Holmes et al. (1999) identified a novel form of autosomal dominant spinocerebellar ataxia (SCA), termed SCA12, in a large pedigree, 'R,' of German descent. The phenotype was variable, but the prototypic phenotype was that of a classic spinocerebellar ... Holmes et al. (1999) identified a novel form of autosomal dominant spinocerebellar ataxia (SCA), termed SCA12, in a large pedigree, 'R,' of German descent. The phenotype was variable, but the prototypic phenotype was that of a classic spinocerebellar ataxia, and the disease resembled the spinocerebellar ataxias more closely than any other form of neurodegenerative disorder. Age of onset ranged from 8 to 55 years. Most individuals presented in the fourth decade with upper extremity tremor, progressing over several decades to include head tremor, gait ataxia, dysmetria, dysdiadokinesis, hyperreflexia, paucity of movement, abnormal eye movements, and, in the oldest subjects, dementia. MRI or CT scans of 5 cases indicated both cortical and cerebellar atrophy. O'Hearn et al. (2001) further characterized the phenotype of the 'R' pedigree and found that action tremor of the head and arms was the most distinguishing feature in comparison to other dominant SCAs. Bahl et al. (2005) reported 25 patients from 20 Indian families with SCA12 who were all members of an endogamous group with origins in the state of Haryana in northern India. Five of the families had been previously reported by Srivastava et al. (2001). Age at onset ranged from 26 to 56 years (mean of 40.2 years), and most presented with upper extremity tremor. Other features included hyperreflexia, dysarthria, and mild or no gait ataxia. Two individuals had axial dystonia, and 3 had facial myokymia. Almost half of patients had a subclinical sensory or sensorimotor neuropathy. Brain MRI or CT scan showed cerebellar and cerebral cortical atrophy. Anticipation was not observed.
Holmes et al. (1999) used repeat expansion detection (RED), as described by Schalling et al. (1993), to identify an expanded CAG repeat in the PPP2R2B gene (604325.0001) in the proband and other affected family members. Using PCR analysis, ... Holmes et al. (1999) used repeat expansion detection (RED), as described by Schalling et al. (1993), to identify an expanded CAG repeat in the PPP2R2B gene (604325.0001) in the proband and other affected family members. Using PCR analysis, they demonstrated that the expression was not 1 of 8 CAG repeats associated with a neurodegenerative disease or 1 of 3 CAG repeats known to undergo nonpathogenic expansion. From the proband, they cloned a 2.5-kb genomic clone that contained a repeat of 93 uninterrupted CAGs. There was no apparent correlation between repeat size and age of onset, although the range of expanded alleles was relatively narrow (66 to 78 repeats) and the precise age of onset of tremor, typically the first symptom, was difficult to define in this disorder. Holmes et al. (1999) assessed the PPP2R2B CAG repeat length in 394 unrelated neurologically normal individuals and 1,099 individuals with neurologic diseases; no expansion was detected, suggesting that SCA12 is rare. The CAG tract lies 133 nucleotides upstream of the reported transcription start site of the PPP2R2B gene (604325), encoding a brain-specific regulatory subunit of the protein phosphatase PP2A. The PPP2R2B gene had been mapped to 5q31-q33 between markers D5S436 and D5S470. Although the possibility that the CAG tract may lie within an unidentified gene overlapping or adjacent to PPP2R2B, an antibody probe did not detect polyglutamine expansions in protein derived from lymphoblastoid cell lines of affected family members. A lod score of 4.61 at theta = 0.0 was obtained for linkage between the expanded repeat and the disorder. It was possible that the expansion was in linkage disequilibrium with a second, as-yet-unidentified, causative mutation. However, the correlation between repeat expansion and disease in pedigree R, the lack of expansions in controls, and the known capacity of expansion mutations outside of protein-coding regions to cause disease indicated that the expansion was causative.
