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Spinocerebellar Ataxia Type 2

Synonym: SCA 2
, MD
Department of Neurology
University of Utah
Salt Lake City, Utah

Initial Posting: ; Last Update: August 1, 2013.

Summary

Disease 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 are 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 of ATXN2. Affected individuals have alleles with 33 or more CAG trinucleotide repeats. Such testing detects nearly 100% of cases.

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 prevents 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 repeat expansion. The repeat may expand significantly, especially when transmitted by the father. Prenatal testing for pregnancies at increased risk is possible if the diagnosis has been established by molecular genetic testing in an affected family member.

Diagnosis

Clinical Diagnosis

The clinical features of spinocerebellar ataxia type 2 (SCA2) do not allow diagnosis with certainty; thus, diagnosis depends on molecular genetic testing.

Molecular Genetic Testing

Gene. ATXN2 is the only gene in which mutations are known to cause SCA2. One hundred percent of individuals affected with SCA2 have an ATXN2 CAG trinucleotide repeat expansion.

Allele sizes

  • Normal alleles. 31 or fewer CAG repeats
  • Intermediate allele of uncertain clinical significance: 32 repeats is an uncommon allele; correlation with clinical findings and family history may be helpful.
  • Pathologic alleles. 33 or more pure CAG repeats or repeats interrupted by a CAA repeat [Pulst et al 1996, Charles et al 2007]:
    • Alleles of 33 CAG repeats are considered "late onset" (after age 50 years).
    • 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 CAA codes for glutamine as well [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.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in SCA2

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
ATXN2Targeted mutation analysis: PCR amplificationSmaller CAG trinucleotide repeat expansions up to ~100 repeats~100%
Targeted mutation analysis: Southern blot analysisHighly expanded CAG trinucleotide repeat expansions (>100 repeats) 4

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Mao et al [2002]. Such testing may be indicated in symptomatic infants and children.

Testing Strategy

To confirm/establish the diagnosis in a proband. The presence of one abnormally expanded ATXN2 allele is diagnostic.

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.

  • Only 2/842 affected individuals without a family history of ataxia in the series of Riess et al [1997] had an ATXN2 expansion in the abnormal range (41 and 49 repeats).
  • Only two of 90 individuals with olivopontocerebellar atrophy without a known family history in the series reported by Cancel et al [1997] had an ATXN2 expansion in the abnormal range (37 and 39 repeats).

Predictive testing for at-risk asymptomatic adult family members requires prior confirmation of the diagnosis in the family by molecular genetic testing.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

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, Velazquez-Perez 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.

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, Infante et al 2004, Lu et al 2004, Charles et al 2007].

Neuropathology. Seven post-mortem 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 scanty. 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 [Rub et al 2003, Rub et al 2004, Rub 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 nigro-luyso-pallidal 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.

A case 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.

The size of the CAG repeat is significantly larger in individuals with dystonia, myoclonus, and myokymia, whereas both CAG length and duration of disease influence the frequency of muscle atrophy, fasciculations, decreased tendon reflexes and vibration sense in the lower extremities, and slow eye movements.

Homozygosity for an expanded ATXN2 allele 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

An increase in the severity of the phenotype and earlier age of onset in later generations, a phenomenon known as anticipation, 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. 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.

In a large series from several ataxia clinics in Germany, SCA2 represented 14% of ADCA pedigrees [Riess et al 1997].

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].

SCA2 is the most common type of ADCA in Korea [Lee et al 2003]. (See also Ataxia Overview.)

Moseley et al [1998] reported that SCA2 was common in individuals presenting to an ataxia clinic at an academic medical center. It represented 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].

Differential Diagnosis

It is difficult and often impossible to distinguish spinocerebellar ataxia type 2 (SCA2) from the other hereditary ataxias (see Ataxia Overview). The differential diagnosis should also include Parkinson disease and acquired causes of cerebellar ataxia.

In six families detected with SCA2 out of 64 families with autosomal dominant cerebellar ataxia (ADCA) of German ancestry, Schols et al [1997b] determined that no specific single feature was sufficient to distinguish SCA2 from the other SCAs; however, slowed saccades, postural and action tremors, myoclonus, and hyporeflexia were more common in individuals with SCA2 than in those with SCA1 and SCA3.

