Abstract Details

Title Familial Monophasic Acute Transverse Myelitis Due to a Pathogenic Variant in VPS37A

Topic Multiple Sclerosis

Presentation(s) S49 - Multiple Sclerosis: Basic Science (2:24 PM-2:36 PM)

Poster/Presentation
Number 008

Objective To identify genetic differences among siblings with a family history of idiopathic transverse myelitis (ITM).

Background

Idiopathic transverse myelitis (ITM) is a monophasic autoimmune attack on the spinal cord, which leads to weakness, numbness, and bowel/bladder dysfunction; however, there is a spectrum of severity, and not all patients have this complete spectrum of deficits. The incidence is approximately 1 per million per year, with a prevalence of approximately 7,500 Americans living with disability from their ITM today. The etiology of ITM is presumed to be an immune-mediated attack 2–3 weeks after a systemic infection, possibly due to molecular mimicry.

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 2 sisters affected by ITM. This unusual occurrence prompted us to seek a genetic basis for ITM.

Design/Methods We compared whole-exome sequencing (WES) on germline samples from the 2 affected sisters with ITM with 3 of their healthy siblings.

Results The 2 sisters with ITM both had acute onset of sensory loss in the legs, weakness, and bowel/bladder dysfunction. Both sisters are homozygous for a missense variant in VPS37A (c.700C>A, p.Leu234Ile) identified by WES. We performed targeted sequencing of VPS37A in an additional 86 samples from patients with ITM and 175 with other diseases to investigate the p.Leu234Ile variant. We identified another patient with ITM homozygous for the same rare variant. No patients with multiple sclerosis, neuromyelitis optica, other neurologic conditions, or any healthy controls in public databases were homozygous for this variant.

Conclusions A rare missense variant in VPS37A may predispose to development of ITM. Further studies are necessary to determine the frequency of this variant in the patient population and the mechanism through which it contributes to the risk of disease.

Authors/Disclosures
Michael Levy, MD, PhD, FAAN (Massachusetts General Hospital/Harvard Medical School) PRESENTER	Dr. Levy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi Pharma. Dr. Levy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB Pharma. Dr. Levy has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Levy has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Levy has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon. Dr. Levy has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Levy has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Levy has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Various law firms. The institution of Dr. Levy has received research support from National Institutes Health.
Maureen A. Mealy, PhD, RN	No disclosure on file
Tai-Seung Nam, MD (Chonnam National University Hospital)	No disclosure on file
	No disclosure on file
Carlos A. Pardo-Villamizar, MD (Johns Hopkins U, Med Dept of Neurology)	The institution of Dr. Pardo-Villamizar has received research support from National Institutes of Health. The institution of Dr. Pardo-Villamizar has received research support from Bart McLean Fund for Neuroimmunology Research .
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file

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