Summary
Clinical characteristics.
Spinocerebellar ataxia type 2 (SCA2) is characterized by progressive cerebellar ataxia, including nystagmus, slow saccadic eye movements, and in some individuals, ophthalmoparesis or parkinsonism. Pyramidal findings are present; deep tendon reflexes are brisk early on and absent later in the course. Age of onset is typically in the fourth decade with a ten- to 15-year disease duration.
Diagnosis/testing.
The diagnosis of SCA2 rests on the use of molecular genetic testing to detect an abnormal CAG trinucleotide repeat expansion in ATXN2. Affected individuals have alleles with 33 or more CAG trinucleotide repeats.
Management.
Treatment of manifestations: Management is supportive. Affected individuals should maintain activity. Canes and walkers help prevent falls; grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary. Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria. Weighted eating utensils and dressing hooks help maintain a sense of independence. When dysphagia becomes troublesome, video swallowing studies can identify the consistency of food least likely to trigger aspiration.
Prevention of secondary complications: Vitamin supplements are recommended; weight control helps minimize difficulties with ambulation and mobility.
Surveillance: Annual examination by a physician experienced in movement disorders and ataxia.
Agents/circumstances to avoid: Alcohol and medications known to affect cerebellar function.
Genetic counseling.
SCA2 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the causative CAG trinucleotide repeat expansion. The repeat may expand significantly, especially when transmitted by the father. Prenatal testing for a pregnancy at increased risk is possible if the diagnosis has been established by molecular genetic testing in an affected family member.
Diagnosis
Suggestive Findings
Spinocerebellar ataxia type 2 (SCA2) should be suspected in individuals with the following:
Slowly progressive ataxia and dysarthria
Nystagmus and slow saccadic eye movements
Family history consistent with autosomal dominant inheritance
Establishing the Diagnosis
The diagnosis of SCA2 is established in a proband with a heterozygous pathogenic variant in ATXN2 (see Table 1). The clinical features of SCA2 do not allow diagnosis with certainty; thus, diagnosis depends on molecular genetic testing.
Allele sizes
Alleles not causing SCA2. Alleles with 31 or fewer CAG repeats
Alleles of uncertain clinical significance. Alleles with 32 repeats are uncommon; correlation with clinical findings and family history may be helpful.
Alleles predisposed to meiotic instability (longer normal alleles) have a CAG length-dependent increased instability [
Almaguer-Mederos et al 2018]. Precise risk estimates based on large numbers of affected individuals from different ethnic groups are not available. In a small number of observations, presence of an uninterrupted (pure CAG) repeat structure increases risk of expansion and conversely, CAA interruptions appear to stabilize the repeat in transmissions.
Dominant SCA2-causing alleles. Alleles with 33 or more CAG repeats (see Note) [
Pulst et al 1996,
Charles et al 2007]. Persons who have an SCA2-causing allele are considered at risk of developing SCA2 in their lifetime. SCA2-causing alleles are further classified as follows:
Reduced-penetrance SCA2-causing alleles. 33-34 CAG trinucleotide repeats. An individual with an allele in this range is at risk for SCA2 but may not develop symptoms. Alleles of 33 CAG repeats are considered "late onset" (age >50 years). An older asymptomatic individual with 34 CAG repeats has been reported [
Riess et al 1997].
Full-penetrance SCA2-causing alleles. The most common disease-causing alleles have 37 to 39 repeats. Extreme CAG repeat expansion (>200) has been reported [
Babovic-Vuksanovic et al 1998] (see
Anticipation).
Note: Interruption of a CAG expanded allele by a CAA repeat does not mitigate the pathogenicity of the repeat size because both CAG and CAA code for glutamine [Costanzi-Porrini et al 2000]; however, the interruption may enhance the meiotic stability of the repeat [Choudhry et al 2001]. Conversely, the lack of CAA interruption in some expanded alleles may increase the instability of the expansion and therefore increase the risk of transmission of a larger expansion to offspring, who may become symptomatic.
Molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
Table 1.
Molecular Genetic Testing Used in SCA2
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| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|
|
ATXN2
| Targeted analysis for pathogenic variants 3 | ~100% |
- 1.
- 2.
- 3.
