|Year : 2019 | Volume
| Issue : 2 | Page : 48-57
Spinocerebellar ataxia type 12: An update
Deepak Kumar1, Achal K Srivastava1, Mohammad Faruq2, Varun R Gundluru1
1 Department of Neurology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
2 CSIR Institute of Genomics and Integrative Biology, New Delhi, India
|Date of Web Publication||13-Aug-2019|
Prof. Achal K Srivastava
Department of Neurology, Room No. 60 GF, CN Center, All India Institute of Medical Sciences, New Delhi 110029
Source of Support: None, Conflict of Interest: None
Spinocerebellar ataxia type 12 (SCA12) is a progressive neurological disorder with a unique prevalence in North Indian population. Trinucleotide CAG repeat expansion beyond certain threshold (>43 repeats) in the upstream region of PPP2R2B gene is associated with cerebello-cortical atrophy in disease affected individuals. Patients with SCA12 predominantly manifest unique distinguishable feature of early slow and progressive action tremor in upper extremities followed by other variable symptoms such as mild to moderate gait ataxia, speech disturbances with tremulous voice, head tremor, and autonomic abnormalities. At present, there is no definite treatment available to cure this disease and the underlying disease mechanism at molecular level largely remains undetermined. This review focuses on epidemiology, clinico-genetic advancements, and therapeutics interventions emerged over the time in this field.
Keywords: Neurodegeneration, PPP2R2B gene, spinocerebellar ataxia type 12, trinucleotide repeat expansion
|How to cite this article:|
Kumar D, Srivastava AK, Faruq M, Gundluru VR. Spinocerebellar ataxia type 12: An update. Ann Mov Disord 2019;2:48-57
|How to cite this URL:|
Kumar D, Srivastava AK, Faruq M, Gundluru VR. Spinocerebellar ataxia type 12: An update. Ann Mov Disord [serial online] 2019 [cited 2020 Feb 23];2:48-57. Available from: http://www.aomd.in/text.asp?2019/2/2/48/264361
SCA12 is a progressive neurodegenerative disease with a unique clinical feature of high amplitude and low frequency hands tremor at onset with or without minimal gait ataxia as a prominent phenotype.
It is caused by CAG repeats expansion of more than 43 copies in 5' region of PPP2R2B gene. At present there is no definitive treatment for curing this disorder.
| Introduction|| |
Spinocerebellar ataxias (SCAs) are a group of autosomal-dominant progressive cerebellar degeneration, which mainly presents as a motor and/or speech incoordination. Involvement of other parts of nervous system has also been variably associated. To date, approximately 46 subtypes of genetically distinct SCAs, which show cerebellar and/or non-cerebellar symptoms, have been reported. A larger fraction of these inherited ataxias are caused by an abnormal tandem trinucleotide repeats expansion in DNA of the respective gene (e.g., SCA1; ATXN1, SCA2; ATXN2, SCA3; ATXN3, and SCA12; PPP2R2B), whereas large numbers of other mutations such as substitution/indel are the causes of other forms of these inherited ataxias (SCA5, SCA13, and SCA28). SCAs have differential occurrence as reported across various geographical and ethnic groups worldwide. For instance, SCA3/Machado–Joseph disease is the most common SCA subtype reported worldwide, whereas SCA2 is the most common SCA in India and Cuba. Some ataxias are population specific, for example, SCA10 is mainly found in Brazilian and Mexican populations, and SCA12 is also common in northern Indian population. SCA12 was first described by Holmes et al. in a German-American kindred who had complaints of hand tremor accompanied by symptoms of cerebellar ataxia in later years of life. Affected individuals also developed features of Parkinsonism More Details, psychiatric manifestations, dementia, and autonomic abnormalities in later stages. Subsequently, the majority of cases have been reported from India., SCA12 is caused by the abnormal CAG repeats expansion in 5’ untranslated region of PPP2R2B gene at locus 5q32. This gene encodes the regulatory part of serine/threonine phosphatase enzyme PP2A, implicated in the regulation of protein phosphorylation, cell cycle, development, cytoskeletal assembly, cell growth, differentiation, and signaling., So far the exact pathogenesis is not known; however, it has been hypothesized that the CAG repeats expansion may dysregulate the expression of PPP2R2B gene, which may be the key underlying abnormality. Neuroimaging shows degenerative changes in cerebral and cerebellar regions of patients with SCA12. Studies in the literature pointed toward several presumptive hypotheses, particularly emphasizing on PPP2R2B-encoded isoforms, Bβ1 and Bβ2; however, the actual underlying disease mechanism is still undetermined.,,,
| Epidemiology of SCA12|| |
Initial observations: In the first report of SCA12, Holmes et al. presented clinico-genetic spectrum of the total 10 affected individuals of a family of German-American descent. The first manifestation of many individuals of the reported family was hand tremor followed by slowly progressive cerebellar dysfunctions in later course of the disease. The length of expanded CAG allele was in the range of 66–78 copies. Subsequently, Fujigasaki et al. screened 247 individuals with cerebellar ataxia and found only a single family of Indian origin who was carrying the pathogenic mutation. Thereafter, Srivastava et al. reported cerebellar ataxia in five unrelated families that were positive for PPP2R2B gene mutation from India in which mean age of onset was 37.2 years (26–50 years). They presented the clinical data of six affected individuals. The size of expanded allele ranged from 55 to 69 copies in six affected members, and three asymptomatic carriers of these families had repeat length of 55, 55, and 66 copies, respectively. Six affected individuals presented hand tremor as an initial symptom followed by cerebellar ataxia. Other clinical features such as dysarthria, slow saccades, brisk reflexes, broken pursuit, dementia, and electrophysiological abnormalities were also noted. Later, Sinha et al. showed that parkinsonism rarely presented in 15 cases of SCA12. In addition, the length of CAG repeated expansion was also similar to the previous reports (53–69 copies).
