RESUMO
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.
Assuntos
Família , Testes Genéticos , Intolerância Ortostática/fisiopatologia , Adolescente , Estudos de Coortes , Feminino , Humanos , Masculino , Intolerância Ortostática/diagnóstico , Intolerância Ortostática/genética , Linhagem , Postura/fisiologia , Inquéritos e Questionários , Teste da Mesa InclinadaRESUMO
Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function. A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2500 fewer steps compared with placebo (Pinteraction=0.04). There were no differences between clonidine and placebo among patients with COMT low-activity alleles. Similar gene-drug interactions were observed for sleep (Pinteraction=0.003) and quality of life (Pinteraction=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine-COMT interaction effects in other conditions.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Catecol O-Metiltransferase/genética , Clonidina/uso terapêutico , Síndrome de Fadiga Crônica/tratamento farmacológico , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Adolescente , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Criança , Clonidina/efeitos adversos , Método Duplo-Cego , Tolerância ao Exercício/efeitos dos fármacos , Síndrome de Fadiga Crônica/diagnóstico , Síndrome de Fadiga Crônica/enzimologia , Síndrome de Fadiga Crônica/genética , Feminino , Estudos de Associação Genética , Homozigoto , Humanos , Masculino , Noruega , Intolerância Ortostática/induzido quimicamente , Intolerância Ortostática/enzimologia , Intolerância Ortostática/genética , Farmacogenética , Fenótipo , Qualidade de Vida , Medição de Risco , Fatores de Risco , Sono/efeitos dos fármacos , Resultado do TratamentoRESUMO
OBJECTIVE: Recent studies have found that the variation of G894T on the region of T786C and 7th exon promoted by endothelial nitric oxide synthase (eNOS) gene is associated with cardiovascular disease. This research explored possible correlations between eNOS gene polymorphisms and orthostatic intolerance (OI) in children through linkage disequilibrium analysis between eNOS genes T786C and G894T and OI. METHODS: PCR, Macrorestriction Map and other molecular biotechnology were used to determine the genotypes of eNOS/T786C and G894T in 60 OI probands and their parents. Correlation analysis and transmission disequilibrium test (TDT) between T786C, G894T and OI were performed. RESULTS: There was linkage disequilibrium of eNOS/T786C and G894T gene polymorphisms in the occurrence of childhood OI (P<0.05). CONCLUSIONS: eNOS genes T786C and G894T may be associated with the pathogenesis of OI.
