Neural pathways of autonomic reflexes in familial autonomic ganglionopathy

Objective: We determined the molecular basis of a new monogenetic recessive disorder that results in familial neurogenic orthostatic hypotension (nOH) with impaired sympathetic (SNS) and parasympathetic (PNS) activity. Methods: Two adult siblings from one family (I-4, I-5) and an another subject from a second family (II-3) presented with severe nOH, poor compensatory increase in heart rate, small non-reactive pupils and constipation. All three affected members had low norepinephrine levels and diffuse autonomic failure. Results: Whole exome sequencing of DNAs from subjects (I-4, I-5) showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115) /c.688G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, alpha 3 subunit (CHRNA3) gene. The II-3 from the second family was homozygous for the same frameshift(fs) variant (p.L303Dfs*115// p.L303Dfs*115). The CHRNA3 is a subunit of nicotinic acetylcholine receptors (nAChRs) that regulate SNS and PNS ...