| SCA12 in Other Parts of the World|| |
Apart from India, very few cases of SCA12 have been reported so far.,,,,,,,,,,, To estimate the epidemiology and ethnic differences of dominantly inherited ataxias, Zhao et al. conducted a study in Singapore. They tested 204 patients with ataxia and found a single patient affected with SCA12 among other prevalent forms of SCAs. Similarly, Jiang et al. studied 120 inherited autosomal-dominant and 60 sporadic cases of SCAs and identified a single SCA12 affected individual in Mainland China. In Germany, Hellenbroich et al. presented a case having Creutzfeldt–Jakob disease with CAG repeats expansion of 49 copies in the allele of PPP2R2B gene. This study further screened 1028 patients with cerebellar ataxia and in addition, identified two cases that carried low range of CAG repeats expansion of 41 and 42 copies in PPP2R2B gene. To determine the general prevalence of SCA12 in Italian population, Brussino et al. screened 159 patients with SCA and identified only two families that carried PPP2R2B gene mutation. In their study, they found overall five clinically affected SCA12 and two asymptomatic cases. Dong et al. explored CAG repeats expansion in PPP2RB gene in 29 uncharacterized cases of SCAs in Southwest China. The result showed three families carried SCA12 mutation with 46 repeats. Among the affected individuals of the family, they observed that nystagmus and dysphagia were uncommon compared to cerebellar ataxia.
Though, SCA12 mutation was first discovered in the United States of America but, later on, several families of disease affected individuals have been identified in Indian population. In 2017, Srivastava et al. described the clinical manifestations of SCA12 cases who carried 43–50 copies of CAG repeats expansion and correlated with clinical features of SCA12 cases who carried 51 copies of CAG repeats expansion. This study highlighted different clinical spectrum of SCA12 and established a new pathogenic cutoff length of 43 copies of CAG repeats expansion for the diagnosis of SCA12. Similarly, in a recent report, Choudhury et al. presented clinical characteristics of 21 genetically confirmed SCA12 cases and suggested that SCA12 is not uncommon as it was previously presumed to be. [Table 1] represents worldwide occurrence of SCA12.
| Co-occurrence of SCA12 with Other Neurological Disorders|| |
Co-occurrence of PPP2R2B gene mutation with other mutation or diseases has been reported [Table 1]. One Iranian family with psychiatric diseases (woman with bipolar disorder along with her twin sons having schizophrenic features) was shown to be associated with 53 copies of CAG repeats expansions. In Germany, a case of Creutzfeldt–Jakob disease was reported to have a pathogenic CAG length of 49 repeats. Similarly, a patient having both SCA12 and SCA2 mutations was found in India. The significance of repeats in these kindred still needs to be explored.
| Clinical and Pathophysiological Features of SCA12|| |
Clinical features of SCA12
SCA12 has a widely variable disease onset ranging from 8 to 62 years but it is usually seen in midlife. In the index SCA12 kindred, the mean age of onset was 34 years, which was similar to the first report in Indian kindred (37.2 years)., However, the disease can develop in the later stage of life. For example, the recent case series involving 21 Indian patients with genetically confirmed SCA12 showed the mean disease onset to be approximately 51.33 years. In earlier kindred, predominantly males were affected, but females can also be equally affected as presented in the later report.,
Clinical manifestations of SCA12 are variable including cerebellar dysfunctions, tremor, gait dysfunction, extrapyramidal features, pyramidal weakness, cognitive, and behavioral disturbances. Tremor, particularly action tremor, is the most common initial presentation of SCA12. This usually begins in the adulthood, and also can be confused with essential tremor (ET) and Parkinson’s disease, leading to diagnostic errors in the early course of illness. The diagnosis of SCA12 may be delayed because the classic cerebellar ataxia, which is a hallmark clinical feature for diagnosing SCA develops many years after the onset of hand tremor. Recently, Choudhury et al. characterized the hand tremors of SCA12. They proposed that the hand tremors in SCA12 differ from ET in terms of frequency and amplitude of tremor. The frequency of hand tremor in SCA12 is slower and the amplitude is larger compared to that of ET. The amplitude is greatly pronounced when upper limbs are flexed at elbows with hands close to chest. They also conclude that the hand tremor in SCA12 is composed of dystonic, ataxic, and postural tremor. Other than hand tremor, orofacial tremor, lingual tremor, head tremor, voice tremor, trunk tremor and wing beating tremor has been reported, but leg tremor has not been reported. Following hand tremor, another common clinical feature observed is cerebellar dysfunction and gait ataxia. When compared with other forms of SCAs, the cerebellar dysfunction in SCA12 is relatively mild and it predominantly affects the tandem walking., Sometimes cerebellar dysfunction with dysarthria may also be the initial presenting symptom. Extrapyramidal features in the form of rigidity, bradykinesia, and dystonia may be seen with variable frequency. In the older case series of German-American descent, predominant extrapyramidal features were bradykinesia and rigidity with rarely presented dystonia in a few younger patients. In the recent Indian case series, dystonia was the predominant extrapyramidal feature, particularly, hand dystonia. Bradykinesia and rigidity were seen in a less percentage of patients. Falls may be seen in a significant proportion of patients. Pyramidal dysfunctions in terms of hyperreflexia and extensor plantar response were seen in many patients with a few patients having spasticity as well., In some of the patients with hyperreflexia, grasping reflex, rooting reflex, and Myerson’s sign may be present, particularly in older patients. Eye movement abnormalities including slow saccades, broken pursuits, and gaze evoked nystagmus may be observed. No neuropathy was reported in the American cohort, but in both Indian cohorts, neuropathy has been reported with subclinical sensorimotor polyneuropathy in one study, whereas painful muscle cramps (most common), paresthesia, numbness, and proprioceptive dysfunction were detected in another study. Cognitive dysfunction, including poor anterograde memory, disorientation, and executive dysfunction, and psychiatric abnormalities, such as agitation, irritability, depression, anxiety, apathy, hallucinations, and delusions, were also reported., Uncommon neurological abnormalities that were reported in SCA12 included facial myokymia and bladder and bowel disturbances. No correlation between CAG repeats number and clinical phenotype expression was observed. However, recent cases series showed that larger CAG repeats expansion is associated with earlier onset of disease development compared to smaller CAG repeats expansion. All clinical features are summarized in [Table 2].
Interestingly, SCA12 shares several clinical features, such as tremor, gait abnormality, cerebellar dysfunction, and generalized brain atrophy, with Fragile X-associated tremor/ataxia syndrome (FXTAS)., At genetic level, both these disorders arise due to expansion of trinucleotide in 5’ untranslated region of the respective gene. These findings suggest that SCA12 may share some similar disease aspects as FXTAS. As in FXTAS, SCA12 also appears to have two clinical subtypes, which include tremor and gait dominant varieties according to unpublished observation of the authors. This also indicates possible role of genetic modifier in its pathogenesis. Despite these characteristic clinical features, considerable overlap exists between SCA12 and other SCAs and it may not always be possible to diagnose SCA12 on clinical grounds only, requiring genetic testing for confirmation.
