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ATP1A3 is a Na,K-ATPase gene expressed specifically in neurons in the brain. Human mutations are dominant and produce an unusually wide spectrum of neurological phenotypes, most notably rapid-onset dystonia parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). Here we compared heterozygotes of two mouse lines, a line with little or no expression ( Atp1a 3 tm1Ling/+ ) and a knock-in expressing p.Asp801Tyr (D801Y, Atp1a3 +/D801Y ). Both mouse lines had normal lifespans, but Atp1a3 +/D801Y had mild perinatal mortality contrasting with D801N mice ( Atp1a3 +/D801N ), which had high mortality. The phenotypes of Atp1a 3 tm1Ling/+ and Atp1a3 +/D801Y were different, and testing of each strain was tailored to its symptom range. Atp1a 3 tm1Ling/+ mice displayed little at baseline, but repeated ethanol intoxication produced hyperkinetic motor abnormalities not seen in littermate controls. Atp1a3 +/D801Y mice displayed robust phenotypes: hyperactivity, diminished posture consistent with hypotonia, and deficiencies in beam walk and wire hang tests. Symptoms also included qualitative motor abnormalities that are not well quantified by conventional tests. Paradoxically, Atp1a3 +/D801Y showed sustained better performance than wild type on the accelerating rotarod. Atp1a3 +/D801Y mice were overactive in forced swimming and afterward had intense shivering, transient dystonic postures, and delayed recovery. Remarkably, Atp1a3 +/D801Y mice were refractory to ketamine anesthesia, which elicited hyperactivity and dyskinesia even at higher dose. Neither mouse line exhibited fixed dystonia (typical of RDP patients), spontaneous paroxysmal weakness (typical of AHC patients), or seizures but had consistent, measurable neurological abnormalities. A gradient of variation supports the importance of studying multiple Atp1a3 mutations in animal models to understand the roles of this gene in human disease., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Liu et al.)

Abstract: A 55-year-old man with renal cell carcinoma extending into the renal vein/inferior vena cava (status post nephrectomy and inferior vena cava thrombectomy, pT3bN0M0), and perioperative pulmonary bland thromboembolism (resolved with 3-month of anticoagulation), followed by 3.5 years of complete remission, developed new incidental pulmonary arterial filling defects on a surveillance CT examination (asymptomatic, normal d -dimer, no deep vein thrombosis). Despite anticoagulation, the filling defects not only persisted but also demonstrated intense FDG activity on a restaging PET/CT performed 4 months later for new pulmonary oligometastasis. The FDG activity resolved after systemic immunotherapy, which suggested the retrospective diagnosis of pulmonary arterial tumor emboli, a rare finding., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)