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Spinocerebellar Ataxia Type 12

Synonym: SCA12

, MD, , PhD, , MBBS, MD, DM, , PhD, and , MD, FRCP.

Author Information

Initial Posting: ; Last Update: November 17, 2011.

Estimated reading time: 17 minutes


Clinical characteristics.

Spinocerebellar ataxia type 12 (SCA12) is characterized by onset of action tremor of the upper extremities in the fourth decade, slowly progressing to include ataxia and other cerebellar and cortical signs. Given the small number of individuals known to have SCA12, it is possible that other clinical manifestations have not yet been recognized.


PPP2R2B is the only gene in which mutation is known to cause SCA12. In the presence of clinical findings consistent with SCA12, an expansion of 51 or more CAG triplets within PPP2R2B is diagnostic; however, the boundary between the normal and mutated allele size remains to be determined.


Treatment of manifestations: Beta-blockers (clonazepam, phenobarbital derivatives) and benzodiazepines can decrease tremor amplitude in some affected individuals; standard treatment for psychiatric syndromes; physical therapy to help maintain mobility; assistance with writing and other fine-motor tasks.

Prevention of secondary complications: A safe home environment.

Other: Educate individuals and their families about natural history, treatment, mode of inheritance, genetic risks to other family members, and consumer-oriented resources.

Genetic counseling.

SCA12 is inherited in an autosomal dominant manner. De novo pathogenic variants causing SCA12 have not been reported. Each child of an individual with SCA12 has a 50% chance of inheriting the pathogenic variant. Prenatal testing is possible but needs to be undertaken with caution as the positive predictive value of the CAG triplet repeat expansion in PPP2R2B is unknown.


Clinical Diagnosis

Clinical information on spinocerebellar ataxia type 12 (SCA12) derives from studies of the index pedigree, an American family of German descent [Holmes et al 1999, O'Hearn et al 2001]; subsequent studies of Indian pedigrees [Fujigasaki et al 2001; Srivastava et al 2001; Sinha et al 2004b; Srivastava et al, unpublished observations]; and recent reports of cases in Italy [Brussino et al 2010] and China [Wang et al 2011a].

The diagnosis of SCA12 should be considered in the following:

  • Individuals of Indian descent who:
    • Develop an action tremor of the upper extremities in mid-life;
      Note: The action tremor of the arms and/or head in individuals with SCA12 may initially resemble essential tremor.
    • Later develop a wide range of findings, including mild cerebellar dysfunction, hyperreflexia, and parkinsonian features.
  • Individuals who are not Indian but have a similar clinical presentation that may also include:
    • A mild gait abnormality and more prominent parkinsonian features;
    • Psychiatric disorders and dementia in some of the oldest individuals.

Brain CT or MRI. Neuroimaging reveals cerebral and/or cerebellar atrophy without evidence of focal lesions [O'Hearn et al 2001; Fujigasaki et al 2001; Srivastava et al 2001; Brussino et al 2010; Sinha et al, unpublished observations; Srivastava et al, unpublished observations]. In many individuals with SCA12, the cerebral cortex is more atrophic than the cerebellar cortex. Atrophy of the cerebellar vermis is more prominent than atrophy of the cerebellar hemispheres.

Basal ganglia, thalamus, brain stem nuclei, and other subcortical brain regions are relatively spared.

Molecular Genetic Testing

PPP2R2B is the only gene in which mutation is known to cause SCA12.

The only known pathogenic PPP2R2B allele is a CAG expansion located within or just upstream from exon 7. The repeat appears to fall in a functional promoter for one of the multiple PPP2R2B splice variants.

Allele Sizes

Normal alleles. 4-32 CAG triplets

Mutable normal alleles. No information is yet available. The skew in the Indian population toward longer normal allele lengths than are observed in European populations may be relevant [Fujigasaki et al 2001; Srivastava et al 2001; Sinha et al, unpublished observations]

Reduced-penetrance alleles. The threshold for complete penetrance is not clear. In the index family, with repeat lengths ranging from 66 to 78 triplets, penetrance was complete. Case reports suggest that some individuals from other pedigrees with an allele in the expanded range may either have very late-onset disease or never develop the disease.

