Genetic Mutation Found in Familial Transverse Myelitis

By Dr. Michael Levy

Associate Professor of Neurology at the Johns Hopkins Hospital and Medical Director of General Neurology at the Johns Hopkins Hospital in Baltimore, MD

We found a rare genetic mutation in some families of patients with acute transverse myelitis (TM) that may provide new insights into the disease process. Two sisters with TM came to our attention through SRNA who agreed to donate their DNA for a thorough genetic analysis called exome sequencing. Only one meaningful difference was found in both sisters, which their two healthy brothers did not have: a mutation in a gene called VPS37A. As it turns out, a genetic mutation like theirs is extraordinarily rare in nature. No other known organism in the animal kingdom has this mutation so we thought this could be biologically important. But we didn’t know how common this was. With the help of SRNA, the Accelerated Cure Project and collaborators at Johns Hopkins, we screened an additional 86 TM patients and found another patient with the same rare mutation! It is statistically beyond coincidence to find three human beings with this same rare genetic mutation unless it has something to do with the rare disease they all share, TM. We do not yet understand how this gene, or the genetic mutation, is associated with TM. But with the continued support of SRNA, funding agencies and of course, our TM patients, we are beginning to piece this puzzle together.

The abstract below was presented at American Academy of Neurology 2017 in Boston, MA.

Maureen Mealy¹, RN, Tai-Seung Nam², MD, PhD, Santiago Pardo¹, Carlos A. Pardo¹, MD, PhD, David Valle³, MD, Kathleen Burns³,⁴, MD, PhD, Michael Levy¹, MD, PhD

1.     Department of Neurology, Johns Hopkins University, Baltimore, MD, USA

2.     Department of Neurology, Chonnam National University Medical School, Gwangju, South Korea

3.     Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA

4.     Department of Pathology, Johns Hopkins University, Baltimore, MD, USA

Background. Idiopathic transverse myelitis is an acute inflammatory attack of the spinal cord leading to weakness, sensory loss and bowel/bladder dysfunction. The prevalence is 0.1-0.2/100,000 and there are no known risk factors.

Objective. To identify a genetic risk for development of idiopathic transverse myelitis.

Methods. We identified two sisters who both have idiopathic transverse myelitis, and compared exome sequencing on DNA samples from them with two healthy siblings. We also sequenced 200 additional samples from patients with idiopathic transverse myelitis, multiple sclerosis, neuromyelitis optica, other neurological conditions and healthy controls.

Results. The two sisters with idiopathic transverse myelitis both had acute onset of sensory loss in the legs, followed by weakness and bowel/bladder dysfunction. The first sister developed myelitis at age 15 with clinical nadir of complete paralysis. Over the next few years, she recovered her ability to walk without assistance. Recent MRI demonstrated persistent T2 lesion in the lower thoracic cord. The second sister developed myelitis at age 50 with nadir of complete sensory loss from T6 down and paraparesis in the legs, associated with an MRI lesion at T6. She also made a partial recovery with treatment. Both sisters share a non-synonymous homozygous mutation in only one gene, VPS37A (c.700C>A, p.Leu234Ile) in the whole genome analyses. One healthy sibling was heterozygous for this mutation. We screened an additional 261 samples from patients with ITM and neuroimmunological diseases by Sanger sequencing of this portion of VPS37A and identified another idiopathic TM patient with this same rare homozygous mutation. No patients with multiple sclerosis, neuromyelitis optica, other neurological conditions or healthy controls contained a homozygous mutation in VPS37A.

Conclusions. A mutation in VPS37A may predispose to development of idiopathic transverse myelitis. Further studies are necessary to determine the frequency of this mutation in this patient population and how this genetic mutation might contribute to risk of disease.