CureSCA12

About SCA12

The SCA12 gene, inheritance, and ancestry

A single altered copy of one gene, PPP2R2B, is enough for SCA12 to occur — and most people diagnosed with it in India share ancestry in one North Indian community.

The gene and inheritance

The SCA12 gene is called PPP2R2B, and it sits on chromosome 5. Everyone has it: it carries the instructions for one part of an enzyme, protein phosphatase 2A, that nerve cells use constantly. Near the start of the gene, three DNA letters — C, A, G — are repeated a number of times in a row. In most people the repeat is short. In SCA12 it is expanded, usually to more than fifty copies. The expansion is unstable, which is why the count can differ between relatives who inherited it from the same parent.

Sources Bahl et al., 2005 (founder study) · GeneReviews

SCA12 is inherited in an autosomal dominant pattern. That means a single altered copy of the gene is enough for the condition to occur, and each child of an affected parent has a 50% chance of inheriting it.

has SCA12 does not inherited itwas 50% did notwas 50% ?50% ?50% 0% 0% each child, separately
One parent has SCA12. Each of their children has a 50% chance of inheriting the altered gene — a coin toss each time, not a share-out. A child who inherited it passes on the same 50% to each of their own children. A child who did not inherit it cannot pass it on: their children’s chance is zero, and the line stops there. It does not skip a generation. “Did not inherit” means the gene, not the symptoms — someone can carry the change without symptoms yet and still pass it on, which is what a genetic test settles.

Inheriting the altered copy is not the same as certainly developing symptoms. How fully the condition shows varies from person to person, particularly for repeat counts in the grey zone, and nobody can currently say how often it stays silent — which is one of the reasons predictive testing is a decision to make with a genetic counsellor rather than alone.

Genetic information rarely stays a purely medical matter — it raises questions about children, siblings, and what to tell whom. This is the reason genetic counselling exists, and why many people find it helps to arrange it before testing as well as after. A genetic counsellor can explain what different results would and would not mean, and help a family think through decisions at their own pace.

Relatives who have no symptoms can be tested for the altered gene, but only once the specific change has been identified in an affected family member — that is what makes a result meaningful. Whether to be tested, and when, is a personal decision, and one to make with a genetic counsellor. Source

Why SCA12 clusters in one community

SCA12 was first described in 1999, in a single American family. Two years later a team at AIIMS New Delhi found it in five of 77 Indian families with dominant ataxia, and wrote that it “may not be as rare in some populations as previously thought”. Every Indian series published since has confirmed it: most people diagnosed with SCA12 in India come from one community, the Agarwal (also spelt Agrawal) community of North India. In the largest published cohort, from NIMHANS Bengaluru in 2022, 39 of 49 patients were Agarwal; in the AIIMS series it was 81%; in a separate 2018 series, most patients were descendants of the same community.

The reason was worked out in 2005 by geneticists at CSIR-IGIB and AIIMS. They compared twenty affected families and found that all of them carried the same stretch of DNA around the expanded repeat — a founder haplotype. The simplest explanation is that the expansion happened once, in one ancestor many generations ago, and has been passed down since. All twenty families belonged to an endogamous community, one that historically married within itself, originating in Haryana. That is what kept the expansion concentrated instead of diluting away. The American family did not share this haplotype, so the expansion has arisen at least twice in human history.

Three things follow from this, and each matters:

  • It is about ancestry, not the surname. Families in the community carry several surnames — in our own community, Gupta and Mittal among them — and the risk follows the family line, not the name on it. What a neurologist needs to know is the family history.
  • It does not mean most Agarwal families are affected. SCA12 is still rare. The cohorts show which community most patients come from; no study has measured how common it is within the community, which is a different question. Most Agarwal families will never encounter it.
  • It does not mean people outside the community cannot have it. One in ten patients in the 2022 cohort came from another community, and the same group reported two further non-Agarwal families in 2021. SCA12 has also been found in the United States, Italy, Singapore and China. The AIIMS team wrote in 2017 that SCA12 “might not be that restricted” to one population, and the 2022 authors’ conclusion was that it should be considered whatever the patient’s ethnicity.

If you are from an Agarwal family and a relative has a tremor that has slowly worsened, or unsteadiness, it is worth telling the neurologist about the family background and asking about SCA12 by name. In the AIIMS series, ataxia that began with tremor, in a person from the community, was the strongest single pointer to SCA12. A genetic test settles it either way.

Sources Srivastava et al., 2001 · Bahl et al., 2005 (founder study) · NIMHANS cohort, 2022 · AIIMS series, 2018 · Choudhury et al., 2018 · Holla et al., 2021 · Srivastava et al., Brain 2017