Cyndya Shibao, M.D., an associate professor of medicine at Vanderbilt University Medical Center, spent 18 years following the health of two siblings with a mysterious condition which, among other symptoms, rendered them unable to stand without a precipitous drop in blood pressure. A third patient would later join them.
Now, her team’s research, published in Neurology, has identified variations in the CHRNA3 gene as the root cause, and named the disorder familial autonomic ganglionopathy. Using a combination of autonomic anatomy and pathophysiology, ocular function, and genetic and molecular modeling, they were able to provide answers to a family that suffered from a rare and unrecognized form of autonomic failure.
Shibao and co-author Karen Joos, M.D., the Joseph and Barbara Ellis Professor of Ophthalmology and Visual Sciences at Vanderbilt, were able to locate errors in nerve transmission in the autonomic ganglia, which convey impulses to the heart, blood vessels and the pupils. Combining this work with whole genome sequencing ultimately led them to fully characterize the disorder.
“Discovering and naming the disease has enabled the centers to immediately implement supportive therapy to these patients whose lives have been so disrupted by this disease.”
“For many years, there was no way to identify the responsible gene, or whether a variant was the cause of the disease,” Shibao said. The answer came later, when the patients were referred to the Undiagnosed Disease Network – an initiative launched in 2014 by Vanderbilt and five other medical centers with funding from the NIH to investigate “mystery” medical conditions. “This led to the detection of a rare variant in these patients’ CHRNA3 gene, which is important in regulating nerve impulses in the autonomic ganglia.”
Errors in Nerve Transmission
CHRNA3 encodes a subunit of the nicotinic acetylcholine receptors essential for proper synaptic transmission in the autonomic ganglia – key hubs that convey both parasympathetic and sympathetic nerve impulses. “Through modeling, we were able to predict that the identified variants in the CHRNA3 gene are disruptive to the normal structure and function of the receptor,” Shibao said.
In the absence of normal neurotransmission through autonomic ganglia, the stimulation of sympathetic and parasympathetic neural pathways fails to modulate blood pressure upon standing and interferes with gastrointestinal and pupillary function. This panautonomic failure results in fainting upon standing, nausea, constipation, excessive fatigue, and urinary retention. Optically, patients have poorly reactive pupils, blurred vision, and mild ptosis.
From Phenotype to Genotype
Working to understand the illness and address the needs of these young patients, the Vanderbilt researchers repurposed pyridostigmine, a drug that enhances ganglionic transmission. One sibling agreed to treatment with the drug and was able to maintain sufficient blood pressure while standing for 10 minutes, providing hope that a treatment tailored to this unique disorder may be developed in the future.
In 2018, when the Undiagnosed Diseases Network helped reveal the genetic cause, Shibao and her team could at last give a name to the disorder. Vanderbilt is a world leader in the diagnosis and treatment of disorders of autonomic blood pressure, with familial autonomic ganglionopathy being the third genetic disease discovered at the Vanderbilt Autonomic Dysfunction Center.
More Cases Identified
In 2019, a third patient with the same genetic variant was identified through the website GeneMatcher and referred to Shibao for evaluation. “This child, once thought to be ‘malingering,’ suffered from both a blood pressure drop upon standing and small pupils,” she recalled.
Since then, yet another patient has been found to have the same symptoms and genetic profile. “Discovering and naming the disease has enabled the centers to immediately implement supportive therapy to these patients whose lives have been so disrupted by this disease,” Shibao said.
How Rare a Disease?
Shibao says when a patient presents with weakness and faintness upon standing, this should hint at autonomic system involvement. “If patients meet the criteria for orthostatic hypotension and also have systemic symptoms associated with autonomic impairment – such as severe constipation, urinary retention, and small pupils – they should undergo thorough autonomic testing and a genetic referral,” she said.
Based on their new understanding of its pathophysiology, the Vanderbilt team is opening a study on repurposing medications to help improve quality of life for patients with familial autonomic ganglionopathy. “Since this disease has just been named, we don’t know how rare it is,” Shibao said. “It’s important that we enhance the recognition of familial autonomic ganglionopathy, and work to offer and expand treatment options.”