Neuroimaging and pathological findings in SCA12
In patients with SCA12, mild to moderate atrophy of cerebellum as well as cerebral cortex with ventriculomegaly with or without subcortical white matter changes and loss of Purkinje cells were observed.,,, In comparison to cerebellar hemispheres, vermis showed more atrophy, whereas no degenerative changes were reported in brain stem and basal ganglia [Figure 1]A–C. Neurometabolic and microstructural changes in the regions of atrophic cerebral cortex and cerebelli were reported in SCA12.,[29 Using diffusion tensor imaging in presymptomatic individuals],[ Li et al. found that initiative changes of the disease firstly occurred in the cerebral cortex and cerebellar vermis. O’Hearn et al. analyzed a SCA12 brain sample and demonstrated the cerebello-cortical degeneration with the loss of Purkinje cells. They also identified the ubiquitin-containing inclusion bodies in substantia nigra pars compacta, motor cortex, and Purkinje cells, which were negative for immunohistochemistry staining of polyglutamine, alpha-synuclein, tau, and transactive response DNA binding protein 43 kDa (TDP-43) proteins. Swarup et al. identified altered expression of plasma proteins of crucial functions (implicated in transport and lipid metabolism) in disease affected individuals. Like many other neurodegenerative disorders, inaccessibility of neuronal tissue is a major factor, which limits the understanding of SCA12. Application of induced pluripotent cells (iPSC) technology has made remarkable impact in the field of neurodegeneration. The unique property of iPSCs is that they can differentiate into several cell types and have capabilities to recapitulate human pathology, thus bypass the need of surgical biopsies. To explore the disease biology, in patient’s own genetic background, Kumar et al. generated SCA12 patient-specific iPSC lines, performed the transcriptomic profiling, and found altered expression of genes in disease state., These may be further used to generate organoids as a functional three-dimensional structures for better understanding of SCA12 pathogenesis.
|Figure 1: Sagittal T2-weighted image (A) shows diffuse vermian atrophy. Axial T1-weighted image (B and C) shows prominent cerebellar folia and cortical sulci suggesting cerebellar and cortical atrophy|
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| Molecular Aspects of SCA12|| |
PPP2R2B gene structure and expression
Total length of PPP2R2B is approximately 493kb. It consists of 16 exons separated with introns and intergenic regions [Figure 2]A. CAG repeats exist in 5’ of PPP2R2B gene. Sixty-nine nucleotide upstream from CAG repeats, a downstream promoter element exists, which is recognized by transcription factor IID. CAG repeat flanked by CREB-1 and SP1, TRAP4 binding site works as a part of functional promoter and modulates its expression. Sixty-five nucleotides downstream from CAG repeats, a multiple start site element downstream-1 is located. After transcription of PPP2R2B gene, several spliced variants that differ in 5’ UTR regions are produced. These variants encode N-terminal differing protein isoforms., Predominant transcription initiation downstream to repeats produces Bβ1 isoforms, whereas isoform Bβ2 expresses through an alternate upstream promoter.,, As per present National Center for Biotechnology Information (NCBI) gene information, 10 splice variants are so far reported (www.ncbi.nlm.nih.gov) [Figure 2]B. Of the various transcript isoforms of PPP2R2B gene, variant 3 (V3) harbor CAG repeats in protein-coding open reading frame (ORF), whereas variant 10 (V10) has repeats in their 5’UTR. Two additional transcripts (V11 and V12) have also been reported to consist of CAG repeats, but due to the presence of 5’ORF and nonsense-mediated mRNA decay sequence, they are considered as noncoding ribose nucleic acids (RNAs). In other variants, CAG tandem units are confined to intronic regions by alternate splicing/exon skipping mechanism. These isoforms encode only seven alternate protein isoforms, that is, e (V3), d (V3 and V10), b (V4), a (V2), c (V5), f (V8), and g (V9).
|Figure 2: (A) Schematic representation of PPP2R2B. (B) PPP2R2B expression producing alternative splice variants. (C) Structure of PP2A heterotrimers complex composed of structural, catalytic and regulatory subunits of different classes. (D) Biological functions of PP2A|
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Transcriptional regulation of PPP2R2B
By using promoter deletion, immunoprecipitation assays, and luciferase experiment, Lin et al. showed that CAG repeats expansion of PPP2R2B gene and its flanking elements regulate its promoter activity. Deletion of CAG repeats and flanking region significantly reduced its promoter activity. Protein CREB-1 and SP1 binding to upstream of CAG was associated with PPP2R2B gene upregulation, whereas TFAP4 binding to downstream of CAG resulted in the downregulation of transcripts. Higher CAG repeats size mediated increased luciferase activity in neuronal cell lines, which was found to be correlated with Bβ1 expression. Decreased number of CAG repeats has also been associated with reduced promoter activity.,
| The Role of PPP2R2B Protein in Various Cellular Processes|| |
PPP2R2B gene encodes one of the regulatory subunit of heterotrimeric enzyme PP2A, which plays a key role in several biological functions,,, [Figure 2C] and [Figure 2D]. PPP2R2B produces majority of isoforms, which differ in N-terminal sequence between 4–27 amino acids. Two isoforms, including Bβ1 and Bβ2, show differential expression pattern with distinct localization of PP2A to cellular compartments and alter the activity of enzyme with respect to phosphorylation of various cellular targets.
