Spinocerebellar Ataxia 2

A number sign (#) is used with this entry because spinocerebellar ataxia-2 (SCA2) is caused by an expanded (CAG)n trinucleotide repeat in the gene encoding ataxin-2 (ATXN2; 601517). Unaffected individuals have 13 to 31 CAG repeats, whereas affected individuals have 32 to 79 repeats, with some in the range of 500 repeats (summary by Almaguer-Mederos et al., 2010).

There is also an association between 29 or more CAG repeats and the development of amyotrophic lateral sclerosis-13 (ALS13). For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).

Description

Autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of disorders that were classified clinically by Harding (1983). Progressive cerebellar ataxia is the primary feature. In ADCA I, cerebellar ataxia of gait and limbs is invariably associated with supranuclear ophthalmoplegia, pyramidal or extrapyramidal signs, mild dementia, and peripheral neuropathy. In ADCA II, macular and retinal degeneration are added to the features. ADCA III is a pure form of late-onset cerebellar ataxia. ADCA I includes SCA1 (164400), SCA2, and SCA3, or Machado-Joseph disease (109150). These 3 are characterized at the molecular level by CAG repeat expansions on 6p24-p23, 12q24.1, and 14q32.1, respectively.

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

Clinical Features

Boller and Segarra (1969) reported the clinical and postmortem findings in a father (E.W.) and son (R.W.) with adult-onset ataxia. The pedigree of the 'W' family, extending through 5 generations, indicated autosomal dominant inheritance. Pogacar et al. (1978) reported 2 additional affected members of the family, R.W.'s daughter (S.W.), and a third cousin who was studied postmortem. Boller and Segarra (1969) had described the condition under the designation 'spinopontine degeneration.' When the family (of Anglo-Saxon extraction living in northern Rhode Island for over 300 years) was followed up by Pogacar et al. (1978), they questioned the separation from olivopontocerebellar ataxia (OPCA), because they found abolished tendon reflexes and flexion contractures of the legs in 1 patient, and onset at 18 years of age, palatal myoclonus, and optic atrophy in the second. Dementia developed in both. Pathologic findings, in contrast to earlier reports, showed involvement of the cerebellum and inferior olivary nuclei. Lazzarini et al. (1992) encountered a large, previously unreported branch of the 'W' family that shared a common ancestor 8 generations removed from the patients reported by Boller and Segarra (1969). Although phenotypically the disorder was similar to that in families with spinocerebellar ataxia-1, the disorder was not linked to HLA on chromosome 6p.

Wadia and Swami (1971) reported the association of spinocerebellar degeneration and abnormal eye movements, specifically, absent rapid saccades and abnormally slow tracking. They described 37 patients in 12 families in India. Some of the patients were 'mentally backward.' Starkman et al. (1972) described the syndrome in a U.S. family. Whyte and Dekaban (1976) described a family with cerebellar degeneration and slow pursuit without nystagmus. Age at onset ranged from 10 to 31 years with earlier onset in successive generations, and a rapidly progressive course. Three individuals showed progressive mental deterioration. The proband had nevus of Ota, which was considered to be unrelated. Whyte and Dekaban (1976) suggested that the eye signs were due to a brainstem lesion of the paramedian pontine reticular formation. They noted that it may be the most frequent form of spinocerebellar degeneration in India. See 271322 for a possible recessive form of the Wadia-Swami syndrome.

Wadia et al. (1998) reported reevaluation and genetic analysis of 6 Indian pedigrees with autosomal dominant spinocerebellar ataxia, some of whom had been reported by Wadia and Swami (1971). Genetic analysis confirmed SCA2. Saccadic velocity was reduced even in early stages of the disease, and the authors emphasized that it was an important diagnostic feature.

Eto et al. (1990) described a family of German extraction with progressive ataxia, eye movement abnormalities, peripheral sensory loss, and spinal muscular atrophy of adult onset. The pedigree pattern in 4 generations was consistent with autosomal dominant inheritance. Eto et al. (1990) suggested that the form of spinopontine atrophy might be different from Machado-Joseph disease (SCA3): the eyes were not protuberant, extraocular movements were abnormal to a minor degree, and neuropathologically the substantia nigra and dentate nucleus were spared. Eto et al. (1990) considered their family to resemble most that reported by Boller and Segarra (1969).