In a study of 145 families with autosomal dominant cerebellar ataxia (ADCA), Fujigasaki et al. (2001) identified a family from India in which 6 affected and 3 unaffected members had an expanded CAG repeat in the PPP2R2B gene ... In a study of 145 families with autosomal dominant cerebellar ataxia (ADCA), Fujigasaki et al. (2001) identified a family from India in which 6 affected and 3 unaffected members had an expanded CAG repeat in the PPP2R2B gene (604325.0001). They determined the distribution of normal PPP2R2B repeat length in 157 French and 100 Indian control subjects. In the French population normal alleles contained 9 to 18 CAG triplets, most frequently 10. In the Indian population, lengths of up to 45 CAG triplets were observed, but the most common allele also carried 10 triplets. Among 293 individuals with ADCA from 77 Indian families, Srivastava et al. (2001) found an expanded SCA12 repeat in 6 patients and 3 asymptomatic at-risk individuals from 5 families, which accounted for 7% of the ADCA cases. The expanded allele length ranged from 55 to 69 repeat units. Notable clinical features included age of onset from 26 to 50 years, initial presentation of hand tremor, lack of dementia, and evidence of a subclinical sensory and motor neuropathy. Of the 77 families, SCA1 (164400) mutation was found in 15.6%, SCA2 (183090) in 24.7%, and SCA3 (109150) and SCA7 (164500) in 2.6% each. SCA6 (186086), SCA8 (603680), and DRPLA (607462) mutations were not found. In an ataxia clinic in California, Cholfin et al. (2001) screened 180 kindreds for the SCA12 mutation. The patients were of highly diverse ethnic origins. None was found to carry the SCA12 expansion. The authors concluded that the SCA12 mutation is a rare cause of spinocerebellar degeneration but that it should be considered in patients with an atypical clinical phenotype, especially when tremor is initially present. Among 20 families from northern India with SCA12, Bahl et al. (2005) identified expanded CAG repeats ranging from 51 to 69 triplets. Unaffected individuals had repeats ranging from 8 to 23 triplets. Of note, 1 asymptomatic individual was homozygous for an expanded repeat (52 and 59 triplets). Haplotype analysis identified 1 haplotype that was associated with the disease alleles, indicating a common founder. Bahl et al. (2005) estimated that SCA12 accounts for about 16% of all ADCA cases in northern India.
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]....
DiagnosisClinical DiagnosisClinical 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 TestingGene. PPP2R2B is the only gene in which mutation is known to cause SCA12. The only known pathologic PPP2R2B allele is a CAG expansion mutation 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 An allele with four CAG triplets, detected in an individual of German descent with ataxia and probably unrelated to SCA12, represents the smallest normal allele observed [Hellenbroich et al 2004]. The largest normal allele has 32 CAG repeats; however, the range seems to become wider as more individuals are tested. The most common repeat length in all samples studied to date is ten triplets [Holmes et al 1999; Cholfin et al 2001; Fujigasaki et al 2001; Srivastava et al 2001; Worth & Wood 2001; Zhao et al 2002; Brusco et al 2004; Sułek et al 2004; Tsai et al 2004; Sinha et al, unpublished data] 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 mutation analysis 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 12View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityPPP2R2BTargeted mutation analysisCAG repeat expansion within or just upstream from exon 7Nearly 100%Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated geneInterpretation of test results. The diagnosis of SCA12 can be excluded if two alleles are detected and neither is longer than 32 CAG triplets. Targeted mutation analysis of 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. Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband, detection of an abnormal CAG expansion in PPP2R2B is mandatory. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersMutations in PPP2R2B have not been clearly associated with other phenotypes. Of note, an Iranian woman with unipolar depression and her monozygotic twin sons with schizophrenia all had a PPP2R2B allele with a 53 CAG triplet repeat [Holmes et al 2002]. It is unknown if the expansion is causally related to the psychiatric disorders in this family, or if the family had undiagnosed features of SCA12. Aside from this Iranian pedigree (see Alleles of unstable repeat length), SCA12 expansions have not been detected in individuals with bipolar disorder, schizophrenia, or Alzheimer disease [Laurent et al 2003; Holmes, unpublished data]
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....
Natural HistorySpinocerebellar 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.
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]. ...
Genotype-Phenotype CorrelationsWith 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 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 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....
Differential DiagnosisThe 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 mutations 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].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 12, the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 12, the following evaluations are recommended:Medical historyTremor rating and gait ataxia assessmentEvaluation for peripheral neuropathy and autonomic dysfunctionRadiologic investigation to evaluate for associated brain structural damage which can influence the disease courseTreatment of ManifestationsSymptomatic 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 Technological assistance with writing and other fine-motor tasks Prevention of Secondary ComplicationsA safe home environment can minimize the risk of injury from falls.SurveillanceAnnual reevaluation may be helpful for disability assessment and identification of comorbidities.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.OtherRecommended:Education of affected individuals and their families Neuroimaging studies as appropriate to exclude the presence of other lesions, particularly after falls
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPPP2R2B5q32Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoformPPP2R2B homepage - Mendelian genesPPP2R2BData 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 12 (View All in OMIM) View in own window 604325PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B, BETA; PPP2R2B 604326SPINOCEREBELLAR ATAXIA 12; SCA12Molecular Genetic PathogenesisThe 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 mutation on expression and function of PPP2R2B and its protein products remains to be determined. Normal allelic variants. 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. Pathologic allelic variants. The only known pathologic allele in PPP2R2B is the CAG expansion mutation. The possibility of other mutation 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.