Detects abnormal number of CAG trinucleotide repeats. PCR amplification detects smaller CAG trinucleotide repeat expansions up to ~100 repeats. Southern blotting is required to detect highly expanded CAG trinucleotide repeat expansions (>100 repeats) and may be indicated in symptomatic infants and children [Mao et al 2002].
Note: Testing individuals with a positive family history of ataxia has a much higher yield than testing individuals with ataxia without an obvious family history.
In the series reported by
Riess et al [1997] only two of 842 affected individuals without a family history of ataxia were heterozygous for an
ATXN2 expansion in the pathogenic allele size range.
In the series reported by
Cancel et al [1997] only two of 90 individuals with olivopontocerebellar atrophy without a known family history were heterozygous for an
ATXN2 expansion in the pathogenic allele size range.
Clinical Characteristics
Clinical Description
Spinocerebellar ataxia type 2 (SCA2) is characterized by slowly progressive ataxia and dysarthria associated with the ocular findings of nystagmus, slow saccadic eye movements, and in some individuals, ophthalmoparesis. Tendon reflexes are brisk during the first years of life, but absent later. Mean age of onset is typically in the fourth decade with a ten- to 15-year disease duration. The disease is more rapidly progressive when onset occurs before age 20 years.
In the original study from Cuba, the earliest symptoms included gait ataxia often accompanied by leg cramps [Orozco Diaz et al 1990]. More than 50% of affected individuals developed a kinetic or postural tremor, decreased muscle tone, decreased tendon reflexes, and abnormal eye movements with slowed saccades progressing to supranuclear ophthalmoplegia. Detailed analyses of the eye movement abnormalities have been reported [Engel et al 2004, Velázquez-Pérez et al 2004].
In individuals with molecularly confirmed ATXN2, Geschwind et al [1997b] found almost universal presence of cerebellar ataxia and slow saccadic eye movements in affected individuals, as well as a relatively high incidence of dystonia or chorea (38%) and dementia (37%). Mild, primarily cerebellar symptoms appeared to segregate in some families, whereas others had an early onset with dementia and chorea. Luo et al [2017] described the initial manifestations in SCA2 and other ataxias.
Similar findings were also reported by Cancel et al [1997] in a series of 111 individuals from 32 families of diverse origins. Slow eye movements were seen in 56%, fasciculations in 25%, and dystonia in 9%. The authors also correlated these findings with disease duration and increasing CAG repeat length.
An SCA2 phenotype that includes L-dopa-responsive parkinsonism has been reported [Furtado et al 2002, Payami et al 2003, Charles et al 2007]. In one Alberta family, the phenotype was consistent with autosomal dominant Parkinson disease, with PET scan showing reduced striatal fluorodopa uptake and normal raclopride binding in two affected members [Furtado et al 2002]. Charles et al [2007] proposed that an interrupted repeat structure may lead to differential binding with RNA-binding proteins and thus result in a parkinsonian rather than a cerebellar phenotype.
Neuropathology. Seven postmortem examinations have been reported in the Holguin population of Cuba [Orozco et al 1989]. A marked reduction in the number of cerebellar Purkinje cells was observed. In silver preparations, Purkinje cell dendrites had poor arborization and torpedo-like formation of their axons as they passed through the granular layer. Parallel fibers were scant and granule cells were decreased in number, whereas Golgi and basket cells were well preserved, as were neurons in the dentate and other cerebellar nuclei. In the brain stem, marked neuronal loss in the inferior olive and pontocerebellar nuclei was observed. Six of seven brains also had marked loss in the substantia nigra. In five spinal cords that were available for analysis, marked demyelination was present in the posterior columns and to a lesser degree in the spinocerebellar tracts. Motor neurons and neurons in Clarke's column were reduced in size and number. In the lumbar and sacral segments, anterior and posterior roots were partially demyelinated. Degeneration in the thalamus and reticulotegmental nucleus of the pons has also been reported [Rüb et al 2003, Rüb et al 2004, Rüb et al 2005].
In addition, Orozco et al [1989] noted severe gyral atrophy, most prominent in the frontotemporal lobes. The cerebral cortex was thinned, but without neuronal rarefaction. The cerebral white matter was atrophic and gliotic. Degeneration in the pallidonigroluysian system mainly involved the substantia nigra. One brain showed patchy loss in parts of the third-nerve nuclei. Adams et al [1997] reported similar findings in one individual.
