The pathophysiology of sickle cell disease (SCD) is driven by chronic inflammation. We show that elevated cell-free DNA (cfDNA) in SCD patients is not just a prognostic biomarker but contributes to the pathological inflammation. Within the elevated cfDNA, SCD patients had significantly higher proportion of mitochondrial (cf-mtDNA) to nuclear cfDNA (cf-nDNA) compared to healthy controls. Additionally, mtDNA in patient samples showed significant disproportionately increased hypomethylation compared to healthy controls, that was further increased in crises when compared to steady-state. Using flow cytometry, structured illumination microscopy and electron microscopy, we showed that circulating SCD red blood cells abnormally retained their mitochondria, and thus likely to be the source of the elevated cf-mtDNA in SCD patients. Patient plasma containing high levels of cf-mtDNA triggered formation of neutrophil extracellular traps (NETs) that was substantially reduced by inhibition of TANK-binding kinase 1 (TBK1) implicating activation of the cGAS-STING pathway. cf-mtDNA is an erythrocytic-DAMP, highlighting an underappreciated role of mitochondria in sickle pathology. Clinicaltrials.gov identifiers: #NCT00081523, #NCT03049475, #NCT00047996

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Introduction/Rationale: Multiple sclerosis (MS) is associated with a higher prevalence of mood and psychiatric disorders, such as bipolar disorder (BD). While mania is most often associated with BD, MS can also induce manic symptoms. However, it is crucial to distinguish which condition is causing mania since medical management is different based on its etiology. Herein, we report a case of a manic episode in a middle-aged female with a prolonged history of BD who received a recent diagnosis of MS 1 year ago. Patient Concerns: A 56-year-old female presented with an episode of mania and psychosis while receiving a phenobarbital taper for chronic lorazepam use. She had a prolonged history of bipolar type 1 disorder and depression. She showed optic neuritis and was diagnosed with MS a year prior. Diagnoses: The patient was diagnosed with BD-induced mania based on the absence of increased demyelination compared to previous MRI and lack of new focal or lateralizing neurologic findings of MS. Interventions: Lithium was given for mood stabilization and decreased dosage of prior antidepressant medication. Risperidone was given for ongoing delusions. Outcomes: After 8 days of hospitalization, patient's mania improved but demonstrated atypical features and ongoing delusions. She was discharged at her request to continue treatment in an outpatient setting. Conclusion/Lesson: In BD patients with an episode of mania, MS should be included in the differential, since both conditions can cause manic symptoms. The origin of mania should be delineated through a detailed neurological exam, neuroimaging, and thorough patient-family psychiatric history for appropriate clinical treatment.