VUMC team discovers new genetic diseaseJun. 3, 2021, 10:06 AM
by Bill Snyder
Researchers at Vanderbilt University Medical Center have discovered a new genetic disease that causes a severe form of neurogenic orthostatic hypotension, a rapid drop in blood pressure upon standing that can cause fainting.
The rare condition, which they named familial autonomic ganglionopathy, is caused by variations in the CHRNA3 gene, which encodes a critical subunit of the nicotinic acetylcholine receptor (nAChR).
This family of receptors allows fast transmission of signals through clusters of nerve cells called ganglia in the autonomic nervous system, which regulates bodily functions including heart rate, digestion and response of the pupils to changes in light.
In addition to orthostatic, or postural hypotension, disorders or mutations that disrupt receptor function can cause gastrointestinal disturbances and an impaired pupillary reflex. A report of the latest discovery was published last month in the journal Neurology.
“The discovery of this novel disease that we named familial autonomic ganglionopathy highlights the incredible collaborative environment at VUMC,” said the report’s corresponding author, Cyndya Shibao, MD, MSCI, associate professor of Medicine at VUMC.
“Using a combination of autonomic anatomy and pathophysiology, ocular function, genetic and molecular modeling, we were able to provide answers to a family that suffered from a rare and unrecognized form of autonomic failure (and) were able to repurpose an old drug, pyridostigmine, for the treatment of this unique disease.
“Since we discovered this disorder, we have been contacted by other centers with children suffering from the same genetic condition,” Shibao said. The discovery enabled the centers to immediately implement supportive therapy, thus avoid delays in providing care to patients, she said.
VUMC is a world leader in the diagnosis and treatment of disorders of autonomic blood pressure regulation. Familial autonomic ganglionopathy is the third genetic disease discovered at the Vanderbilt Autonomic Dysfunction Center, which was founded by co-author David Robertson, MD, and a core group of investigators in 1978.
In the current report, two members of the same family with severe neurogenic orthostatic hypotension, constipation and miosis, excessive constriction of the pupil, were referred in 1995 to the Vanderbilt Autonomic Dysfunction Center for evaluation.
Shibao and co-author Karen Joos, MD, PhD, who holds the Joseph N. and Barbara H. Ellis Family Chair in Ophthalmology, were able to locate errors in autonomic nerve transmission in the autonomic ganglia that convey these nerve impulses to the heart, blood vessels and the pupils.
The family members were later referred for genetic evaluation to the Undiagnosed Diseases Network, an initiative launched in 2014 by VUMC and five other medical centers with funding from the National Institutes of Health to investigate “mystery” medical conditions.
They were reevaluated at VUMC in early 2019 after the genetic mutation that likely caused their condition was discovered. A third, unrelated patient, whose mutation was identified through the web-based GeneMatcher tool, was evaluated at VUMC later that year.
The VUMC researchers plan to study the effect of pyridostigmine on different aspects of autonomic function in other patients diagnosed with familial autonomic ganglionopathy.
Others from VUMC who contributed to the study were John Phillips III, MD, Joy Cogan, PhD, John Newman, MD, Rizwan Hamid, MD, Jens Meiler, PhD, John Capra, PhD, Bonnie Black, RN, NP, Andre Diedrich, MD, PhD, and Italo Biaggioni, MD.
The research was supported by the Lori Ann Fishel Fund of the Jewish Federation and Jewish Foundation of Nashville and Middle Tennessee, the Joseph Ellis Family and William Black Research Funds, and an unrestricted grant to the VUMC Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness.