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

Kurzfassung

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