RESUMO
Panic disorder is a common psychiatric disorder characterized by recurrent anxiety attacks and anticipatory anxiety. Due to the severity of the symptoms of the panic attacks and the frequent additional occurrence of agoraphobia, panic disorder is an often debilitating disease. Elevation of central serotonin levels by drugs such as clomipramine represents one of the most effective treatment options for panic disorder. This points to an important role of dysregulation of the serotonergic system in the genetic etiology of panic disorder. The novel brain-specific 5-HT synthesizing enzyme, tryptophan hydroxylase-2 (TPH2), which represents the rate-limiting enzyme of 5-HT production in the brain, may therefore be of particular importance in panic disorder. We focused on the putative transcriptional control region of TPH2 and identified two novel common single nucleotide polymorphisms (SNPs) of TPH2 in and close to this region. Moreover, a recently described loss-of-function mutation of TPH2 which results in an 80% reduction of serotonin production, was assessed. In an analysis of the putative transcriptional control region SNPs in a sample of panic disorder patients and controls no association of the disorder with the TPH2 SNPs or haplotypes was found. Moreover, the loss-of-function R441H mutation of TPH2 was not present in the panic disorder patients. The results of this first study of TPH2 in panic disorder argue against an importance of allelic variation of TPH2 in the pathogenesis of panic disorder with or without agoraphobia.
Assuntos
Química Encefálica/genética , Transtorno de Pânico/genética , Triptofano Hidroxilase/genética , Adulto , Agorafobia/genética , Agorafobia/psicologia , Alelos , Substituição de Aminoácidos , Éxons/genética , Feminino , Regulação da Expressão Gênica/genética , Frequência do Gene , Genótipo , Humanos , Masculino , Transtorno de Pânico/psicologia , Polimorfismo Genético/genética , Escalas de Graduação Psiquiátrica , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição GênicaRESUMO
BACKGROUND: Genetic analyses of fatal familial insomnia, a prion disease, disclose a broader range of symptoms than previously described. Although insomnia and dysautonomia have been described as hallmarks of the disease, there is substantial variability in clinical presentation. OBJECTIVE: To evaluate serial fluorodeoxyglucose positron emission tomographic and electroencephalographic findings in atypical fatal familial insomnia without clinical insomnia. PATIENT: A 63-year-old man who had a history of gait ataxia developed rapidly progressive dementia with mild dysautonomic features. Genetic investigation confirmed diagnosis of fatal familial insomnia (D178N mutation of the prion protein gene and Val/Met polymorphism on position 129 of the mutated allele) with typical neuropathologic findings. RESULTS: Clinical signs were not specific. An electroencephalogram showed scanty triphasiclike elements and general slowing. We found thalamic hypometabolism in positron emission tomographic scans to be present in a very early stage with progressive deterioration, and patchy cortical alterations showing progression over 6 months. CONCLUSIONS: In the absence of clear clinical signs, an electroencephalogram was of major diagnostic value, although its specificity in fatal familial insomnia is under debate. Selective thalamic hypometabolism seems to be an early marker in fatal familial insomnia, while cortical changes vary with clinical presentation and stage.
Assuntos
Insônia Familiar Fatal/diagnóstico por imagem , Insônia Familiar Fatal/mortalidade , Tomografia Computadorizada de Emissão/métodos , Humanos , Insônia Familiar Fatal/patologia , Masculino , Pessoa de Meia-Idade , Tálamo/diagnóstico por imagem , Tálamo/patologiaRESUMO
Panic disorder is a common anxiety disorder which frequently co-occurs with agoraphobia. A functional promoter polymorphism in the serotonin receptor 1A (5-HT1A) gene has been found to be associated with major depression as well as anxiety- and depression-related personality traits. We investigated a possible association between this 5-HT1A gene promoter polymorphism and panic disorder by genotyping the 1019C>G single nucleotide polymorphism in 134 panic-disorder patients with and without agoraphobia and matched 134 controls. In our sample no significant evidence of allelic association in the combined panic-disorder group was found. However, our results show a significant association with the G allele in patients with panic disorder with agoraphobia (p=0.03, n=101). In conclusion, our findings do not support a major contribution of this polymorphism to the pathogenesis of panic disorder, but provide evidence for a possible role in the subgroup with agoraphobia.