cases of idiopathic adult-onset cerebellar ataxia showed this expansion. This suggested that SCA1 is not a significant cause of idiopathic cerebellar ataxia in Germany. Studying 77 German families with autosomal dominant cerebellar ataxia of SCA types 1, 2, 3, and 6, Schols et al. (1997) found that the SCA1 mutation accounted for 9%, SCA2 for 10%, SCA3 for 42%, and SCA6 for 22%. There was no family history of ataxia in 7 of 27 SCA6 patients. Age at onset correlated inversely with repeat length in all subtypes. Yet the average effect of 1 CAG unit on age of onset was different for each SCA subtype. Riess et al. (1997) found that in both SCA1 and SCA3 patients in German families there was distortion of the mendelian 1:1 segregation of the disease. They noted that mutations in the ataxin-1 gene are responsible for autosomal dominant spinocerebellar ataxia in about 10% of all families, whereas SCA3 is the most common cause in Germany, accounting for up to 50% of cases.

Ramesar et al. (1997) investigated 14 South African kindreds and 22 sporadic individuals with SCA for expanded ATXN1 (601556.0001) and ATXN3 (607047.0001) repeats. The authors stated that, in the present study, ATXN1 mutations accounted for 43% of known ataxia families in the Western Cape region. They found that expanded ATXN1 and CAG repeats cosegregated with the disorder in 6 of the families, 5 of mixed ancestry and 1 Caucasian, and were also observed in a sporadic case from the indigenous Black African population. The use of the microsatellite markers D6S260, D6S89, and D6S274 provided evidence that the expanded ATXN1 repeats segregated with 3 distinct haplotypes in the 6 families. None of the families nor the sporadic individuals showed expansion of the MJD repeat.

Among 202 Japanese and 177 Caucasian families with autosomal dominant SCA, Takano et al. (1998) found that the prevalence of SCA1 was significantly higher in the Caucasian population (15%) compared to the Japanese population (3%). This corresponded to higher frequencies of large normal ATXN1 CAG repeat alleles (greater than 30 repeats) in Caucasian controls compared to Japanese controls. The findings suggested that large normal alleles contribute to the generation of expanded alleles that lead to dominant SCA.

In Spain, Pujana et al. (1999) performed molecular analysis on 87 unrelated familial and 60 sporadic cases of spinocerebellar ataxia of autosomal dominant type. For the familial cases of ADCA, 6% were SCA1, 15% were SCA2, 15% were SCA3, 1% represented SCA6, 3% were SCA7, and, in 1%, the diagnosis was DRPLA (125370), an extremely rare mutation in Caucasoid populations. About 58% of ADCA cases remained genetically unclassified. All the SCA1 cases belonged to the same geographic area and shared a common haplotype for the SCA1 mutation. The expanded alleles ranged from 41 to 59 repeats for SCA1, 35 to 46 for SCA2, 67 to 77 for SCA3, and 38 to 113 for SCA7. The 1 SCA6 case had 25 repeats and the 1 DRPLA case had 63 repeats. The highest CAG repeat variation in meiotic transmission of expanded alleles was detected in SCA7, this being an expansion of 67 units in one paternal transmission, giving rise to a 113 CAG repeat allele in a patient who died at 3 years of age. Meiotic transmissions showed a tendency to more frequent paternal transmission of expanded alleles in SCA1 and maternal in SCA7. All SCA1 and SCA2 expanded alleles analyzed consisted of pure CAG repeats, whereas normal alleles were interrupted by 1 to 2 CAT trinucleotides in SCA1, except for 3 alleles of 6, 14, and 21 CAG repeats, and by 1 to 3 CAA trinucleotides in SCA2. The failure to find SCA or DRPLA mutations in the 60 sporadic cases of spinocerebellar ataxia is consistent with the lack of evidence of de novo mutations noted by Andrew et al. (1997).

