Context: Through application of radiotracer catecholamine kinetics methodology, we have previously demonstrated that a phenotype of impairment of neuronal reuptake of noradrenaline is commonly present in patients with panic disorder. The clinical consequences of this abnormality, and its cause, are unclear.
Objectives: No loss of function noradrenaline transporter (NET) gene coding region mutations are detectable in panic disorder. We have tested for the presence of an alternative, epigenetic mechanism silencing the NET gene. The NET gene promoter region contains CpG islands potentially subject to DNA methylation, a basis for gene silencing.
Methods and results: Methylation-specific PCR was applied in 27 patients with untreated panic disorder (DSM 1V criteria), and 30 age- and sex-matched healthy people. Epigenetic change, taking the form of NET gene promoter region DNA methylation, was present in 11 of 27 panic disorder patients (P < 0.01). Chromatin immunoprecipitation methodology disclosed that the methylation-related gene silencing transcription factor, MeCP2, was bound to the promoter region DNA in panic disorder patients only. Sympathetic nerve tissue in panic disorder patients, accessed by biopsy of small hand veins, had reduced levels of sympathetic nerve NET protein, demonstrated by Western blot analysis.
Conclusions: An epigenetic disorder causing faulty noradrenaline reuptake is present in panic disorder. We suspect that this abnormality, in sensitizing people to heart symptom development, is a cause of panic disorder; it was linked to “cardiac panicker” status, i.e. patients having predominantly cardiac symptoms. Further, by magnifying the sympathetic neural signal in the heart, the abnormality would increase cardiac risk.