Bale et al. (1987) studied a 3-generation kindred in which several persons had dominantly inherited spinopontine atrophy. Linkage analysis gave negative lod scores with both HLA and GLO1. Bale et al. (1987) also reviewed 4 published kindreds with adequate clinical and neuropathologic descriptions in addition to HLA linkage studies. Persons in the 3 families showing evidence for HLA linkage had clinical and pathologic changes consistent with OPCA type 1. The conditions in the 2 'unlinked' families were phenotypically distinct with respect to extraocular movements and peripheral sensory nervous system signs. They differed markedly from each other in neuropathologic changes.

Auburger et al. (1990) could find no evidence of linkage to HLA in over 100 affected members of a Cuban kindred of Spanish ancestry, first reported by Orozco et al. (1989). The diagnosis of spinocerebellar ataxia was confirmed at autopsy in 11 cases. Points of differentiation from Machado-Joseph disease (SCA3), including absence of the limitation of upward gaze, were outlined. The origins of the family group in Spain could not be traced. Age of onset varied from 2 to 65 years, with 40% of patients presenting before 25 years of age. Optic atrophy, retinopathy, dementia, spasticity, and rigidity were not part of the phenotype. Auburger et al. (1990) stated that 'the 300 patients already receiving medical attention constitute a severe problem for the regional health authorities in Holguin.'

Spadaro et al. (1992) were unable to demonstrate linkage to HLA on chromosome 6 in 3 of 5 Italian families with late-onset autosomal dominant SCA. They reported clinical studies of 26 patients and neuropathologic study of 1. The disease was characterized by cerebellar and pyramidal involvement, variably associated with cranial nerve and peripheral nervous system disorders. MRI of a 53-year-old man with symptoms for 7 years showed marked atrophy of the cerebellar hemispheres and vermis as well as of the pons and medulla oblongata.

Ueyama et al. (1998) studied 2 Japanese kindreds with spinocerebellar ataxia-2, for a total of 25 patients, 19 patients in 1 family and 6 patients in the other. Thirteen patients were fully evaluated, including a neurologic evaluation. The mean age of onset of symptoms was 43.5 years. The most common neurologic finding was cerebellar ataxia with deep sensory disturbance. Slow saccades were found only in patients younger than age 35 years. Brain MRI showed pontocerebellar atrophy, and PCR analysis showed that all patients had an expanded CAG allele in the ataxin-2 gene.

Schols et al. (1997) compared clinical, electrophysiologic, and 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 (183086) 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.

Giuffrida et al. (1999) performed brain MRI on 20 SCA2 patients, from 11 Sicilian families, and 20 age-matched control subjects. The findings confirmed that olivopontocerebellar atrophy is a typical pattern in SCA2. No significant correlation was found between infratentorial atrophy, disease duration, or the number of CAG repeats, but there was a significant correlation between supratentorial atrophy, which was found in 12 patients, and disease duration. OPCA appeared to represent the 'core' abnormality of SCA2; however, central nervous system involvement was not limited to pontocerebellar structures. Giuffrida et al. (1999) concluded that central nervous system degeneration in SCA2 is a widespread atrophy.

In 19 of 27 (70%) patients with confirmed SCA types 1, 2, 3, 6, or 7 (164500), 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. All 3 patients with SCA2 had a neuronopathy.

Velazquez-Perez et al. (2004) found that maximal horizontal saccade velocity (MSV) was significantly decreased in 82 SCA2 patients compared to controls (60-degree MSV range of 17 to 464 degrees per second and 277 to 678 degree per second, respectively). MSV was negatively correlated with polyglutamine expansion size and ataxia score; ataxia score was positively correlated with disease duration, and less so with polyglutamine expansion. Slowing of MSV was detected as early as 1 year after onset of ataxia. Velazquez-Perez et al. (2004) concluded that MSV is a sensitive and specific endophenotype useful for the identification of modifier genes in SCA2.

Using high-resolution volumetric MRI to examine 8 SCA2 patients, Ying et al. (2006) found a significant correlation between region-specific cerebellar and pontine atrophy and a global measure of clinical dysfunction. Atrophy was also highly correlated with disease duration.

Oculomotor Abnormalities

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.

Infantile Onset

Babovic-Vuksanovic et al. (1998) reported an infant who presented with neonatal hypotonia, developmental delay, and dysphagia. Ocular findings of retinitis pigmentosa (RP) were noted at 10 months of age. Her father had mild SCA2 first noted at 22 years of age. Molecular studies showed that the father had a SCA2 CAG repeat expansion of 43 repeats, whereas the baby had an extreme expansion of more than 200 repeats. Babovic-Vuksanovic et al. (1998) noted the variable phenotype and genotype of SCA2.