  • Two Northern Germans with ataxia had CAG repeats of 40 and 41 triplets; it is unclear if their ataxia was related to the expansions [Hellenbroich et al 2004].
  • A 28-year-old unaffected individual from India with no known family history of degenerative neurologic disorder had a CAG repeat of 45 triplets, a finding of uncertain significance [Fujigasaki et al 2001].
  • An individual with typical Creutzfeld-Jacob disease (CJD) (see Prion Diseases) had an allele of 49 triplets at the SCA12 locus; the relationship between the CJD and the expansion is unknown [Hellenbroich et al 2004].
  • A 46-year-old woman with SCA12 from Changsha in the Hunan region of China was reported to have 51 repeats. Disease onset was at age 34 years with mild progressive upper- and lower-limb ataxia, dysarthria, and dysphagia. MRI showed mild cerebellar cortical atrophy with little change over 12 years. International Cooperative Ataxia Rating Scale (ICARS) score was 6 at 12 years after symptom onset. An asymptomatic younger brother and an asymptomatic daughter had alleles of 52 repeats.
  • In an Italian kindred with SCA12, a sister of the proband who had 57 repeats was unaffected at age 70 years.
  • A 52-year-old woman from India with an allele of 62 CAG triplets did not show symptoms.

Alleles of unstable repeat length. Repeats in the expanded range appear to be modestly unstable, with length variations of a few triplets among members of a sibship. This information is based on expanded alleles identified in ten members of the American family, 18 individuals from the six published Indian families [Holmes et al 1999, Fujigasaki et al 2001, Srivastava et al 2001], and 20 individuals from 12 unrelated families [Wadia et al 2005].

Clinical Testing

Targeted analysis for pathogenic variants using PCR. The PCR assay determines within one to two triplets the length of the CAG repeat in PPP2R2B. The test should detect nearly all expanded alleles.

Table 1.

Summary of Molecular Genetic Testing Used in the Diagnosis of Spinocerebellar Ataxia Type 12

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
PPP2R2BTargeted analysis for pathogenic variantsCAG repeat expansion within or just upstream from exon 7Nearly 100%

See Molecular Genetics for information on allelic variants.


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

Interpretation of test results. The diagnosis of SCA12 can be excluded if two alleles are detected and neither is longer than 32 CAG triplets.

Targeted analysis for pathogenic variants in PPP2R2B should detect nearly all expanded alleles. However, it is possible that expanded alleles may not be detected if a normal variant is present at the primer hybridization site or if the repeat expansion is unusually long. Therefore, results showing only a single allele, while probably reflecting homozygosity, should be interpreted with caution. Southern blotting may help confirm homozygosity.

Testing Strategy

To confirm/establish the diagnosis in a proband, detection of an abnormal CAG expansion in PPP2R2B is mandatory.

Clinical Characteristics

Clinical Description

Spinocerebellar ataxia type 12 (SCA12) typically presents with action tremor of the arms or head followed by development of mild ataxia and/or limb dysmetria, along with generalized hyperreflexia; however, intrafamilial variability can be considerable.

Onset ranges from age eight to 62 years, but is typically in midlife. The mean age of onset in the index SCA12 kindred [Holmes et al 1999] was 34 years and in a series of individuals of Indian descent, 38 years [Wadia et al 2005].

The action tremor is most prominent in the limbs, but can occur in the trunk, neck, lips, and tongue [Wadia et al 2005]. Postural tremor (tremor at rest) and intention tremor (tremor with purposeful movements) are also observed.

Signs of cerebellar dysfunction (e.g., ataxia, dysmetria) tend to be less prominent and less disabling in individuals with SCA12 than in other types of SCA.

Some members of the American pedigree developed bradykinesia or dementia. Eight of the ten affected individuals of the American pedigree have the combination of action tremor of the head or arms, hyperreflexia, mild cerebellar dysfunction, subtle bradykinesia, and paucity of spontaneous movement.