Two studies reported quantitative eye movement recordings in individuals with SCA2 and compared them with other ADCAs:

  • Burk et al [1996] compared several individuals with SCA2 defined by linkage analysis with individuals who had SCA1 or SCA3. Individuals with SCA2 had significantly slower saccadic speed (138°/sec) than individuals with SCA1 (244°/sec) or SCA3 (347°/sec). All eight individuals with SCA2 had saccadic velocities two standard deviations below the mean of a control group.
  • Buttner et al [1998] compared saccades in individuals with SCA1, SCA2, SCA3, and SCA6 identified by molecular genetic testing. Individuals with SCA2 had the slowest peak saccadic velocity, ranging from 80 to 295°/sec (normal: >400°/sec). Saccades were also slowed in individuals with SCA1, but individuals with SCA3 and SCA6 had normal saccades.

SCA2 should be in the differential diagnosis of adult-onset sporadic progressive ataxia, multiple system atrophy (MSA, Shy-Drager syndrome), L-dopa-responsive parkinsonism, and atypical Friedreich ataxia [Abele et al 2002].

Table 2. Proportion of Individuals with SCA2 Manifesting Phenotypic Features Compared with Individuals with SCA1, SCA3, and SCA6

Phenotypic FeatureSCA2SCA1SCA3SCA6
Cerebellar dysfunction100%100%100%100%
Reduced saccadic velocity71%-92%50%10%0%-6%
Myoclonus0%-40%0%4%0%
Dystonia or chorea0%-38%20%8%0%-25%
Pyramidal involvement29%-31%70%70%33%-44%
Peripheral neuropathy44%-94%100%80%16%-44%
Intellectual impairment31%-37%20%5%0%

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 2 (SCA2), the following are recommended:

  • Neurologic examination
  • Ophthalmologic examination
  • Baseline assessment of cognition
  • Neuroimaging
  • Consideration of medical genetics consultation

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 patient showed improvement with stimulation of the subthalamic nucleus [Freund et al 2007].

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 for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face 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

Note: Although most individuals diagnosed with SCA2 have an affected parent, 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.

Sibs of a proband

  • The risk to the sibs of an affected person depends on the genetic status of the parents.
  • If a parent of the proband has an expanded ATXN2 allele, the risk to the sibs is 50%.
  • When neither parent has an expanded ATXN2 allele, the risk to the sibs of a proband appears to be low.
  • If neither parent of the proband has an expanded ATXN2 allele detectable in DNA extracted from leukocytes, germline mosaicism in a parent is a possible explanation. No instances of germline mosaicism have been reported, although it remains a possibility.

Offspring of a proband

  • Each child of an individual with SCA2 has a 50% chance of inheriting the mutation.
  • Further expansion in ATXN2 may occur when the expanded ATXN2 allele is transmitted to offspring. This results in anticipation (an earlier age of onset and more severe disease manifestations in offspring).
  • Large expansions are almost exclusively observed when the repeat is passed through the paternal germline [Geschwind et al 1997b, Riess et al 1997]. Nonetheless, the 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 expansion.

Other family members of a proband

  • 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 are at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adults. Testing of asymptomatic adults at risk for SCA2 is possible using the techniques described in Molecular Genetic Testing. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for SCA2, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply "the need to know."

Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of SCA2, neurologic status, and the possible impact of positive and negative test results are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Also to consider are the implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.

Testing of at-risk individuals younger than age 18 years. Consensus holds that asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders should not have testing in the absence of symptoms. The principal arguments against such testing are that it removes the individual’s choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications [Bloch & Hayden 1990, Harper & Clarke 1990]. Individuals younger than age 18 years who are symptomatic usually benefit from having a specific diagnosis established. (See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.)

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the presence of an expanded ATXN2 allele in an affected family member has been confirmed, prenatal testing for pregnancies at increased risk for SCA2 is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Prenatal testing must take into account the possibility of a highly expanded ATXN2 allele [Babovic-Vuksanovic et al 1998].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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
  • Spinocerebellar Ataxia: Making an Informed Choice about Genetic Testing
    Booklet providing information about Spinocerebellar Ataxia
  • Ataxia UK
    Lincoln House
    1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: 0845 644 0606 (helpline); 020 7582 1444 (office); +44 (0) 20 7582 1444 (from abroad)
    Email: helpline@ataxia.org.uk; office@ataxia.org.uk
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    9 Winchester House
    Kennington Park
    London SW9 6EJ
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: marco.meinders@euro-ataxia.eu
  • International Network of Ataxia Friends (INTERNAF)
    Email: internaf-owner@yahoogroups.com
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • Spanish Ataxia Federation (FEDAES)
    Spain
    Phone: 34 983 278 029; 34 985 097 152; 34 634 597 503
    Email: sede.valladolid@fedaes.org; sede.gijon@fedaes.org; sede.bilbao@fedaes.org
  • CoRDS Registry for the National Ataxia Foundation
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423
    Email: Cords@sanfordhealth.org