Moretti et al. (2004) reported a Mexican-American child who developed abnormal eye movements at 2 months of age. Motor and language development were delayed. At age 6 years, poor coordination, arm tremor, and cognitive deficits were noted. The clinical course slowly progressed, and he had difficulty walking, incontinence, drooling, and worsening tremor by age 9 years. MRI showed cerebellar atrophy and mild cerebral atrophy, and mutation analysis identified a 62 CAG repeat expansion of the ATXN2 gene. Moretti et al. (2004) emphasized that SCA2 can have rare infantile or childhood onset, that earlier onset is associated with a higher number of CAG repeats, and that the SCA2 phenotype is clinically heterogeneous.

Vinther-Jensen et al. (2013) reported a family in which a father was diagnosed with SCA2 at age 49 years, after which it was discovered that his daughter, who had died 13 years earlier of multiorgan failure at age 19 months, had had infantile-onset SCA2. The father presented with classic adult-onset progressive SCA2, including gait ataxia, imbalance, dysarthria, fasciculations, abnormal saccades, and mild cognitive impairment. Brain MRI showed cerebellar atrophy. The daughter presented at age 3 months with delayed motor development, myoclonic jerks, and visual impairment. She later showed uncoordinated eye movements, pallor of the optic nerves, dystrophic retinas, poor head control, hypotonia, and dyskinetic movements. Molecular genetic analysis showed that the father carried an expanded ATXN2 allele of 45 CAG repeats, and the daughter carried an expanded allele of 124 repeats inherited from the father. Analysis of the father's spermatozoa showed that 4 (22%) had an expansion beyond the 45 CAG repeats detected in somatic cells, including 2 with repeat lengths of at least 92 and 116, respectively. Study of spermatozoa from another man with SCA2 showed similar meiotic instability of the expanded repeat allele. Vinther-Jensen et al. (2013) suggested that meiotic instability may be a general feature of SCA2, and noted that rare genetic disorders should be considered during diagnosis of infants and children even without a family history of a neurodegenerative disorder.

Parkinsonian Phenotype

Gwinn-Hardy et al. (2000) described 4 patients from a Chinese kindred with parkinsonian features and CAG expansions at the SCA2 locus. The youngest patient had findings typical for the SCA2 ataxic phenotype with decreased saccadic velocity, limb and truncal ataxia, and a subclinical sensory neuropathy, but also had parkinsonian features such as markedly reduced blink rate, bradykinesia, and asymmetry. His SCA2 CAG repeat length was 43. Three patients from earlier generations had mildly elevated CAG repeat lengths of 33 to 36 with varying phenotypes, but all predominantly parkinsonian features, including masked facies, diminished blink rate, and bradykinesia in addition to mild cerebellar findings such as broad-based gait. Two benefited from carbidopa-levodopa therapy, reminiscent of typical late-onset Parkinson disease (PD; 168600). The third patient, with a phenotype reminiscent of progressive supranuclear palsy, did not show a response to treatment. None of the patients had cognitive disturbance or resting tremor. The authors suggested that some cases of familial parkinsonism may be due to SCA2 mutations.

Among 23 Chinese patients with familial parkinsonism, Shan et al. (2001) identified 2 patients who had expanded trinucleotide repeats (mildly elevated at 36 and 37 repeats) in the ATXN2 gene. Both patients had onset of leg tremor at age 50 years, followed by gait difficulty, rigidity, and slow, hypometric saccades. L-DOPA produced marked improvement in symptoms in both patients. In addition, PET scan showed reduced dopamine distribution in the caudate and putamen in both patients. Shan et al. (2001) noted that these 2 patients represented approximately one-tenth of their population with familial parkinsonism.

In commenting on the paper by Shan et al. (2001), Kock et al. (2002) stated that in a study of 270 unrelated patients of mixed ethnic background with dopa-responsive parkinsonism, including 64 cases of early onset (age of onset less than 50 years) with a family history, 174 cases of early onset with no family history, and 32 cases of late onset with a family history, they found no expanded SCA2 alleles. Parkin (PARK2; 602544) mutations were found in 31 (18%) of 173 screened early-onset patients. In a reply, Shan and Soong (2002) suggested that SCA2-related parkinsonism is more likely to be found in late-onset cases, which tend to have lower numbers of repeats, and likely accounts for no more than one-tenth of familial parkinsonism.