In contrast, individuals of Indian descent tend to have fewer parkinsonian features; some have pyramidal signs and cognitive impairment. Some Indian families have prominent cerebellar findings. As many as 50% of affected individuals of Indian descent have a sensory or sensory motor neuropathy.

SCA12 progresses slowly and may not have a major impact on longevity. Several affected individuals in the American kindred with SCA12 remained employed throughout adulthood.

Three affected members of two Italian families, each with an expanded repeat of 57 triplets, had onset between age 45 and 60 years with action tremor of head and hands, impaired fine motor movements, or gait instability. Progression was also slow.


Preliminary findings in the brain of one individual with SCA12 suggest atrophy of the cerebral cortex and loss of cerebellar Purkinje cells, without evidence of tangles, senile plaques, Lewy bodies, or Pick bodies [O'Hearn, unpublished data].

Genotype-Phenotype Correlations

With evaluation of increasing numbers of affected individuals from India, a correlation between longer repeat length and younger age of onset has been detected [Srivastava & Mukherji, unpublished data].

Homozygosity. A 25-year-old Indian man with allele lengths of 61 CAG repeats and 65 CAG repeats (son of the 52-year-old clinically unaffected woman discussed in Allele Sizes, Reduced-penetrance alleles) is asymptomatic, suggesting that homozygosity is not lethal nor is it related to a markedly more severe phenotype. Longitudinal assessment will be required to determine if the homozygous phenotype differs from the heterozygous phenotype.


The penetrance is unknown, but as noted some individuals with an expansion may have a very late onset, or potentially may never develop the disease. However, relatively few at-risk individuals without clinical evidence of SCA12 have been tested.


A moderate degree of anticipation has been observed in SCA12.


The presence of SCA12 in more than 35 families from India appears to make SCA12 the second most common form of SCA in India, less prevalent than SCA2 and equal to or slightly more prevalent than SCA1 [Srivastava et al 2001; Sinha et al 2004a; Sinha et al 2004b; Bahl et al 2005; Sinha 2005; Srivastava et al, unpublished data].

SCA12 has been detected primarily in a single ethnic group from northern India [Sinha et al 2004b, Bahl et al 2005].

SCA12 has been detected in a single family in North America [Holmes et al 1999, Cholfin et al 2001, O'Hearn et al 2001, Holmes et al 1999, Fujigasaki et al 2001, Worth & Wood 2001, Brusco et al 2004, Hellenbroich et al 2004].

Two of 159 unrelated Italian patients with cerebellar ataxia were found to have SCA12, both from the Ferrara Province of northeastern Italy [Brussino et al 2010].

No cases of SCA12 were detected among 1598 individuals with ataxia in Poland [Sułek-Piatkowska et al 2010].

No cases of SCA12 were detected among 45 autosomal dominant ataxia families in Portugal [Vale et al 2010] (see Allele Sizes, Alleles of unstable repeat length for possible exceptions).

Among persons who presented with ataxia of unknown etiology, one individual in Singapore [Zhao et al 2002] and two in China [Jiang et al 2005, Xie et al 2005] were found to have SCA12. Additional clinical information about these three individuals and their families has not been reported.

Differential Diagnosis

The key to the differential diagnosis of spinocerebellar ataxia type 12 (SCA12) is the presence of prominent upper-extremity tremor; minimal gait ataxia; a variety of signs and symptoms associated with the cerebral cortex, the cerebellum, and in some cases the basal ganglia; slow progression; and a dominant pattern of inheritance. SCA12 typically has a more prominent action tremor and fewer signs of cerebellar dysfunction than other SCAs.

