Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Idiopathic transverse myelitis (ITM) is a single autoimmune attack on the spinal cord that leads to weakness, numbness, and bowel/bladder dysfunction. The incidence is approximately 1-2 per million per year with a prevalence of approximately 7,500 Americans living with disability from their ITM today. There is are two peak age distributions with onsets in the teenage years and in adulthood. Men and women are equally affected. Treatment involves immunosuppression at the time of the attack but neurologic disability persists in greater than two thirds of cases. ITM is conventionally viewed as a sporadic disease, with no strong familial risk factors and no recognized genetic contribution to risk. Recently, we encountered a family of Polish origin with two sisters affected by ITM, one presenting at age 15 and one presenting at age 50. This unusual occurrence prompted us to seek a genetic basis for ITM. Genetic sequencing of these sisters revealed that they both harbor a very rare mutation in a gene called Vacuolar Protein Sorting-Associated Protein 37A (VPS37A). VPS37A is a component of the endosomal sorting complex required for transport I (ESCRT-1) complex, which is involved in recycling proteins. This genetic mutation is exceedingly rare in human populations, but among a group 86 ITM patients we discovered a third patient of Irish/Scottish origin who harbored the same VPS37A genetic mutation. Our results strongly implicate VPS37A in the cause of ITM and suggest that familial forms of ITM has a genetic component. The goals of this proposal are to understand how a genetic mutation in VPS37A causes ITM. Specifically, we will focus on how this genetic mutation leads to a predisposition to develop an immune mediated attack of the spinal cord.
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