SNOMEDCT: 719208005; ORPHA: 98762; DO: 0050962;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q32 | Spinocerebellar ataxia 12 | 604326 | Autosomal dominant | 3 | PPP2R2B | 604325 |
A number sign (#) is used with this entry because spinocerebellar ataxia-12 (SCA12) is caused by a heterozygous expansion of a CAG repeat in a brain-specific regulatory subunit of the protein phosphatase PP2A (PPP2R2B; 604325) on chromosome 5q32.
Normal alleles carry 7 to 32 triplets, whereas disease alleles carry 51 to 78 triplets (Bahl et al., 2005).
For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
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.
The transmission pattern of SCA12 in the family reported by Holmes et al. (1999) was consistent with autosomal dominant inheritance.
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 with SCA12. 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 (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 (183086), 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.
Bahl, S., Virdi, K., Mittal, U., Sachdeva, M. P., Kalla, A. K., Holmes, S. E., O'Hearn, E., Margolis, R. L., Jain, S., Srivastava, A. K., Mukerji, M. Evidence of a common founder for SCA12 in the Indian population. Ann. Hum. Genet. 69: 528-534, 2005. [PubMed: 16138911] [Full Text: https://doi.org/10.1046/j.1529-8817.2005.00173.x]
Cholfin, J. A., Sobrido, M.-J., Perlman, S., Pulst, S. M., Geschwind, D. H. The SCA12 mutation as a rare cause of spinocerebellar ataxia. Arch. Neurol. 58: 1833-1835, 2001. [PubMed: 11708992] [Full Text: https://doi.org/10.1001/archneur.58.11.1833]
Fujigasaki, H., Verma, I. C., Camuzat, A., Margolis, R. L., Zander, C., Lebre, A.-S., Jamot, L., Saxena, R., Anand, I., Holmes, S. E., Ross, C. A., Durr, A., Brice, A. SCA12 is a rare locus for autosomal dominant cerebellar ataxia: a study of an Indian family. Ann. Neurol. 49: 117-121, 2001. [PubMed: 11198281]
Holmes, S. E., O'Hearn, E. E., McInnis, M. G., Gorelick-Feldman, D. A., Kleiderlein, J. J., Callahan, C., Kwak, N. G., Ingersoll-Ashworth, R. G., Sherr, M., Sumner, A. J., Sharp, A. H., Ananth, U., Seltzer, W. K., Boss, M. A., Vieria-Saecker, A.-M., Epplen, J. T., Riess, O., Ross, C. A., Margolis, R. L. Expansion of a novel CAG trinucleotide repeat in the 5-prime region of PPP2R2B is associated with SCA12. (Letter) Nature Genet. 23: 391-392, 1999. [PubMed: 10581021] [Full Text: https://doi.org/10.1038/70493]
O'Hearn, E., Holmes, S. E., Calvert, P. C., Ross, C. A., Margolis, R. L. SCA-12: tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion. Neurology 56: 299-303, 2001. [PubMed: 11171892] [Full Text: https://doi.org/10.1212/wnl.56.3.299]
Schalling, M., Hudson, T. J., Buetow, K. H., Housman, D. E. Direct detection of novel expanded trinucleotide repeats in the human genome. Nature Genet. 4: 135-139, 1993. [PubMed: 8348150] [Full Text: https://doi.org/10.1038/ng0693-135]
Srivastava, A. K., Choudhry, S., Gopinath, M. S., Roy, S., Tripathi, M., Brahmachari, S. K., Jain, S. Molecular and clinical correlation in five Indian families with spinocerebellar ataxia 12. Ann. Neurol. 50: 796-800, 2001. [PubMed: 11761478] [Full Text: https://doi.org/10.1002/ana.10048]