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Severe autonomic failure in a patient compound heterozygous for a frame shift mutation and deletion of the ganglionic acetylcholine receptor alpha-3 subunit

Heusser, K. and Erger, F. and Namer, B. and Ebner, U. and Eisenhofer, G. and Haensch, C.-A. and Tank, J. and Netzer, C. and Jordan, J. (2022) Severe autonomic failure in a patient compound heterozygous for a frame shift mutation and deletion of the ganglionic acetylcholine receptor alpha-3 subunit. 33rd International Symposium on the Autonomic Nervous System, 2022-11-02 - 2022-11-05, Hawaii.

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Abstract

The alpha-3 subunit is a crucial component of the ganglionic acetylcholine receptor. Indeed, pharmacological ganglionic blockade or antagonistic antibodies against the alpha-3 subunit virtually abolish postganglionic sympathetic and parasympathetic traffic in human beings. Mutations of the CHRNA3 gene encoding the alpha-3 subunit appear to be a rare cause of autonomic failure. We encountered an 18-year-old woman who had exhibited a fixed heart rate in utero and a rocky clinical course with repeated hypoglycemic episodes following birth. She presented with warm skin, hypohidrosis, pupillary rigidity, accommodation disorder, severe orthostatic hypotension, gastrointestinal dysmotility with a megacolon, and suprapubic catheter for urinary drainage. Intraneural nerve recordings from skin and muscle fascicles showed normal afferent but missing sympathetic activity. Isometric handgrip did not increase blood pressure. Axon reflex sweating and respiratory sinus arrhythmia were minimal. Very low supine and upright plasma norepinephrine but normal levels of related precursors and metabolites as well as skin biopsy suggested the presence of biochemically intact postganglionic neurons yet defective ganglionic neurotransmission. We performed trio whole exome sequencing using the Agilent SureSelect Human All Exon v8 enrichment chemistry on an Illumina NovaSeq6000 platform. Variant calling and copy number variant detection was done using the QIAGEN CLC Genomics Workbench, variant annotation and filtering with in-house developed software. We detected the hemizygous frameshift variant c.907_908delCT (p.Lys303Asnfs*115) in trans with a heterozygous deletion of exons 5–6 in the CHRNA3 (NM_000743.5) gene in the index patient. The frameshift variant was inherited paternally, the deletion maternally. Both variants were classified as pathogenic. We describe the first case of a patient compound heterozygous for previously described frame shift mutation and a deletion of the gene encoding the alpha-3 subunit of the ganglionic acetylcholine receptor. Clinically, the condition is associated with life-long autonomic failure with severe cardiovascular, gastrointestinal, and urogenital involvement

Item URL in elib:https://elib.dlr.de/190427/
Document Type:Conference or Workshop Item (Poster)
Title:Severe autonomic failure in a patient compound heterozygous for a frame shift mutation and deletion of the ganglionic acetylcholine receptor alpha-3 subunit
Authors:
AuthorsInstitution or Email of AuthorsAuthor's ORCID iDORCID Put Code
Heusser, K.UNSPECIFIEDhttps://orcid.org/0000-0002-2571-5585UNSPECIFIED
Erger, F.Institute of Human Genetics, Medical Faculty, University of Cologne, Cologne, GermanyUNSPECIFIEDUNSPECIFIED
Namer, B.Institute of Physiology and Pathophysiology and Department of Medicine 1, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany and Research Group Neuroscience, Interdisciplinary Centre for Clinical Research within the Faculty of Medicine aUNSPECIFIEDUNSPECIFIED
Ebner, U.General Practice, Regensburg, GermanyUNSPECIFIEDUNSPECIFIED
Eisenhofer, G.Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus and Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty, Technical University Dresden, GermanyUNSPECIFIEDUNSPECIFIED
Haensch, C.-A.Kliniken Maria Hilf Mönchengladbach, Autonomic Laboratory, Department of Neurology, Faculty of Health, University of Witten/Herdecke, Mönchengladbach, GermanyUNSPECIFIEDUNSPECIFIED
Tank, J.UNSPECIFIEDhttps://orcid.org/0000-0002-5672-1187UNSPECIFIED
Netzer, C.Institute of Human Genetics, Medical Faculty, University of Cologne, Cologne, GermanyUNSPECIFIEDUNSPECIFIED
Jordan, J.UNSPECIFIEDhttps://orcid.org/0000-0003-4518-0706UNSPECIFIED
Date:2022
Refereed publication:Yes
Open Access:No
Gold Open Access:No
In SCOPUS:No
In ISI Web of Science:No
Status:Published
Keywords:Dysautonomia; Ganglionic acetylcholine receptor; CHRNA3 Gene; Trio whole exome sequencing
Event Title:33rd International Symposium on the Autonomic Nervous System
Event Location:Hawaii
Event Type:international Conference
Event Start Date:2 November 2022
Event End Date:5 November 2022
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Space
HGF - Program Themes:Research under Space Conditions
DLR - Research area:Raumfahrt
DLR - Program:R FR - Research under Space Conditions
DLR - Research theme (Project):R - CardioBrain
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine
Institute of Aerospace Medicine > Cardiovascular Medicine in Aerospace
Institute of Aerospace Medicine > Leitungsbereich ME
Deposited By: Schrage, Larissa
Deposited On:22 Nov 2022 13:11
Last Modified:24 Apr 2024 20:51

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