Diagnoses to consider in the differential diagnosis:

  • Familial essential tremor in its more severe forms could mimic SCA12.
  • SCA2, SCA3, SCA6, and DRPLA may occasionally include action tremor.
  • Ataxia associated with FGF14 pathogenic variants includes tremor, although this disease tends to have more prominent cerebellar findings than SCA12 [van Swieten et al 2003].
  • SCA14. Axial myoclonus in a Japanese pedigree could potentially be confused with the action tremor of SCA12.
  • Multiple system atrophy may include a variety of signs and symptoms that mimic SCA12.
  • Familial forms of Creutzfeldt-Jakob disease may present with action tremor (see Prion Diseases).
  • A small Japanese family with a somewhat different phenotype and without the SCA12 repeat expansion has been mapped to a region of chromosome 5q that includes PPP2R2B [Sato et al 2010].


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 12, the following evaluations are recommended:

  • Medical history
  • Tremor rating and gait ataxia assessment
  • Evaluation for peripheral neuropathy and autonomic dysfunction
  • Radiologic investigation to evaluate for associated brain structural damage which can influence the disease course

Treatment of Manifestations

Symptomatic treatment including the following may be of great value:

  • Pharmacologic agents, including beta-blockers, clonazepam and phenobarbital derivatives, and benzodiazepines to decrease tremor amplitude. Modest success has been observed in some affected individuals.
  • Supplements of antioxidants, which may have some beneficial effects. However, their effect on disease outcome has not been validated through clinical trials.
  • Treatment of psychiatric syndromes as needed
  • Physical therapy to help maintain strength, flexibility, and independent mobility
  • Technical assistance with writing and other fine-motor tasks

Prevention of Secondary Complications

A safe home environment can minimize the risk of injury from falls.


Annual reevaluation may be helpful for disability assessment and identification of comorbidities.

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 in the US and in Europe 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.



  • Education of affected individuals and their families
  • Neuroimaging studies as appropriate to exclude the presence of other lesions, particularly after falls

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 12 (SCA12) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with SCA12 have an affected parent.
  • De novo pathogenic variants causing SCA12 have not been reported but are possible.
  • It is appropriate to offer molecular genetic testing to a symptomatic parent.

Note: Although most individuals diagnosed with SCA12 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 the proband depends on the genetic status of the proband's parents: if a parent of the proband is affected or has the PPP2R2B expansion, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • Although it is conceivable that an expanded allele at or near the disease threshold in a parent could expand to a fully penetrant allele in transmission to one sib but remain unexpanded in another sib, such a situation has not yet been reported.

Offspring of a proband. Each child of an individual with SCA12 has a 50% chance of inheriting the pathogenic variant.

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 PPP2R2B expansion and/or is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with SCA12 has the PPP2R2B expansion or clinical evidence of the disorder, it is possible that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Presymptomatic testing. To the best of the authors' knowledge, presymptomatic testing of at-risk adults has not yet been implemented in either the United States or Europe, although such testing could be considered if the limitations of the current knowledge about SCA12 are clearly stated to individuals considering presymptomatic testing. The concerns are that the minimum length of expansion necessary for disease, the penetrance of different repeat lengths near the disease threshold, and the association between age of onset and repeat length have not been well established. As additional individuals with SCA12 are reported, the reliability of clinical predictions based on the length of the SCA12 expansion will increase. One approach could be to assign at-risk individuals with an expansion of 51 or more triplets a status of "high probability."

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic PPP2R2B expansion has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for SCA12 are possible. Abnormal test results do not predict the age of onset or severity of the disease.

Requests for prenatal testing for typically adult-onset conditions that do not affect intellect are not common. While cognitive impairment may be a late manifestation of SCA12, it is less prominent than in many other neurodegenerative disorders. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


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.

  • 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)
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    Lincoln House, Kennington Park, 1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: +44 (0) 207 582 1444
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
  • NCBI Genes and Disease
  • Spanish Ataxia Federation (FEDAES)
    Phone: 34 983 278 029; 34 985 097 152; 34 634 597 503
  • Spinocerebellar Ataxia: Making an Informed Choice about Genetic Testing
    Booklet providing information about Spinocerebellar Ataxia
  • CoRDS Registry
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423

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 12: Genes and Databases

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.

Table B.

