SCA12 is an autosomal dominant hereditary progressive neurodegenerative disorder which means each child of an individual with SCA12 has a 50% chance of inheriting the pathogenic variant.

A mutation in the CAG (cytosine, adenine, guanine) stretch specifically a CAG repeat expansion in the PPP2R2B gene causes SCA12. PPP2R2B is the only gene in which mutation is known to cause SCA12 and is located on chromosome 5q-31-33. In the presence of clinical findings consistent with SCA12, an expansion of 51 or more CAG triplets within PPP2R2B is diagnostic. However, a few reports have also described an unusual occurrence of

CAG repeat length 36-51 repeats among patients of different geographical population.
CAG triplet encodes for glutamine but a repetitive CAG will result in polyglutamine.

Because of this mutation, the protein making machinery of the brain is affected as the gene PPP2R2B regulates a specific enzyme in the brain i.e protein phosphatase 2 A. This protein is involved in various cellular activities like protein phosphorylation and neuronal cell death. Lack of this vital regulatory protein results in injury or death of certain neurons in the brain.

In a study conducted at Ranchi in the Institute of Neurology, London and Saha Institute of Nuclear Physics in Kolkata, 12 families with SCA12 mutation were identified. There were a total of twenty one members in these families that tested for the mutant SCA12 locus. The age of onset ranged between 16 and 62 years. Eleven of these families belonged to a specific ethnic caste, known as the Agrawals, a well known North Indian community which originated in antiquity from a small town called Agroha in Haryana.

Symptoms are characterised by problems with movement that tend to get worse over time. Affected people may experience the following:

• Problems with coordination and balance (ataxia)
• Uncoordinated walk
• Poor hand-eye coordination
• Abnormal speech (dysarthria)
• Involuntary eye movement
• Vision problems
• Difficulty processing, learning and remembering information

SCA12 usually presents in mid-life anywhere between 40s to 60s. However, juvenile SCA12 can present anytime in childhood, early adulthood or youth.

• Treatment is based on the severity of symptoms
• 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, its 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

• Current treatment therapy involves the use of pharmacological molecules to target affected downstream pathways, as well as genetic therapies to decrease toxic polyglutamine gene products.
• Antisense oligonucleotides (ASOs) are small single-stranded sequences of DNA that have the gene-targeting effect of reducing levels of toxic protein or making non-toxic modifications which are valuable tools for neurodegenerative diseases.ASOs decrease the expression of the target protein using Watson–Crick hybridization to bind to complementary mRNA transcripts and recruit RNase H enzyme.
• Therapeutics based on RNA interface (RNAi) harness the cellular mechanism of gene expression silencing to reduce the expression of pathological proteins. Synthetic small interfering RNA (siRNAs) and short hairpin RNA (shRNAs) control the RNAi process of target mRNA enzymatic cleavage in a predictable and consistent action.
• Some stem cell-based therapies have been performed on several cerebellar mutant mice. Phase I and II clinical trials, one of which involved intravenously infused human umbilical cord mesenchymal stem cell (UC-MSC) into SCA1, 2 or 3 cohorts reported no transplantation side effects and an improved International Cooperative Ataxia Rating Scale (ICARS) and Berg Balance Scale (BBS) score after 6 months post-transplantation. However, assessment of efficacy and safety requires further clinical trials.