When answers eluded the doctors of a young patient previously hospitalized for acute but disparate autoimmune symptoms, her family approached experts at NYU Langone’s Dysautonomia Center to identify the underlying cause and pursue a diagnosis. Through a deliberate analysis combining clinical expertise and basic science research, center experts diagnosed a rarely reported autonomic disorder—providing certainty for the patient’s care and treatment and new clues to expand the understanding of autoimmune-associated dysautonomic symptoms.

Troubling Symptoms Elude a Clear Clinical Picture

With a series of progressively worsening symptoms, the 10-year-old patient had continued to decline while her clinical picture puzzled physicians at another institution searching for an underlying cause.

Symptom onset had begun as a febrile illness with sore throat, facial erythema, and repeated vomiting, and at that point a mild viral illness was suspected. When vomiting and abdominal pain persisted, accompanied by pancreatitis and bladder retention, the patient was admitted to the intensive care unit (ICU) at the other institution. Over the weeks-long course of her stay, unusual symptoms mounted—bladder and bowel paralysis, pupillary paralysis, anhidrosis, tear deficiency, and dry mouth—and a dysautonomic clinical picture began to take shape. Attempted treatment with prednisolone and intravenous immunoglobulin failed to achieve an adequate symptom response.

With autonomic nervous system involvement suspected, the patient’s parents were advised to contact Horacio Kaufmann, MD, the Felicia B. Axelrod Professor of Dysautonomia Research in the Department of Neurology and director of the Dysautonomia Center, for consultation. Though the physician treating the patient at that time suspected autoimmune autonomic ganglionopathy (AAG), the symptom profile did not add up to that condition, according to Dr. Kaufmann and his colleague Jose Alberto Palma Carazo, MD, PhD, associate professor in the Department of Neurology and assistant director of the Dysautonomia Research Laboratory.

“Though it’s not uncommon to see an autoimmune response like AAG in the setting of a flulike infection, those patients typically have severe problems with blood pressure, orthostatic hypotension, and other issues,” notes Dr. Kaufmann. “This patient had a range of autonomic involvement but none of those particular symptoms, so we recommended a treatment protocol to make her well enough to be discharged from the other hospital and seen in our clinic as soon as possible.”

Diagnosis by Exclusion Demands a Novel Diagnostic

To prepare for the patient’s visit, Dr. Kaufmann and Dr. Palma examined the case symptom by symptom, ruling out conditions to reach a probable cause: an autoimmune response centered in specific muscarinic receptors in the autonomic ganglia. Such receptors are abundant in the nervous system and critical to transmitting nerve signals to activate systems throughout the body. “The prevailing theory was that this patient’s condition was caused by a problem with the nerve itself,” says Dr. Kaufmann. “But we felt it was a problem with receptors in target organs, not nerves—the keyhole versus the key itself.”

The patient’s lack of central nervous system involvement pointed to an antibody binding to M3, one of five muscarinic receptors. “Now that we had a suspected cause—an autoimmune process affecting this M3 receptor—we needed to create experiments that could confirm the presence of antibodies and, in particular, characterize the interaction with the M3 receptor,” notes Dr. Palma.

The related research of a longtime colleague led Dr. Palma to extend multidisciplinary collaboration beyond the walls of NYU Langone to partner with Salvador Sierra, MD, PhD, whose external laboratory was leading research focused on M3 receptors. Together the physicians and researchers created tests to identify an antibody blocking activation of M3, as well as to rule out the other receptors’ involvement. With the tests complete, the patient presented for examination and diagnostics.

“Our findings supported our theory: Significantly increased levels of antibody were found to bind to M3,” says Dr. Palma. The subsequent diagnosis of postganglionic cholinergic dysautonomia (PCD)—a rare disorder of unknown cause described in approximately 10 people—indicated continued therapy with the oral muscarinic receptor bethanechol. A repeat antibody assay found reduced levels of the antibody in the patient, whose symptoms had eased. “That second finding was consistent with our diagnosis, confirming that these antibodies had a relationship with the symptom severity in this patient,” adds Dr. Palma.

Rare Disease Offers Broad Implications

The path to diagnosis, published in August 2020 in Annals of Neurology, represents a translational medicine achievement with tremendous impact, both for this patient and beyond. The patient is now feeling well, with the majority of her symptoms resolved. With her definitive diagnosis—a known antibody blocking a receptor that unequivocally caused her disease—it’s possible that her future treatment can be refined. “Most autoimmune problems today are treated the same way, with medications that target the immune system,” notes Dr. Kaufmann. “But as we further understand these disorders, we may be able to better target this patient’s receptors with a more selective therapeutic.”

Further, the identification of antibodies as a marker of PCD could be used to rapidly diagnose other patients with the disease—a condition that, with a wide spectrum of clinical presentation, could be underdiagnosed.

“In this case, the translation of medicine happened from the clinic to the lab,” concludes Dr. Kaufmann. “When a rare condition like this one comes along, important discovery happens when you can connect a high degree of clinical knowledge to make observations, then bring in the best basic scientists to confirm them.”