Role of PPP2R2B isoforms in pathogenesis of SCA12
Bβ1 protein isoform has cytoplasmic distribution. Overexpression of ectopic Bβ1 construct in human neuroblastoma and human neuroepithelioma, metastasis to supraorbital area (SKNMC) cell line has been shown to increase the basal level of autophagy irrespective of oxidative insults in neuroblastoma cells.[9 Its overexpression also causes neuronal cytotoxicity in rat neurons. Role of Bβ1 isoform has also been shown in cancer. Tan et al. have shown that the epigenetic loss of Bβ1 isoform through promoter hypermethylation may cause rapamycin-resistant colorectal cancer. Bβ2 isoform has unique N-terminal 24 amino acids that recruit heterotrimeric enzyme PP2A to mitochondrial membrane and induce apoptosis by the activation of drp1 by dephosphorylation of its 656th serine residue. This makes it active and induces mitochondrial fragmentation resulting in apoptosis.,, Bβ2 overexpression has been shown to be sensitive to toxic insults such as growth factor deprivation, H2O2, and tunicamycin-induced toxicity (autophagy).
Overexpressing Bβ2 (gene twins fly homologue, tws) drosophila model of SCA12 has shown various disease features including mitochondrial fragmentation, apoptosis, and decrease in fly life span. These transgenic flies were found to be more prone to paraquat. Ectopic expression of superoxide dismutase 2 and antioxidant treatments has shown reduction in reactive oxygen species, caspase 3 activity, and increment in flies’ life expectancy. Advancements in molecular aspects of SCA12 have been summarized in [Table 3].
On the basis of available literature of trinucleotide repeat expansion disorders, the overall CAG expansion mediated pathogenesis might arise due to (1) altered expression of the spliced isoform resulting in alteration of regulatory subunit (B/PPP2R2B) of PP2A, leading to aberrant PP2A activity, including phosphorylation of various cellular targets and gain of target substrates leading to cell death; (2) dysregulation of alternative splicing may alter transcripts isoform diversity, which could form novel transcripts that can harbor CAG repeats in the coding region, resulting in protein isoforms with polyglutamine stretches that cause cellular toxicity like other SCAs; and (3) PPP2R2B gene transcripts carrying an expanded CAG repeat may form unusual RNA structures that can sequester to diverse RNA-binding proteins involved in splicing regulation, ribosomal biogenesis, and double-stranded RNA degradation, leading to form insoluble RNA foci.
| Therapeutic Interventions|| |
No definitive treatment is available for SCA12, which can reverse the disease manifestations. But several beta-blocking compounds such as propanol/primidone are found to be effective in symptomatic relief of tremor in disease-affected individuals. Several anxiolytic drugs, including benzodiazepine, are helpful in the management of psychiatric features of patients. Application of GABAergic drugs (neuropathic pain), baclofen (muscle spasticity), and phosphodiesterase inhibitors (erectile dysfunction) can be helpful in some patients as per requirement. Apart from this, riluzole and some antioxidants drugs have been under trial for other SCA types. Several rehabilitative approaches such as physiotherapy, psychological therapy, and occupational therapy have been showing improvements in some features such as postural stability, motor learning, motor control, and reduced dependency on walking aids as in several types of SCAs., Although application of such rehabilitative approaches has not been formally tested in SCA12, but their use may improve the quality of life of the patients with SCA12 as well. According to an unpublished report, deep brain stimulation has been tried in a patient with SCA12. This approach reduced the tremor but worsened ataxia in the patient.
| Futuristic Therapeutic Options|| |
Besides aforementioned pharmacological and rehabilitative approaches, advancement in cell- and gene-based therapies has shown neuroprotective effects in regenerative medicine. In different SCAs, application of mesenchymal stem cells derived from human umbilical cord has shown delay in the progression of neurologic deficits.,, Similarly, antisense oligonucleotides targeting approach is a promising hope for several genetic disorders including cerebellar ataxias. Such cutting-edge approaches could also be explored from SCA12 point of view and might be a useful method for such a devastating disorder.
Gene editing using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (CAS9) could also be used for repeat correction in these cells, which may bring hope for cell transplantation therapies in future.
| Conclusion|| |
SCA12 is a neurological disorder of unclear pathogenesis with unique prevalence in Indian population. Though literature-based studies point toward several presumptive hypotheses, which may be behind SCA12 pathogenesis, several factors such as presence of clinical heterogeneity, occurrence in an endogamous population, and rarity of the disease, pose a challenge for research on disease pathogenesis, prognosis, and therapeutic interventions. However, studying prevalence, identification of founders, genotype to phenotype correlation, establishment of biorepository of genetic material, and cell lines of patients can provide new leads for prospective translational research.
