To describe genetic variants in acetylcholine processing found in a patient with postural orthostatic tachycardia syndrome (POTS) and positive response to pyridostigmine

Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder of heterogeneous pathophysiology involving relative sympathetic overactivity and/or parasympathetic hypofunction. POTS is characterized by exaggerated postural tachycardia in the absence of orthostatic hypotension, orthostatic intolerance and other cardiovascular and neurologic features.

We report a 30-year-old woman with POTS who experienced significant improvement with pyridostigmine. The whole genome sequencing demonstrated four single nucleotide polymorphisms - AchE,  BChE, PEMT and CHDH - variants involved in acetylcholine processing that may have led to acetylcholine deficiency and resultant parasympathetic hypofunction with relative sympathetic hyperactivity in this patient. Her Composite Autonomic Symptom Score-31 (COMPASS-31) after initiation of pyridostigmine decreased from 56.15 pre-treatment to 32 post-treatment, which indicated a 43% improvement in autonomic symptom burden, while her step count increased from an average of 4000 steps pre- to 7500 steps post-treatment with pyridostigmine.

We conclude that genetic variants in acetylcholine processing may result in acetylcholine deficiency state and may represent one of many pathophysiologic mechanisms of POTS. Whole genome sequencing and validated genetic tests for these and other genetic variants may be valuable diagnostic tools in delineating specific pathophysiology, POTS phenotypes and personalized treatment approaches.