A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.

The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.

Mesenteric Panniculitis and COVID-19: A Rare Association.

Coronavirus disease 2019 (COVID-19) typically involves the respiratory system, but gastrointestinal involvement is common. Further, patients with severe COVID-19 are at high risk to develop gastrointestinal complications, including bowel ischemia, ileus, and deranged liver enzymes. We present the case of a 44-year-old woman with mild COVID-19 pneumonia who was in home isolation. Ten days after the isolation, the patient presented to the emergency department complaining of generalized abdominal pain that was sharp in nature and associated with nausea and recurrent episodes of vomiting. The patient did not complain of any respiratory symptoms. Physical examination showed diffuse tenderness with no clinical signs to suggest generalized peritonitis. The laboratory parameters showed normal hematological, renal, and hepatic profiles. No elevation in the inflammatory markers was observed. The amylase level was within the normal range. Abdominal computed tomography scan demonstrated the presence of misty mesentery with increased density of the mesentery with fat stranding encasing the mesenteric vessels along with mesenteric adenopathy. Such radiological features suggested the diagnosis of mesenteric panniculitis. Subsequently, intravenous corticosteroid therapy was initiated and the patient exhibited significant improvement after 24 hours. The patient was discharged after nine days of hospitalization. She was followed up after one month and she had no complaints. Mesenteric panniculitis is a rare idiopathic inflammatory condition involving the mesenteric adipose tissue. The case shed a light on the possible association of COVID-19 with mesenteric panniculitis. The clinical manifestations of mesenteric panniculitis are non-specific and imaging studies are essential to suggest the diagnosis.

Substance Use and Misuse among Adults with Chronic Obstructive Pulmonary Disease in the United States, 2015-2019: Prevalence, Association, and Moderation.

BACKGROUND: Despite the advancements in chronic obstructive pulmonary disease (COPD) treatment, complications related to COPD exacerbation remain challenging. One associated factor is substance use/misuse among adults with COPD. Fewer studies, however, examined the prevalence and association between COPD and substance use and misuse. In addition, limited knowledge existed about the moderation effects of serious psychological distress and gender among adults with COPD and substance use/misuse. We aimed, therefore, to measure such prevalence, association, and moderation from nationally representative samples in the United States. METHOD: Data were drawn from the 2015-2019 National Survey on Drug Use and Health. Weighted logistic regressions were used to measure the associations of last-month tobacco (cigarettes, cigars, pipe, and smokeless tobacco products), other licit and illicit substance use (alcohol, marijuana, cocaine, crack, heroin, hallucinogens, and inhalants), and substance misuse (pain relievers, tranquilizers, stimulants, and sedatives) among adults with COPD. Serious psychological distress and gender were tested as moderators in the association between COPD and substance use/misuse. RESULTS: The findings revealed that adults with COPD [Weighted N = 53,115,718) revealed greater odds of cigarettes [adjusted odds ratio (aOR) = 2.48 (95%CI = 1.80-3.42)) and smokeless tobacco (aOR = 3.65 (95%CI = 1.75-7.65)). However, they were less likely to use alcohol (aOR = 0.61 (95%CI = 0.45-0.84)). Adults with COPD who had serious psychological distress were more likely to use pipe tobacco and alcohol; however, they were less likely to use hallucinogens and inhalants. Finally, males compared to females with COPD were less likely to use smokeless tobacco. CONCLUSION: Adults with COPD in the United States were more likely to use tobacco products and less likely to use alcohol. In addition, serious psychological distress and gender were moderators in associations between COPD and substance use but not in substance misuse. Future studies should longitudinally assess the factors that may contribute to the initiation and progression of substance use and misuse among adults with COPD.