Furtado et al. (2002) reported a family in which 10 members over 5 generations were affected with dopa-responsive parkinsonism, without cerebellar abnormalities, transmitted in an autosomal dominant pattern. Average age of onset was 59 years (range, 31 to 86). Three patients exhibited dystonia. Genetic analysis showed identical expanded repeats for SCA2 in all affected individuals tested (22 and 39 repeats on each allele), which were stable between generations despite a clinical suggestion of anticipation. Furtado et al. (2002) emphasized that the genetic findings were unexpected because the family's presentation was consistent with typical cases of Parkinson disease (168600).

Lu et al. (2004) stated that the normal range of SCA2 CAG repeats is 14 to 31, and that it ranges from 34 to more than 200 in affected patients. A range of 32 to 33 repeats is considered indeterminate. In 7 Taiwanese patients from 4 families with parkinsonism (representing approximately 10% of the initial group), Lu et al. (2004) found expanded CAG repeats in the ATXN2 gene. The phenotype was characterized by tremor, rigidity, and bradykinesia, and response to L-DOPA. A control group of 8 patients from 6 families had the ataxic SCA2 phenotype, characterized by cerebellar gait, slow saccades, ataxic dysarthria, hypotonia, and tendency to fall, without any parkinsonian features. Patients with the parkinsonism phenotype had an older mean age at onset (45.8 years) and shorter CAG repeats (36.2 repeats) compared to those with the ataxic phenotype (26.9 years) caused by SCA2 repeats (43.1 repeats). Lu et al. (2004) noted that there were a few overlapping features between the 2 groups, including dysarthria and postural instability, but emphasized the otherwise clear phenotypic distinction.

Ragothaman et al. (2004) reported a consanguineous Indian family with SCA2 expansions and a complex phenotype comprising ataxia, parkinsonism, and retinitis pigmentosa, either in isolation or in combination. Two patients with homozygous SCA2 repeat expansions (35 to 39 repeats) presented with dopa-responsive parkinsonism, including tremor, rigidity, and bradykinesia. Age at onset was 15 and 22 years. Twelve other family members who were heterozygous for SCA2 repeat expansions had isolated late-onset parkinsonism (2 patients), late-onset parkinsonism and ataxia (1 patient), isolated ataxia (6 patients), ataxia and RP (2 patients), and isolated RP (1 patient). Approximately 38% of family members with expanded SCA2 repeats were asymptomatic.

Charles et al. (2007) found that 3 (2%) of 164 French families with autosomal dominant parkinsonism had SCA2 expansions ranging in size from 37 to 39 repeats that were interrupted by CAA triplets. These interrupted expansions were stable in transmission. All 9 patients had levodopa-responsive parkinsonism without cerebellar signs and had less rigidity and more symmetric signs compared to patients with other causes of PD. Two sisters with both the SCA2 expansion and the LRRK2 mutation G2019S (609007.0006) had earlier onset that their mother who had only the SCA2 expansion, suggesting an additive pathogenic effect in the sisters. As a phenotypic comparison, 53 SCA2 patients with similar-sized, uninterrupted SCA2 repeats showed predominant cerebellar ataxia with rare signs of parkinsonism. The findings suggested that the configuration of SCA2 repeat expansions plays an important role in phenotypic variability.

Other Features

By polysomnography of 8 patients from 5 families with SCA2, Tuin et al. (2006) observed evidence of REM sleep behavior disorder. Patient age ranged from 14 to 55 years; disease duration ranged from 3 to 31 years. Clinically, almost all patients reported good subjective sleep quality. Four patients with early disease stage showed REM without atonia accompanied by a consistent reduction of REM density. Three patients with later stage disease had undetectable REM sleep, whereas slow wave sleep was increased at the cost of light sleep. In addition, patients showed a progressive loss of dream recall that correlated with stages of REM and theoretically corresponded to progressive brain atrophy from the pons, nigrostriatal projection, and locus ceruleus to the thalamus.

There is a wide range in the age at onset of SCA2, both between and within families, and several studies have shown a strong inverse correlation between the size of the (CAG)n repeat and the age of onset of SCA2 symptoms (Sanpei et al., 1996; Imbert et al., 1996). Almaguer-Mederos et al. (2010) analyzed a large group of 924 Cuban individuals, including 394 presymptomatic and 530 affected individuals with 32 to 79 CAG repeats. There was a highly significant negative linear relation between mean age at onset and CAG repeat number. There was a significant increase in the probability of manifesting disease for a given age as the CAG repeat number increased from 34 to 45 units. Cumulative probability curves for disease manifestation at a particular age for each CAG repeat length in the 34 to 45 unit range were significantly different for each studied CAG repeat number, stressing the importance of expanded allele CAG repeat number as the principal factor in determining age at onset in SCA2. Overall, the mean age at onset diminished by 4.15 +/- 3.45 years for each increase in the CAG repeat number.