We are thankful to patients and their family members who have participated in ataxia research. We also wish to acknowledge entire ataxia group members of All India Institute of Medical Sciences and Institute of Genomics and Integrative Biology, Delhi, India, for their valuable contribution in ataxia research program.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Dueñas AM, Goold R, Giunti P Molecular pathogenesis of spinocerebellar ataxias. Brain 2006;129:1357-70.
Durr A Autosomal dominant cerebellar ataxias: Polyglutamine expansions and beyond. Lancet Neurol 2010;9:885-94.
Kumari R, Kumar D, Brahmachari SK, Srivastava AK, Faruq M, Mukerji M Paradigm for disease deconvolution in rare neurodegenerative disorders in Indian population: Insights from studies in cerebellar ataxias. J Genet 2018;97:589-609.
Holmes SE, O’Hearn EE, McInnis MG, Gorelick-Feldman DA, Kleiderlein JJ, Callahan C, et al
. Expansion of a novel CAG trinucleotide repeat in the 5’ region of PPP2R2B is associated with SCA12. Nat Genet 1999;23:391-2.
Bahl S, Virdi K, Mittal U, Sachdeva MP, Kalla AK, Holmes SE, et al
. Evidence of a common founder for SCA12 in the Indian population. Ann Hum Genet 2005;69:528-34.
Srivastava AK, Choudhry S, Gopinath MS, Roy S, Tripathi M, Brahmachari SK, et al
. Molecular and clinical correlation in five Indian families with spinocerebellar ataxia 12. Ann Neurol 2001;50:796-800.
Janssens V, Goris J Protein phosphatase 2A: A highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 2001;353:417-39.
Sangodkar J, Farrington CC, McClinch K, Galsky MD, Kastrinsky DB, Narla G All roads lead to PP2A: Exploiting the therapeutic potential of this phosphatase. FEBS J 2016;283:1004-24.
Cheng WT, Guo ZX, Lin CA, Lin MY, Tung LC, Fang K Oxidative stress promotes autophagic cell death in human neuroblastoma cells with ectopic transfer of mitochondrial PPP2R2B (Bbeta2). BMC Cell Biol 2009;10:91.
Dagda RK, Merrill RA, Cribbs JT, Chen Y, Hell JW, Usachev YM, et al
. The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission. J Biol Chem 2008;283:36241-8.
O’Hearn EE, Hwang HS, Holmes SE, Rudnicki DD, Chung DW, Seixas AI, et al
. Neuropathology and cellular pathogenesis of spinocerebellar ataxia type 12. Mov Disord 2015;30:1813-24.
Wang YC, Lee CM, Lee LC, Tung LC, Hsieh-Li HM, Lee-Chen GJ, et al
. Mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of spinocerebellar ataxia type 12 (SCA12). J Biol Chem 2011;286:21742-54.
Fujigasaki H, Verma IC, Camuzat A, Margolis RL, Zander C, Lebre AS, et al
. SCA12 is a rare locus for autosomal dominant cerebellar ataxia: A study of an Indian family. Ann Neurol 2001;49:117-21.
Sinha KK, Worth PF, Jha DK, Sinha S, Stinton VJ, Davis MB, et al
. Autosomal dominant cerebellar ataxia: SCA2 is the most frequent mutation in eastern India. J Neurol Neurosurg Psychiatry 2004;75:448-52.
Aydin G, Dekomien G, Hoffjan S, Gerding WM, Epplen JT, Arning L Frequency of SCA8, SCA10, SCA12, SCA36, FXTAS and c9orf72 repeat expansions in SCA patients negative for the most common SCA subtypes. BMC Neurol 2018;18:3.
Brusco A, Gellera C, Cagnoli C, Saluto A, Castucci A, Michielotto C, et al
. Molecular genetics of hereditary spinocerebellar ataxia: Mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families. Arch Neurol 2004;61:727-33.
Cholfin JA, Sobrido MJ, Perlman S, Pulst SM, Geschwind DH The SCA12 mutation as a rare cause of spinocerebellar ataxia. Arch Neurol 2001;58:1833-5.
Choubtum L, Witoonpanich P, Hanchaiphiboolkul S, Bhidayasiri R, Jitkritsadakul O, Pongpakdee S, et al
. Analysis of SCA8, SCA10, SCA12, SCA17 and SCA19 in patients with unknown spinocerebellar ataxia: A Thai multicentre study. BMC Neurol 2015;15:166.
Koutsis G, Pemble S, Sweeney MG, Paudel R, Wood NW, Panas M, et al
. Analysis of spinocerebellar ataxias due to expanded triplet repeats in Greek patients with cerebellar ataxia. J Neurol Sci 2012;318:178-80.
Lone WG, Khan IA, Poornima S, Shaik NA, Meena AK, Prabhakar Rao K, et al
. Exploration of CAG triplet repeat in nontranslated region of SCA12 gene. J Genet 2016;95:427-32.
Musova Z, Sedlacek Z, Mazanec R, Klempir J, Roth J, Plevova P, et al
. Spinocerebellar ataxias type 8, 12, and 17 and dentatorubro-pallidoluysian atrophy in Czech ataxic patients. Cerebellum 2013;12:155-61.
Silveira I, Miranda C, Guimarães L, Moreira MC, Alonso I, Mendonça P, et al
. Trinucleotide repeats in 202 families with ataxia: A small expanded (CAG)n allele at the SCA17 locus. Arch Neurol 2002;59:623-9.
van de Warrenburg BPC, Sinke RJ, Verschuuren-Bemelmans CC, Scheffer H, Brunt ER, Ippel PF, et al
. Spinocerebellar ataxias in the Netherlands: Prevalence and age at onset variance analysis. Neurology 2002;58:702-8.
Venkatesh SD, Kandasamy M, Moily NS, Vaidyanathan R, Kota LN, Adhikarla S, et al
. Genetic testing for clinically suspected spinocerebellar ataxias: Report from a tertiary referral centre in India. J Genet 2018;97:219-24.
Worth PF, Wood NW Spinocerebellar ataxia type 12 is rare in the United Kingdom. Neurology 2001;56:419-20.
Zhao Y, Tan EK, Law HY, Yoon CS, Wong MC, Ng I Prevalence and ethnic differences of autosomal-dominant cerebellar ataxia in Singapore. Clin Genet 2002;62:478-81.
Jiang H, Tang B, Xia K, Zhou Y, Xu B, Zhao G, et al
. Spinocerebellar ataxia type 6 in mainland China: Molecular and clinical features in four families. J Neurol Sci 2005;236:25-9.
Hellenbroich Y, Schulz-Schaeffer W, Nitschke MF, Köhnke J, Händler G, Bürk K, et al
. Coincidence of a large SCA12 repeat allele with a case of Creutzfeld-Jacob disease. J Neurol Neurosurg Psychiatry 2004;75:937-8.
Brussino A, Graziano C, Giobbe D, Ferrone M, Dragone E, Arduino C, et al
. Spinocerebellar ataxia type 12 identified in two Italian families may mimic sporadic ataxia. Mov Disord 2010;25:1269-73.
Dong Y, Wu JJ, Wu ZY Identification of 46 CAG repeats within PPP2R2B as probably the shortest pathogenic allele for SCA12. Parkinsonism Relat Disord 2015;21:398-401.
Srivastava AK, Takkar A, Garg A, Faruq M Clinical behaviour of spinocerebellar ataxia type 12 and intermediate length abnormal CAG repeats in PPP2R2B. Brain 2017;140:27-36.
Choudhury S, Chatterjee S, Chatterjee K, Banerjee R, Humby J, Mondal B, et al
. Clinical characterization of genetically diagnosed cases of spinocerebellar ataxia type 12 from India. Mov Disord Clin Pract 2018;5:39-46.
Margolis RL, O’Hearn E, Holmes SE, Srivastava AK, Mukherji M, Sinha KK Spinocerebellar ataxia type 12. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, et al
, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2016 Oct 18]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1202/. [Last accessed on Nov 17, 2011].
Faruq M, Shakya S, Garg A, Srivastava AK Spinocerebellar ataxia 2 and 12 mutations in an Indian family with cerebellar ataxia and slow saccades. Mov Disord Clin Pract 2014;1:267-70.
O’Hearn E, Holmes SE, Calvert PC, Ross CA, Margolis RL SCA-12: Tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion. Neurology 2001;56:299-303.
Nicoletti G, Annesi G, Carrideo S, Tomaino C, Di Costanzo A, Zappia M, et al
. Familial essential tremor is not associated with SCA-12 mutation in southern Italy. Mov Disord 2002;17:837-8.
Faruq M, Srivastava AK, Suroliya V, Kumar D, Garg A, Shukla G, et al
. Identification of FXTAS presenting with SCA 12 like phenotype in India. Parkinsonism Relat Disord 2014;20:1089-93.