Seidel et al [2017] studied the distribution of polyQ aggregates in brain stem sections of individuals with SCA2 and found that cytoplasmic aggregates correlated with disease severity.
An affected individual with white matter pathology has been described [Armstrong et al 2005].
Nerve biopsy has shown moderate loss of large myelinated fibers [Filla et al 1995].
Genotype-Phenotype Correlations
Probands. In general, a clear inverse correlation exists between age of onset and CAG repeat length. However, repeat length cannot predict age of onset or disease severity in an individual. About 50% of age-of-onset variance is not explained by CAG repeat length [Figueroa et al 2017].
The widest range of age of onset is observed among individuals with fewer than 40 CAG repeats. Some individuals with alleles of 33 and 34 repeats have had onset after age 60 years. In one study, the presence of 37 repeats was associated with ages of onset ranging from 20 to 60 years [
Pulst et al 1996].
Homozygosity for expanded ATXN2 alleles (2 alleles in the pathogenic range) does not appear to influence age of onset [Sanpei et al 1996].
At-risk individuals. The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be predicted by the family history or by molecular genetic (DNA) testing.
Anticipation
Anticipation (i.e., an increase in the severity of the phenotype and earlier age of onset in later generations) has been observed in SCA2. The tendency of the ATXN2 CAG repeat to expand as it is transmitted provides a biologic explanation for the earlier age of onset in subsequent generations.
Paternal transmission of alleles with full penetrance or reduced penetrance is most likely to demonstrate meiotic instability and result in anticipation, although large expansions can also be seen in maternally inherited alleles [Figueroa et al 2017]. In one case report, a man who had 43 repeats and onset of symptoms at age 22 years had an infant with apnea, hypotonia, and dysphagia and an allele of 202 CAG repeats [Babovic-Vuksanovic et al 1998]. Mao et al [2002] identified large expansions in four individuals using a Southern blot assay.
Nomenclature
Terms used in the past for SCA2 and other hereditary ataxias include Marie's ataxia, OPCA, and forme fruste of Friedreich ataxia. These terms are no longer in use.
Prevalence
Geschwind et al [1997b] found that in an ethnically varied population in the University of California Los Angeles ataxia clinic, SCA2 accounted for 13% of the autosomal dominant cerebellar ataxias (ADCAs) compared with 6% for SCA1 and 23% for SCA3. A similar percentage (15%) was reported by Cancel et al [1997] in 184 families from an ethnically and geographically diverse population.
In the Baylor College of Medicine ataxia clinic, SCA2 was the most common ADCA (18%) [Lorenzetti et al 1997]. Moseley et al [1998] reported that SCA2 was common in individuals presenting to an ataxia clinic at an academic medical center, representing 15% of persons from families with autosomal dominant inheritance and 2% of simplex cases (i.e., a single occurrence in a family) [Moseley et al 1998].
In a large series from several ataxia clinics in Germany, SCA2 represented 14% of ADCA pedigrees [Riess et al 1997].
SCA2 is the most common type of ADCA in Korea [Lee et al 2003]. (See also Hereditary Ataxia Overview.)
Differential Diagnosis
It is difficult and often impossible to distinguish spinocerebellar ataxia type 2 (SCA2) from the other hereditary ataxias (see Hereditary Ataxia Overview). The differential diagnosis should also include Parkinson disease and acquired causes of cerebellar ataxia.
SCA2-related ATXN2 pathogenic variants should be in the differential diagnosis of adult-onset sporadic progressive ataxia, multiple system atrophy (MSA, Shy-Drager syndrome; OMIM 146500), L-dopa-responsive parkinsonism, atypical Friedreich ataxia [Abele et al 2002], and amyotrophic lateral sclerosis [Neuenschwander et al 2014].
Table 2.
Proportion of Individuals with SCA2 Manifesting Phenotypic Features Compared with Individuals with SCA1, SCA3, and SCA6
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| Phenotypic Feature | SCA2 | SCA1 | SCA3 | SCA6 |
|---|
| Cerebellar dysfunction | 100% | 100% | 100% | 100% |
| Reduced saccadic velocity | 71%-92% | 50% | 10% | 0%-6% |
| Myoclonus | 0%-40% | 0% | 4% | 0% |
| Dystonia or chorea | 0%-38% | 20% | 8% | 0%-25% |
| Pyramidal involvement | 29%-31% | 70% | 70% | 33%-44% |
| Peripheral neuropathy | 44%-94% | 100% | 80% | 16%-44% |
| Intellectual impairment | 31%-37% | 20% | 5% | 0% |
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 2 (SCA2), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Neurologic examination
Ophthalmologic examination
Baseline assessment of cognition
Neuroimaging
Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Management of individuals remains supportive as no known therapy to delay or halt the progression of the disease exists.
Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals should maintain activity.
Canes and walkers help prevent falls.
Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.
Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria.
Weighted eating utensils and dressing hooks help maintain a sense of independence.
When dysphagia becomes troublesome, video esophagrams can identify the consistency of food least likely to trigger aspiration.
Improvement of severe tremor with thalamic stimulation has been reported in one individual [Pirker et al 2003]. Another individual showed improvement with stimulation of the subthalamic nucleus [Freund et al 2007].
The American Academy of Neurology has developed guidelines for the treatment of motor dysfunction in patients with ataxia [Zesiewicz et al 2018].
Prevention of Secondary Complications
No dietary factor has been shown to curtail symptoms; however, vitamin supplements are recommended, particularly if caloric intake is reduced.
Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.
Surveillance
Affected individuals should be examined at least annually by a physician experienced in movement disorders and ataxia.
Agents/Circumstances to Avoid
Alcohol and medications known to affect cerebellar function should be avoided.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Other
Tremor-controlling drugs do not work well for cerebellar tremors.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
Spinocerebellar ataxia type 2 (SCA2) is inherited in an autosomal dominant manner.
Risk to Family Members
Parents of a proband
Most individuals diagnosed with SCA2 have an affected parent.
A proband with SCA2 may have the disorder as the result of an expansion of a reduced-penetrance allele or a longer normal allele inherited from an unaffected parent.
Recommendations for the evaluation of apparently asymptomatic parents of a proband include physical examination and consideration of ATXN2 molecular genetic testing.
Although most individuals diagnosed with SCA2 have an affected parent or a parent with a longer normal allele, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
Sibs of a proband. The risk to the sibs of a proband depends on the genetic status of the parents:
If a parent of the proband has an ATXN2 CAG trinucleotide repeat expansion, the risk to the sibs is 50%. However, age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be predicted by the family history or the size of the inherited expansion.
If an expanded ATXN2 allele cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism (no instances of germline mosaicism have been reported, although it remains a possibility).
Offspring of a proband
Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the expanded ATXN2 allele, his or her family members may be at risk.
Prenatal Testing and Preimplantation Genetic Testing
Once an ATXN2 CAG trinucleotide repeat expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for SCA2 are possible.
Note: Prenatal testing must take into account the possibility of a highly expanded ATXN2 allele [Babovic-Vuksanovic et al 1998].
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
NCBI Genes and Disease
Ataxia UK
United Kingdom
Phone: 0800 995 6037; +44 (0) 20 7582 1444 (from abroad)
euro-ATAXIA (European Federation of Hereditary Ataxias)
United Kingdom
National Ataxia Foundation
Phone: 763-553-0020
Spanish Ataxia Federation (FEDAES)
Spain
Phone: 601 037 982
CoRDS Registry
Sanford Research
Phone: 605-312-6300
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Spinocerebellar Ataxia Type 2: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Benign variants. Normal alleles have 31 or fewer CAG repeats. The two normal alleles, which account for more than 95% of alleles in most studies, have 22 and 23 CAG repeats [Pulst et al 1996, Sanpei et al 1996, Riess et al 1997].
Normal alleles typically show one or two CAA trinucleotide repeat interruptions. Because the CAA codon also encodes glutamine, these interruptions do not interrupt the glutamine tract at the protein level. The 5' sequence of the ATXN2 cDNA is extremely GC rich and two potential ATG initiation codons can be identified. The most 5' ATG is located 78 bp downstream of an in-frame stop codon. Use of this translation initiation site predicts a protein of 140.1 kd. The second ATG, which has a better Kozak consensus sequence, is located just 5' to the CAG repeat region and would result in a protein with a relative molecular weight of 125 kd.
Allele of uncertain clinical significance. A 32-CAG repeat is an uncommon allele and information is insufficient to classify it as normal or pathogenic.