Inheritance

SCA2 is most often transmitted in an autosomal dominant pattern of inheritance, and genetic anticipation is observed (Pulst et al., 1996). However, rare patients with homozygous ATXN2 repeat expansions have been reported (Ragothaman et al., 2004).

Mapping

In a Nebraska kindred with 33 affected members, of whom 12 were living, Ranum et al. (1992) excluded linkage to the highly informative GT-repeat marker D6S89, which had been located on 6p and found to be closely linked to the SCA1 locus in 5 other large kindreds. They excluded linkage to this marker for moderate to tight linkage, less than 11% recombination. The disorder was clinically indistinguishable from that in the linked kindreds. The clinical features were also identical to those in the Cuban family described by Orozco Diaz et al. (1990).

Gispert et al. (1993) found that in the large Cuban (Holguin) kindred that failed to show linkage to chromosome 6 markers, the locus, designated SCA2, could be assigned to 12q23-q24.1 by linkage analysis. Probable flanking markers were D12S58 and phospholipase A2 (PLA2A; 172410). Hernandez et al. (1995) performed further studies on 11 large pedigrees from the Holguin SCA2 family collective. Three-point analysis localized the SCA2 mutation within the 6-cM interval between D12S84 and D12S79. The microsatellite D12S105 within that interval showed a peak 2-point lod score 16.14 at theta = 0.00, as well as complete linkage disequilibrium among affected individuals. A common disease haplotype was found in all family ancestors, supporting an SCA2 founder effect in Holguin. Investigation of linkage to the interval containing SCA2 in 7 French autosomal dominant SCA families, previously excluded from linkage to SCA1, provided preliminary data suggesting the existence of a third locus, SCA3 (607047). In 2 kindreds, 1 Austrian-Canadian and 1 French-Canadian, Lopes-Cendes et al. (1994) found that an autosomal dominant form of SCA could be mapped within a region of approximately 16 cM between the microsatellite markers D12S58 and D12S84/D12S105. Silveira et al. (1993) found that Machado-Joseph disease is not linked to the phenylalanine hydroxylase locus (PAH; 612349) on chromosome 12q; MJD was subsequently mapped to chromosome 14.

Gispert et al. (1995) reported that complete allelic association was established with the microsatellite marker D12S105. The D12S105 sequence, including 342 basepairs representing the region of maximal allelic association in the Cuban SCA2 founder effect, was subjected to sequence homology analysis at the European Molecular Biology Laboratories database and yielded an almost perfect match (99.7% similarity) with intron 1 of the human D-amino acid oxidase gene (DAO; 124050), which had previously been shown to be linked to all SCA2 pedigrees worldwide with no recombination (Hernandez et al., 1995). The small sequence differences were the result of length variations in the 4 primitive repeat motifs contained in this intron. The authors stated that a mutation in the DAO gene could fit well with previous hypotheses on the pathologic mechanism of spinocerebellar degeneration, since oral loading tests with glutamate in such patients have demonstrated a decreased metabolism of glutamic acid and aspartic acid, and since accumulation of the excitotoxic neurotransmitter glutamate is known to lead to cerebellar Purkinje neuron death. However, Gispert et al. (1995) found recombinants between SCA2 and a second microsatellite marker within intron 1 of the DAO gene. These and other recombination data of Gispert et al. (1995) excluded the DAO gene from the SCA2 region.

Belal et al. (1994) described an affected Tunisian family that showed linkage to the SCA2 locus. Multipoint linkage analysis, including markers D12S78, D12S79, and D12S105, generated a peak lod score of 3.46 at the D12S105 locus. By this analysis the SCA2 gene was localized to a 12.8-cM interval between D12S78 and D12S79. The members of the Tunisian pedigree exhibited progressive cerebellar ataxia and dysarthria with or without ophthalmoplegia, optic atrophy, pyramidal signs, sensory loss, dementia, or extrapyramidal features. Extrapyramidal signs were found in 23% of the Tunisians but in none of the Cubans. Ihara et al. (1994) identified Japanese families with OPCA showing linkage to a 6.2-cM interval between IGF1 (147440) and D12S84/D12S85 on chromosome 12.