OMIM Entries for Spinocerebellar Ataxia Type 12 (View All in OMIM)


Molecular Genetic Pathogenesis

The CAG repeat expansion associated with spinocerebellar ataxia type 12 (SCA12) appears to be located within a promoter region of PPP2R2B [Holmes et al 1999]. PPP2R2B is a brain-specific regulatory subunit of the protein phosphatase PP2A, an enzyme implicated in a wide array of cellular processes, including apoptosis. Preliminary evidence suggests that the SCA12 repeat expansion may alter the level of expression of one or more splice variants of PPP2R2B [Lin et al 2010; Margolis, Holmes, O'Hearn, unpublished observation] by influencing the efficiency of the promoter driving expression. However, PPP2R2B structure is quite complex. At least seven splice variants with probable consequences for protein function exist, each potentially under a different promoter (NCBI gene ID 5521). Two of the splice variants include the CAG repeat in 5’UTR of PPP2R2B. The exact role of CAG expansion on expression and function of PPP2R2B and its protein products remains to be determined.

Gene structure. The CAG repeat expansion associated with SCA12 appears to be located within a promoter region of PPP2R2B, the gene encoding PPP2R2B, and is located immediately upstream of what has been designated exon 1 of PPP2R2B. Additional analysis suggests that this exon is actually the seventh in the gene, and that rare transcripts may include the repeat in the 5' UTR. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The only known pathogenic allele in PPP2R2B is the CAG expansion. The possibility of other variant types has not been investigated.

Normal gene product. PPP2R2B is a brain-specific regulatory subunit of the protein phosphatase PP2A (serine/threonine protein phosphatase 2A, 55-kd regulatory subunit B, beta isoform), an enzyme implicated in a wide array of cellular processes, including apoptosis [Van Hoof & Goris 2003]. PP2A consists of three separately encoded protein units: a catalytic unit (two different isoforms in humans), a structural unit (two different forms in humans), and a regulatory unit (over 30 different forms in humans). It is variation in the nature of the N-terminal region of the regulatory unit that directs the holoenzyme to different substrates [Dagda et al 2003]. PPP2R2B is variably spliced, with at least seven different splice variants so far detected. The splice variants differ by their initial exons. Each variant 5' region appears to encode a Bbeta protein with a different N-terminal region. This N-terminal region appears to be critical in determining the substrate with which the holoenzyme interacts or its subcellular localization.

Abnormal gene product. Preliminary evidence suggests that CAG repeats in the full penetrance allele size range may alter the level of expression of one splice variant (termed Bbeta1) of PPP2R2B by influencing the efficiency of the promoter driving expression of the Bbeta1 transcript [Lin et al 2010; Hwang, Holmes, O'Hearn, & Margolis, unpublished observation]. PP2R2B isoform-b (Bβ2) encoded by transcript variant 4 (NM_181676.2) localizes PP2A to mitochondria with a role in mitochondrial fission in PC12 cell lines [Dagda et al 2008]. In an SCA12 transgenic Drosophila model, overexpression of human PPP2R2B variant encoding Bβ2 or the Drosophila homologue tws resulted in oxidative stress-mediated apoptosis of neuronal cells that was associated with mitochondrial dysfunction [Wang et al 2011b]. It remains possible that the SCA12 expansion could also have an effect on PPP2R2B splicing or could alter gene expression in some other fashion. Thus far, there is little evidence to suggest that the repeat is translated into polyglutamine.


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Chapter Notes

Author History

Susan E Holmes, PhD (2004-present)
Russell L Margolis, MD (2004-present)
Mitali Mukherji, PhD (2004-present)
Elizabeth O'Hearn, MD; Johns Hopkins University (2004-2012)*
KK Sinha, MD, FRCP (2004-present)
Achal K Srivastava, MBBS, MD, DM (2004-present)

*Dr O’Hearn died November 15, 2012

Revision History

  • 17 November 2011 (me) Comprehensive update posted live
  • 12 March 2007 (cd) Revision: mutation scanning no longer clinically available
  • 20 February 2007 (me) Comprehensive update posted live
  • 1 October 2004 (me) Review posted live
  • 1 June 2004 (rm) Original submission
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