Hagerman P Fragile X-associated tremor/ataxia syndrome (FXTAS): Pathology and mechanisms. Acta Neuropathol 2013;126:1-19.
Li H, Ma J, Zhang X Diffusion tensor imaging of spinocerebellar ataxia type 12. Med Sci Monit 2014;20:1783-91.
Swarup V, Srivastava AK, Rajeswari MR Identification and quantification of differentially expressed proteins in plasma of spinocerebellar ataxia type 12. Neurosci Res 2012;73:161-7.
Sterneckert JL, Reinhardt P, Schöler HR Investigating human disease using stem cell models. Nat Rev Genet 2014;15:625-39.
Kumar D, Hussain A, Srivastava AK, Mukerji M, Mukherjee O, Faruq M Generation of three spinocerebellar ataxia type-12 patients derived induced pluripotent stem cell lines (IGIBi002-A, IGIBi003-A and IGIBi004-A). Stem Cell Res 2018;31:216-21.
Kumar D, Ladaniya MS, Gurjar M Underutilized citrus sp. Pomelo (Citrus grandis
) and Kachai lemon (Citrus jambhiri
) exhale in phytochemicals and antioxidant potential. J Food Sci Technol 2019;56:217-23.
Ince TA, Scotto KW A conserved downstream element defines a new class of RNA polymerase II promoters. J Biol Chem 1995;270:30249-52.
Lin CH, Chen CM, Hou YT, Wu YR, Hsieh-Li HM, Su MT, et al
. The CAG repeat in SCA12 functions as a cis element to up-regulate PPP2R2B expression. Hum Genet 2010;128:205-12.
Dagda RK, Zaucha JA, Wadzinski BE, Strack S A developmentally regulated, neuron-specific splice variant of the variable subunit Bbeta targets protein phosphatase 2A to mitochondria and modulates apoptosis. J Biol Chem 2003;278:24976-85.
Holmes SE, O’Hearn E, Margolis RL Why is SCA12 different from other SCAS? Cytogenet Genome Res 2003;100:189-97.
Chen CM, Hou YT, Liu JY, Wu YR, Lin CH, Fung HC, et al
. PPP2R2B CAG repeat length in the Han Chinese in Taiwan: Association analyses in neurological and psychiatric disorders and potential functional implications. Am J Med Genet B Neuropsychiatr Genet 2009;150B:124-9.
Virshup DM Protein phosphatase 2A: A panoply of enzymes. Curr Opin Cell Biol 2000;12:180-5.
Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E, et al
. Structure of the protein phosphatase 2A holoenzyme. Cell 2006;127:1239-51.
Tan J, Lee PL, Li Z, Jiang X, Lim YC, Hooi SC, et al
. B55β-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer. Cancer Cell 2010;18:459-71.
Strack S, Ruediger R, Walter G, Dagda RK, Barwacz CA, Cribbs JT Protein phosphatase 2A holoenzyme assembly: Identification of contacts between B-family regulatory and scaffolding A subunits. J Biol Chem 2002;277:20750-5.
Sarva H, Shanker VL Treatment options in degenerative cerebellar ataxia: A systematic review. Mov Disord Clin Pract 2014;1:291-8.
Ilg W, Brötz D, Burkard S, Giese MA, Schöls L, Synofzik M Long-term effects of coordinative training in degenerative cerebellar disease. Mov Disord 2010;25:2239-46.
Ilg W, Schatton C, Schicks J, Giese MA, Schöls L, Synofzik M Video game-based coordinative training improves ataxia in children with degenerative ataxia. Neurology 2012;79:2056-60.
Dongmei H, Jing L, Mei X, Ling Z, Hongmin Y, Zhidong W, et al
. Clinical analysis of the treatment of spinocerebellar ataxia and multiple system atrophy-cerebellar type with umbilical cord mesenchymal stromal cells. Cytotherapy 2011;13:913-7.
Jin HJ, Bae YK, Kim M, Kwon SJ, Jeon HB, Choi SJ, et al
. Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int J Mol Sci 2013;14:17986-8001.
Yang WZ, Zhang Y, Wu F, Zhang M, Cho SC, Li CZ, et al
. Human umbilical cord blood-derived mononuclear cell transplantation: Case series of 30 subjects with hereditary ataxia. J Transl Med 2011;9:65.
Fiszer A, Olejniczak M, Switonski PM, Wroblewska JP, Wisniewska-Kruk J, Mykowska A, et al
. An evaluation of oligonucleotide-based therapeutic strategies for polyQ diseases. BMC Mol Biol 2012;13:6.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]