Pulst et al. (1993) identified a pedigree with linkage to 12q and established closer flanking markers for SCA2 than had been achieved in the Cuban pedigree. The second family was of southern Italian descent and showed segregation for SCA in 5 generations. All affected persons showed marked appendicular and gait ataxia as well as slow saccadic eye movements (Starkman et al., 1972). Mean age of onset in 19 affecteds was 26.9 +/- 12.5. Anticipation was demonstrated in this family; in 14 of 15 parent-child pairs, onset of the disease in the offspring occurred earlier than in the parent by 14.4 +/- 7.9 years. Pulst et al. (1993) suggested that this indicates that an expanded triplet repeat underlies SCA2 as it does in SCA1.

Pathogenesis

Using a monoclonal antibody that recognizes expanded polyglutamine stretches in TATA box-binding protein (600075), mutant huntingtin (613004), mutant ataxin-1 (164400), and glutamine expanded proteins in patients with SCA3 (109150), Trottier et al. (1995) used Western blotting to detect a 150-kD protein in a patient with SCA2, but not his normal relative. By analogy to other disorders associated with anticipation in expanded triplet repeats, they suggested that this may be the protein encoded by the mutant gene responsible for this disorder.

Proteins with long polyQ tracts have an increased tendency to aggregate, often as truncated fragments forming ubiquitinated intranuclear inclusion bodies. In SCA2 brains, Huynh et al. (2000) found cytoplasmic, but not nuclear, microaggregates. Mice expressing ataxin-2 with Q58 (58 CAG repeats) showed progressive functional deficits accompanied by loss of the Purkinje cell dendritic arbor and finally loss of Purkinje cells. Despite similar functional deficits and anatomic changes observed in ataxin-1(Q80) transgenic lines, ataxin-2(Q58) remained cytoplasmic without detectable ubiquitination.

Sisodia (1998) reviewed the significance of nuclear inclusions in glutamine repeat disorders.

The ATXN2 promoter is located exon 1 of the ATXN2 gene in a typical CpG island devoid of a TATA box and is usually partially methylated. Using a methyl-specific PCR protocol, Laffita-Mesa et al. (2012) found differences in the methylation levels of the ATXN2 promoter in a family in which anticipation was observed without CAG repeat expansion. Specifically, the promoter was hypomethylated in an affected son with earlier onset of SCA2 compared to that of his affected mother with later onset of the disorder, even though both patients carried CAG expansions of 39 repeats on the pathogenic allele. In 9 SCA2 patients, quantitative analysis indicated that hypermethylation at the promoter, leading to partial or complete epigenetic silencing, was associated with longer expansions of the ATXN2 repeat and that alleles with pathogenic CAG expansions were preferentially hypermethylated. These findings may represent part of the cellular defense mechanism to reduce the burden of cytotoxic mutant ATXN2. Study of 2 patients with homozygous expansions of 43 and 39 CAG repeats, respectively, found an association between hypermethylation at the ATXN2 promoter and delayed age at onset. SCA3 (109150) is caused by a similar CAG repeat expansion in the ATXN3 gene (607047), which is closely connected to ATXN2. Laffita-Mesa et al. (2012) also found that hypermethylation at the ATXN2 promoter was associated with lower age of onset of SCA3, although methylation at the ATXN3 promoter had no effect on age at onset of SCA3. These findings suggested that the development of SCA3 may involve physiologic functions of ATXN2. Overall, the report of Laffita-Mesa et al. (2012) showed that methylation of the ATXN2 promoter can occur, consistent with epigenetic control of ATXN2 expression, and that differences in methylation may affect disease course.

Molecular Genetics

Spinocerebellar Ataxia 2

In patients with spinocerebellar ataxia-2, Pulst et al. (1996) identified a (CAG)n repeat located in the 5-prime end of the coding region of the ATXN2 gene (601517.0001). They detected expansions of 36 to 52 repeats in affected individuals; the most common allele contained 37 repeats. They noted that the SCA2 repeat is unusual in that only 2 alleles were demonstrated in the normal population. A common allele with 22 repeats was found in people of European descent. Using RT-PCR, Pulst et al. (1996) determined that the SCA2 (CAG)n repeat is transcribed in lymphoblastoid cell lines and that the cells could be used to express the expanded repeat genes from patients with SCA2.

Sanpei et al. (1996) analyzed 286 normal chromosomes and found that the (CAG)n repeats ranged in size from 15 to 24, with a unit of 22 repeats accounting for 94% of the alleles. In contrast, SCA2 patient chromosomes contained expanded repeats ranging in size from 35 to 59 units. Sanpei et al. (1996) reported that there was a strong inverse correlation between the size of the (CAG)n repeat and the age of onset of SCA2 symptoms.