Risk alleles. Amyotrophic lateral sclerosis risk alleles have 30, 31, or 32 repeats.
Alleles predisposed to meiotic instability (longer normal alleles) have a CAG length-dependent increased instability [Almaguer-Mederos et al 2018]. Precise risk estimates based on large numbers of affected individuals from different ethnic groups are not available. In a small number of observations, presence of an uninterrupted (pure CAG) repeat structure increases risk of expansion and conversely, CAA interruptions appear to stabilize the repeat in transmissions.
Pathogenic variants. Disease alleles have 33 or more CAG repeats [Pulst et al 2005].
Note: Interruption of a CAG expanded allele by a CAA repeat does not mitigate the pathogenicity of the repeat size because both CAG and CAA code for glutamine [Costanzi-Porrini et al 2000]; however, the interruption may enhance the meiotic stability of the repeat [Choudhry et al 2001]. Conversely, the lack of CAA interruption in some expanded alleles may increase the instability of the expansion and therefore increase the risk of transmission of a larger expansion to offspring, who may become symptomatic.
Table 3.
ATXN2 Variants Discussed in This GeneReview
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| Variant Classification | DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
|---|
|
Benign
| c.496_498CAG(≤31)
(≤31 CAG repeats) | p.Gln166(≤31) |
NM_002973.3
NP_002964.3
|
|
Pathogenic
| c.496_498CAG(≥33)
(≥33 CAG repeats) | p.Gln166(≥33) |
Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. The ATXN2 protein product, designated ataxin-2, is typically 1,312 amino acids (with a tract of 22 glutamines) or predicted 1,313 amino acids (with a tract of 23 glutamines) [Imbert et al 1996, Pulst et al 1996, Sanpei et al 1996].
In brains from both unaffected individuals and individuals with SCA2, ataxin-2 has a cytoplasmic localization. It associates with Golgi membranes [Huynh et al 2003]. Using antibodies to ataxin-2, the expression pattern of ataxin-2 was identical in brains of unaffected individuals and those affected with SCA2 [Huynh et al 2000].
Ataxin-2 interacts with a number of proteins (reviewed in Scoles & Pulst [2018]), including an ataxin-2 binding protein designated as RNA-binding protein fox-1 homolog 1 (NP_001135805.1; encoded by RBFOX1 (NM_001142333.1), which contains RNA-recognition motifs [Figueroa & Pulst 2003]. Interaction of these two proteins suggests a role for ataxin-2 in mRNA translation or transport [Shibata et al 2000]. Ataxin-2-deficient mice do not develop marked neurodegeneration but show obesity, reduced fertility, and changes in hippocampal plasticity [Kiehl et al 2006, Huynh et al 2009]. Subsequent studies have shown additional ataxin-2 interactions most notably with RNA-binding and stress granule proteins including TDP-43 [Becker et al 2017, Paul et al 2018].
Abnormal gene product. Pathogenic alleles of ATXN2 encode a protein that has an abnormally long stretch of glutamine amino acid residues. The biologic consequence of this abnormal protein is undetermined. Studies of cultured cells, human brains, and transgenic mouse lines showed accumulation of ataxin-2 in the cytoplasm without evidence of intranuclear aggregates Huynh et al [2000]. In vitro expression of an abnormally expanded ataxin-2 caused apoptotic cell death [Huynh et al 2003]. In the Atxn2 transgenic mouse, ataxin-2 interacted with the inositol-triphosphate receptor type 1, causing abnormally increased Ca++ release from intracellular calcium stores that was ameliorated by feeding mice dantrolene prior to onset of symptoms [Liu et al 2009].
References
Published Guidelines / Consensus Statements
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
online. 2013. Accessed 3-30-22. [
PubMed: 23428972]
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available
online. 2018. Accessed 3-30-22.
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Chapter Notes
Revision History
14 February 2019 (sw) Comprehensive update posted live
12 November 2015 (me) Comprehensive update posted live
1 August 2013 (me) Comprehensive update posted live
5 October 2010 (me) Comprehensive update posted live
25 January 2006 (me) Comprehensive update posted live
31 October 2003 (me) Comprehensive update posted live
13 January 2001 (me) Comprehensive update posted live
23 October 1998 (pb) Review posted live
2 March 1998 (smp) Original submission