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

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Spinocerebellar Ataxia Type 2 (View All in OMIM)

183090SPINOCEREBELLAR ATAXIA 2; SCA2
601517ATAXIN 2; ATXN2

Normal allelic variants. Normal alleles have 31 or fewer CAG repeats. The normal alleles are not highly polymorphic. 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]. Rare normal alleles ranging from 15 to 31 repeats have also been identified [Imbert et al 1996, Sanpei et al 1996, Riess et al 1997].

Normal alleles typically show one or two CAA interruptions. In contrast to the CAT interruptions coding for histidine that are found in SCA1, the CAA 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. Usage 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 and would result in a protein with a relative molecular weight of 125 kd.

Intermediate allele of uncertain clinical significance. 32 repeats is an uncommon allele and information is insufficient to classify it as normal or pathologic.

Pathologic allelic variants. Disease alleles have 33 or more CAG repeats without interruption [Pulst et al 2005].

Note: Intermediate alleles (i.e., meiotically unstable alleles that expand into an abnormal allele in the subsequent generation) are not reported in SCA2.

Table 3. ATXN2 Allelic Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Normalc.496_498CAG(≤31)
(≤31 CAG repeats)
p.Gln166(≤31)NM_002973​.3
NP_002964​.3
Pathologicc.496_498CAG(≥33)
(≥33 CAG repeats)
p.Gln166(≥33)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Pulst et al [1996] predicted 1312 amino acids (22 glutamines) and Sanpei et al [1996] predicted 1313 amino acids (23 glutamines) with the CAG repeat coding for polyglutamine. Proteins observed by western blot analysis and conservation of the 5' ATG in mouse [Nechiporuk et al 1998] suggest that the 5' ATG is the predominant site of translation initiation. In analogy to gene products encoded by other SCA-related genes, the ATXN2 gene product has been designated ataxin-2.

In normal brains and in brains from 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 normal individuals and those affected with SCA2 [Huynh et al 2000].

Ataxin-2 interacts with ataxin-2 binding protein 1 (NM_001142333.1), a protein containing RNA-recognition motifs [Figueroa & Pulst 2003]. Interaction of ataxin-2 with ataxin-2 binding protein suggests involvement of ataxin-2 in mRNA translation or transport [Shibata et al 2000]. Ataxin-2-deficient mice do not develop marked neurodegeneration but show reduced fertility, obesity, and changes in hippocampal plasticity [Kiehl et al 2006, Huynh et al 2009].

Abnormal gene product. The CAG expansion codes for a protein that has an abnormally long stretch of glutamine amino acid residues. The biologic consequence of this abnormal protein is undetermined. A mouse model of SCA2 has been described by Huynh et al [2000]. Atxn2 transgenic mice had accumulation of ataxin-2 in the cytoplasm. Intranuclear aggregates were not observed. In vitro, expression of mutant ataxin-2 causes apoptotic cell death [Huynh et al 2003]. In the Atxn2 transgenic mouse, ataxin-2 interacts with the inositol-triphosphate receptor type 1 causing abnormally increased Ca++ release from intracellular calcium stores. This can be ameliorated by treatment in vivo with dantrolene prior to onset of symptoms [Liu et al 2009].

References

Published Guidelines/Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 7-30-13. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 7-30-13.

Literature Cited

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Chapter Notes

Revision History

  • 1 August 2013 me) Comprehensive update posted live
  • 5 October 2010 (me) Comprehensive update posted live
  • 25 January 2006 (me) Comprehensive update posted to live Web site
  • 31 October 2003 (me) Comprehensive update posted to live Web site
  • 13 January 2001 (me) Comprehensive update posted to live Web site
  • 23 October 1998 (pb) Review posted to live Web site
  • 2 March 1998 (smp) Original submission
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