Pareyson et al. (1999) evaluated 73 Italian families with type I ADCA. SCA1 was the most common genotype, accounting for 41% of cases (30 families); SCA2 was slightly less frequent (29%, 21 families), and the remaining families were negative for the SCA1, SCA2, and SCA3 mutations. Among the positively genotyped families, SCA1 was found most frequently in families from northern Italy (50%), while SCA2 was the most common mutation in families from the southern part of the country (56%). Slow saccades and decreased deep tendon reflexes were observed significantly more frequently in SCA2 patients, while increased deep tendon reflexes and nystagmus were more common in SCA1.

Storey et al. (2000) examined the frequency of mutations for SCA types 1, 2, 3, 6, and 7 in southeastern Australia. Of 63 pedigrees or individuals with positive tests, 30% had SCA1, 15% had SCA2, 22% had SCA3, 30% had SCA6, and 3% had SCA7. Ethnic origin was of importance in determining SCA type: 4 of 9 SCA2 index cases were of Italian origin, and 4 of 14 SCA3 index cases were of Chinese origin.

Zhou et al. (2001) performed molecular analysis of 109 patients in 75 Chinese families with autosomal dominant SCA and 16 patients with sporadic SCA or spastic paraplegia. SCA type 1 was found in 5 families (7%), and all patients with the SCA1 phenotype were heterozygous for alleles with CAG repeat numbers ranging from 51 to 64 (control groups, 26-35). There was a significant negative correlation between age of disease onset and number of CAG repeat units. SCA3/MJD was found in 26 families, SCA2 in 9 families, SCA6 in 2 families, and SCA7 in 2 families. The combined frequency of SCA1, SCA2, and SCA3/MJD was 53%. None of the 16 sporadic cases was positive for the mutations tested, and no patients were positive for SCA8 (608768), SCA12, or DRPLA. Clinically, the authors noted that SCA3/MJD tended to manifest more frequently with ophthalmoparesis, eyelid retraction, facial myokymia, ataxia, spasticity, and amyotrophy. The frequency of single CAT interruptions in the ATXN1 gene was higher in the Siberian Sakha control group, which also had a higher prevalence of SCA1 than the Chinese population, suggesting that a substitution of CAT for CAG may be the initial event contributing to the generation of expanded alleles.

Of 253 unrelated Korean patients with progressive cerebellar ataxia, Lee et al. (2003) identified 52 (20.6%) with expanded CAG repeats. The most frequent SCA type was SCA2 (33%), followed by SCA3 (29%), SCA6 (19%), SCA1 (12%), and SCA7 (8%). There were characteristic clinical features, such as hypotonia and optic atrophy for SCA1, hyporeflexia for SCA2, nystagmus, bulging eye, and dystonia for SCA3, and macular degeneration for SCA7.

Mittal et al. (2005) found SCA1 in 37 (22%) of 167 Indian families with ADCA. The frequency of SCA1 in the south Indian population was twice (33%) that of the north Indian population (16%). The nonaffected repeat length ranged from 21 to 39 triplets. Haplotype analysis identified an ancestral C-4-C haplotype (rs1476464, D6S288, and rs2075974) that was mostly present in the affected individuals, suggesting that this background might have been predisposed for repeat expansion. This haplotype, when present in the nonaffected chromosomes, had multiple interruptions in the repeat tract, which the authors hypothesized would provide genetic stability. However, in disease chromosomes, this haplotype showed large normal (greater than 30 repeats) expansions and was associated with the expanded chromosomes in about 44% of SCA1 families.

Among 113 Japanese families from the island of Hokkaido with autosomal dominant SCA, Basri et al. (2007) found that SCA6 was the most common form of the disorder, identified in 35 (31%) families. Thirty (27%) families had SCA3, 11 (10%) had SCA1, 5 (4%) had SCA2, 5 (4%) had DRPLA, 10 (9%) had 16q22-linked SCA, and 1 (1%) had SCA14 (605361). The specific disorder could not be identified in 16 (14%) families.

History

Weiner and Konigsmark (1971) provided a review of hereditary diseases of the cerebellum. Affected families have been described