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Abstract
Objective To determine the molecular basis of a new monogenetic recessive disorder that results in familial autonomic ganglionopathy with diffuse autonomic failure.
Methods Two adult siblings from one family (I-4 and I-5) and another participant from a second family (II-3) presented with severe neurogenic orthostatic hypotension (nOH), small nonreactive pupils, and constipation. All 3 affected members had low norepinephrine levels and diffuse panautonomic failure.
Results Whole exome sequencing of DNA from I-4 and I-5 showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115)/c.688 G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, α3 subunit gene (CHRNA3). II-3 from the second family was homozygous for the same frameshift (fs) variant (p.L303Dfs*115//p.L303Dfs*115). CHRNA3 encodes a critical subunit of the nicotinic acetylcholine receptors (nAChRs) responsible for fast synaptic transmission in the autonomic ganglia. The fs variant is clearly pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). The p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits based on structural modeling and is predicted to destabilize the nAChR pentameric complex.
Conclusions We report a novel genetic disease that affected 3 individuals from 2 unrelated families who presented with severe nOH, miosis, and constipation. These patients had rare pathologic variants in the CHRNA3 gene that cosegregate with and are predicted to be the likely cause of their diffuse panautonomic failure.
Glossary
- BP=
- blood pressure;
- CNV=
- copy number variant;
- DBH=
- dopamine β-hydroxylase;
- DHPG=
- dihydroxyphenylglycol;
- HF=
- high-frequency;
- HFrri=
- high-frequency heart rate variability;
- HR=
- heart rate;
- LF=
- low-frequency;
- LFsbp=
- low-frequency systolic blood pressure;
- nAChR=
- nicotinic acetylcholine receptor;
- nOH=
- neurogenic orthostatic hypotension;
- PNS=
- parasympathetic nervous system;
- PRT=
- prolonged blood pressure recovery time;
- RRI=
- R-R interval;
- SNS=
- sympathetic nervous system;
- UDN=
- Undiagnosed Diseases Network;
- WES=
- whole exome sequencing
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
- Received December 16, 2019.
- Accepted in final form April 8, 2021.
- © 2021 American Academy of Neurology
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