Background and Objectives: Acute COVID-19 infection has been associated with neurological involvement. We report a case series of newly diagnosed patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) developed in a short period of time after acute COVID-19 infection. Methods: New MS patients developing initial symptoms shortly after an acute COVID-19 infection were diagnosed based on the 2017 McDonald Criteria [Garcia-Ramos et al. in Cells, 2021]. The patients diagnosed with NMOSD met the 2015 International Panel criteria for the diagnosis of NMOSD (IPDN) [Thompson et al. in Lancet Neurol 17:162-173, 2018]. Results From the MS Patient Group: Ten patients were included who had developed initial MS symptoms after COVID-19 infection. Gender distribution was equal (50% male). The mean age was 28 (range 17-39) years. Average time to neurological presentation was between 2 and 6 weeks following acute COVID-19 infection. Partial transverse myelitis was the initial presentation in 40% of the cases, and 60% of patients had spinal cord lesions present at the moment of diagnosis. All patients showed enhancing lesions on brain magnetic resonance imaging (MRI). The presence of cerebrospinal fluid (CSF) oligoclonal bands was found in all six tested cases. The majority of patients (80%) were unvaccinated for COVID-19. The two vaccinated patients had received two doses of the monovalent COVID-19 messenger ribonucleic acid (mRNA) (Pfizer Biotech) vaccine and no booster, a year prior to contracting COVID-19.Results From the NMOSD Group: Two patients with NMOSD were included. Positive aquoporin-4 protein antibody (AQP-4 Ab) was detected in serum in both cases [one Enzyme Linked immunosorbent assay (ELISA) and one cell based]. Both patients had mild COVID-19 infection prior to presentation, initial neurologic symptoms presented between 3 and 6 weeks after COVID-19 infection. Neither patients were vaccinated. Both responded partially to steroids, one developed a relapse 40 days after diagnosis. Conclusion: COVID-19 infection has been linked to several neurological and immune-driven conditions. This study suggests that in susceptible individuals, acute COVID-19 infection may act as a trigger for developing MS and NMOSD.

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Heterozygous germline variants inATP1A1, the gene encoding the α1 subunit of the Na+/K+-ATPase (NKA), have been linked to diseases including primary hyperaldosteronism and the peripheral neuropathy Charcot-Marie-Tooth disease (CMT).ATP1A1variants that cause CMT induce loss-of-function of NKA. This heterodimeric (αβ) enzyme hydrolyzes ATP to establish transmembrane electrochemical gradients of Na+and K+that are essential for electrical signaling and cell survival. Of the 4 catalytic subunit isoforms, α1 is ubiquitously expressed and is the predominant paralog in peripheral axons. Human population sequencing datasets indicate strong negative selection against both missense and protein-nullATP1A1variants. To test whether haploinsufficiency generated by heterozygous protein-null alleles are sufficient to cause disease, we tested the neuromuscular characteristics of heterozygousAtp1a1+/-knockout mice and their wildtype littermates, while also evaluating if exercise increased CMT penetrance. We found thatAtp1a1+/-mice were phenotypically normal up to 18 months of age. Consistent with the observations in mice, we report clinical phenotyping of a healthy adult human who lacks any clinical features of knownATP1A1-related diseases despite carrying a protein-null early truncation variant, p.Y148*. Taken together, these results suggest that a malfunctioning gene product is required for disease induction byATP1A1variants and that if any pathology is associated with protein-null variants, they may display low penetrance or high age of onset.