Jennifer E Posey1, Rebecca Martinez2, Jeremy E Lankford3, James R Lupski4, Mohammed T Numan5, Ian J Butler3. 1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. Electronic address: Jennifer.Posey@bcm.edu. 2. Division of Child and Adolescent Neurology, Department of Pediatrics, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas. Electronic address: Rebecca.Martinez@uth.tmc.edu. 3. Division of Child and Adolescent Neurology, Department of Pediatrics, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas. 4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, Texas Children's Hospital, Houston, Texas; Department of Pediatrics, Baylor College of Medicine, Houston, Texas. 5. Division of Cardiology, Department of Pediatrics, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas.
Abstract
BACKGROUND: Orthostatic intolerance is typically thought to be sporadic and attributed to cerebral autonomic dysfunction. We sought to identify families with inherited autonomic dysfunction manifest as symptomatic orthostatic intolerance to characterize mode of inheritance and clinical features. METHODS: Sixteen families with two or more first- or second-degree relatives with autonomic dysfunction and orthostatic intolerance were enrolled. A clinical diagnosis of autonomic dysfunction defined by symptomatic orthostatic intolerance diagnosed by head-up tilt table testing was confirmed for each proband. Clinical features and evaluation were obtained from each proband using a standardized intake questionnaire, and family history information was obtained from probands and available relatives. RESULTS: Comprehensive pedigree analysis of 16 families (39 individuals with orthostatic intolerance and 40 individuals suspected of having orthostatic intolerance) demonstrated dominant transmission of autonomic dysfunction with incomplete penetrance. Affected individuals were predominantly female (71.8%, 28/39; F:M, 2.5:1). Male-to-male transmission, although less common, was observed and demonstrated to transmit through unaffected males with an affected parent. Similar to sporadic orthostatic intolerance, probands report a range of symptoms across multiple organ systems, with headaches and neuromuscular features being most common. CONCLUSIONS: Familial occurrence and vertical transmission of autonomic dysfunction in 16 families suggest a novel genetic syndrome with dominant transmission, incomplete penetrance, and skewing of the sex ratio. Elucidation of potential genetic contributions to orthostatic intolerance may inform therapeutic management and identification of individuals at risk. Adolescent evaluation should include identification and treatment of potential at-risk relatives.
BACKGROUND: Orthostatic intolerance is typically thought to be sporadic and attributed to cerebral autonomic dysfunction. We sought to identify families with inherited autonomic dysfunction manifest as symptomatic orthostatic intolerance to characterize mode of inheritance and clinical features. METHODS: Sixteen families with two or more first- or second-degree relatives with autonomic dysfunction and orthostatic intolerance were enrolled. A clinical diagnosis of autonomic dysfunction defined by symptomatic orthostatic intolerance diagnosed by head-up tilt table testing was confirmed for each proband. Clinical features and evaluation were obtained from each proband using a standardized intake questionnaire, and family history information was obtained from probands and available relatives. RESULTS: Comprehensive pedigree analysis of 16 families (39 individuals with orthostatic intolerance and 40 individuals suspected of having orthostatic intolerance) demonstrated dominant transmission of autonomic dysfunction with incomplete penetrance. Affected individuals were predominantly female (71.8%, 28/39; F:M, 2.5:1). Male-to-male transmission, although less common, was observed and demonstrated to transmit through unaffected males with an affected parent. Similar to sporadic orthostatic intolerance, probands report a range of symptoms across multiple organ systems, with headaches and neuromuscular features being most common. CONCLUSIONS: Familial occurrence and vertical transmission of autonomic dysfunction in 16 families suggest a novel genetic syndrome with dominant transmission, incomplete penetrance, and skewing of the sex ratio. Elucidation of potential genetic contributions to orthostatic intolerance may inform therapeutic management and identification of individuals at risk. Adolescent evaluation should include identification and treatment of potential at-risk relatives.
Authors: J R Shannon; N L Flattem; J Jordan; G Jacob; B K Black; I Biaggioni; R D Blakely; D Robertson Journal: N Engl J Med Date: 2000-02-24 Impact factor: 91.245
Authors: Karl Martin Klein; Catherine J Bromhead; Katherine R Smith; Christopher J O'Callaghan; Susan J Corcoran; Sarah E Heron; Xenia Iona; Bree L Hodgson; Jacinta M McMahon; Kate M Lawrence; Ingrid E Scheffer; Leanne M Dibbens; Melanie Bahlo; Samuel F Berkovic Journal: Neurology Date: 2013-04-16 Impact factor: 9.910
Authors: Satish R Raj; Kate M Bourne; Lauren E Stiles; Mitchell G Miglis; Melissa M Cortez; Amanda J Miller; Roy Freeman; Italo Biaggioni; Peter C Rowe; Robert S Sheldon; Cyndya A Shibao; Andre Diedrich; David M Systrom; Glen A Cook; Taylor A Doherty; Hasan I Abdallah; Blair P Grubb; Artur Fedorowski; Julian M Stewart; Amy C Arnold; Laura A Pace; Jonas Axelsson; Jeffrey R Boris; Jeffrey P Moak; Brent P Goodman; Kamal R Chémali; Tae H Chung; David S Goldstein; Anil Darbari; Steven Vernino Journal: Auton Neurosci Date: 2021-06-30 Impact factor: 2.355