Imbert et al. (1996) reported that normal SCA2 alleles contained 17 to 29 (CAG)n repeats and 1 to 3 (CAA)n repeats (also glutamine-encoding). Mutated alleles contained 37 to 50 repeats and appeared to be particularly unstable in maternal and paternal transmissions. Sequence analysis of expanded repeats from 3 individuals revealed pure CAG stretches. Imbert et al. (1996) reported a steep inverse correlation between the age of onset of disease and (CAG)n repeat number.

Riess et al. (1997) investigated the (CAG)n repeat length of the ATXN2 gene in 842 patients with sporadic ataxia and in 96 German patients with dominantly inherited SCA that did not harbor the SCA1 or MJD1/SCA3 mutation. The SCA2 (CAG)n expansion was identified in 71 patients from 54 families. The (CAG)n stretch of the affected allele varied between 36 and 64 trinucleotide units. Significant repeat expansions occurred most commonly during paternal transmission. Analysis of the (CAG)n repeat lengths with respect to the age of onset in 41 patients revealed an inverse correlation. They found that 241 apparently healthy octogenarians carried alleles between 16 and 31 repeats. One 50-year-old healthy individual had 34 repeats; she had transmitted an expanded allele to her child. Riess et al. (1997) commented that the small difference between 'normal' and disease alleles makes it necessary to define the extreme values of their reaches. With one exception, the trinucleotide expansion was not observed in 842 ataxia patients without a family history of the disease. The SCA2 mutation causes the disease in nearly 14% of autosomal dominant SCA in Germany.

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.

Spadafora et al. (2007) reported 2 brothers and a nephew with SCA2. Molecular analysis identified CAG repeat numbers of 35/36, 22/35, and 22/42, respectively. The brother and nephew with the 35/36 and 22/42 repeat expansions showed earlier age at onset and a more severe progressive disorder compared to the brother with the 22/35 repeat expansions. The family was from Sicily and denied consanguinity, although both deceased parents of the brothers were reportedly affected late in life. Spadafora et al. (2007) concluded that SCA2 shows gene dosage effects on phenotype.

Amyotrophic Lateral Sclerosis 13

Elden et al. (2010) demonstrated genetic, biochemical, and neuropathologic interactions between TDP43 (605078), a protein involved in amyotrophic lateral sclerosis (ALS10; 612069), and ATXN2, which raised the possibility that mutations in ATXN2 may have a causative role in ALS. The ATXN2 polyQ tract length, although variable, is most frequently 22-23, with expansions of greater than 34 causing SCA2. However, the variable nature of the polyQ repeat indicated a mechanism by which such mutations in ATXN2 could be linked to ALS: Elden et al. (2010) proposed that intermediate-length expansions greater than 23 but below the threshold for SCA2 may be associated with ALS. They studied the frequency of intermediate-length ATXN2 polyglutamine repeat in ALS, comparing 915 subjects with ALS with 980 neurologically normal controls. Among those with ALS, 4.7% (43) had repeat lengths of 27 to 33, whereas only 1.4% (14) of neurologically normal subjects had glutamine expansions. The P value for this difference was 3.6 x 10(-5) with an odds ratio (OR) of 2.80. Elden et al. (2010) analyzed ATXN2 protein levels in patient-derived lymphoblastoid cells from ALS cases harboring intermediate-length polyQ expansions, ALS cases with normal-range repeat lengths, and controls. These studies showed that whereas the steady-state levels of ATXN2 were comparable, cyclohexamide treatment, which blocks new protein synthesis, revealed an increase in stability (or decreased degradation) of ATXN2 in cells with intermediate-length polyQ repeats. Elden et al. (2010) found that polyQ expansions in ATXN2 enhance its interaction with TDP43. Both ATXN2 and TDP43 relocalize to stress granules, sites of RNA processing, under various stress situations such as heat shock and oxidative stress. Under normal conditions TDP43 localized to the nucleus and ATXN2 to the cytoplasm in both control cells and cells harboring polyQ repeat expansions. The authors proposed that intermediate-length ATXN2 polyQ repeats might confer genetic risk for ALS by making TDP43 more prone to mislocalize from the nucleus to the cytoplasm under situations of stress.

In a case-control study of 556 ALS patients and 471 controls of French or French Canadian origin, Daoud et al. (2011) found that 7.2% of patients and 5.1% of controls had 1 intermediate repeat allele (24-33 repeats), which was not significantly different. However, receiver operating characteristic curve analysis yielded a significant association between ALS and high-length ATXN2 repeat alleles (29 or more repeats). CAG repeats of 29 or more were found in only 4 controls (0.8%), whereas they were found in 25 patients (4.5%) (OR, 5.5; p = 2.4 x 10(-4)). The association was even stronger for familial cases when stratified by familial versus sporadic cases (OR for familial cases, 9.29; p = 5.2 x 10(-5)). There was no correlation between size of repeat and age of onset. In addition, 2 familial and 9 sporadic ALS cases carried SCA2-sized pathogenic alleles (more than 32 repeats), and none had features of SCA2 such as cerebellar or brainstem atrophy.

Among 1,845 sporadic and 103 familial ALS cases and 2,002 controls from Belgium and the Netherlands, Van Damme et al. (2011) found an association between ALS and an expanded repeat of 29 or more CAG repeats in the ATXN2 gene (OR, 1.92; p = 0.036). In controls, the repeat length ranged from 16 to 31, with 22 being the most abundant. Repeat sizes of 31 or less were not significantly different between patients and controls. However, receiver operating characteristic analysis showed that the greatest sensitivity and specificity of discriminating ALS from control was using a cutoff of 29 repeats: 1.5% of patients had 29 or more repeats compared to 0.8% of controls (OR, 1.92; p = 0.036). There was no correlation between repeat length and disease parameters. When combined in a metaanalysis with the data of Elden et al. (2010), the association was highly significant (OR, 2.93; p less than 0.0001). Ten patients (0.05%) with sporadic ALS had 32 or more repeats, and none of these patients had signs of SCA2. Two of 91 families with ALS (2.2%) had expanded repeats: 1 with 31 repeats and the other with 33 repeats. In the 33-repeat family, which was consanguineous, 2 affected individuals had repeat expansions on both alleles, 33:33 and 33:31, respectively, although the phenotype was not significantly different from classic ALS, except for some sensory abnormalities. Two sibs from a third family with a heterozygous repeat length of 34 and 35, respectively, had classic SCA2 with no signs of upper motor neuron involvement. The findings indicated a genetic overlap between SCA2 and ALS13.

Among 3,919 patients with various neurodegenerative diseases, including 532 with ALS, 641 with frontotemporal dementia (FTD; 600274), 1,530 with Alzheimer disease (AD; 104300), 702 with Parkinson disease (PD; 168600), and 514 with progressive supranuclear palsy (PSP; 601104), and 4,877 healthy controls, Ross et al. (2011) found that ATXN2 repeat lengths greater than 30 units were significantly associated with ALS (odds ratio of 5.57; p = 0.001) and with PSP (OR of 5.83; p = 0.004). Repeat expansions were found in 8 (1.5%) ALS patients, 4 (0.8%) PSP patients, and 9 (0.2%) controls. Significant associations between repeats greater than 30 were not observed in patients with FTD, AD, or PD. The findings of expanded repeat alleles (31 to 33) in control individuals indicated that caution should be taken when attributing specific disease phenotypes to these repeat lengths. However, 6 of the controls with expanded repeats were under the mean onset age of all patient groups except PD. The findings confirmed the role of ATXN2 as an important risk factor for ALS and suggested that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.

Population Genetics

In the vicinity of Holguin in northeastern Cuba (neighboring the Guantanamo Naval Base), Orozco et al. (1989) estimated a frequency of 41 per 100,000 for a form of dominantly inherited olivopontocerebellar atrophy occurring in persons of Spanish ancestry. The high prevalence was thought to be the result of founder effect. The clinical and biochemical features were described together with the neuropathologic findings in 7 autopsied patients.

Geschwind et al. (1997) found that SCA2 accounts for 13% of patients with autosomal dominant cerebellar ataxia (without retinal degeneration), which is intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively. Together, SCA1, SCA2, and SCA3/MJD constitute more than 40% of the mutations leading to autosomal cerebellar ataxia type I. Geschwind et al. (1997) found that no patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3. No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, was observed. Repeat length correlated inversely with age at onset, accounting for approximately 80% of the variability in onset age. Haplotype analysis provided no evidence for a single founder chromosome, and diverse ethnic origins were observed among SCA2 kindreds. In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia.

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.

Watanabe et al. (1998) investigated 101 kindreds with spinocerebellar ataxias from the central Honshu island of Japan, using a molecular diagnostic approach with amplification of the CAG trinucleotide repeat of the causative genes. SCA2 accounted for 5.9% of the cases.

Among 202 Japanese and 177 Caucasian families with autosomal dominant SCA, Takano et al. (1998) found that the prevalence of SCA2 was significantly higher in the Caucasian population (14%) compared to the Japanese population (5%). This corresponded to higher frequencies of large normal CACNA1A CAG repeat alleles (greater than 22 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.

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