Cysteine-Altering NOTCH3 Variants Are Associated with an Increased Risk of Autoimmune Diseases.

Autoimmune conditions have been reported among patients with cysteine-altering NOTCH3 variants and CADASIL. This study aimed to investigate the occurrence of autoimmune illnesses and markers of inflammation in such populations. Cases were identified who had a NOTCH3 cysteine-altering variant from the Geisinger MyCode® Community Health Initiative (MyCode®). We further performed external validation using the UK Biobank cohort. A cohort of 121 individuals with a NOTCH3 cysteine-altering variant from MyCode® was compared to a control group with no non-synonymous variation in NOTCH3 (n = 184). Medical records were evaluated for inflammatory markers and autoimmune conditions, which were grouped by the organ systems involved. A similar analysis was conducted using data from the UK Biobank (n~450,000). An overall increase in inflammatory markers among participants with a NOTCH3 cysteine-altering variant was observed when compared to an age- and sex-matched MyCode® control group (out of participants with laboratory testing: 50.9% versus 26.7%; p = 0.0047; out of total participants: 23.1% versus 10.9%; p = 0.004). Analysis of UK Biobank data indicated any autoimmune diagnosis (1.63 [1.14, 2.09], p= 2.665 × 10-3) and multiple sclerosis (3.42 [1.67, 6.02], p = 9.681 × 10-4) are associated with a NOTCH3 cysteine-altering variant in any domain. Our findings suggest a possible association between NOTCH3 cysteine-altering variants and autoimmune conditions.

Atypical Variant of Guillain Barre Syndrome in a Patient with COVID-19.

OBJECTIVE: A rare variant Miller Fisher Syndrome overlap with Guillain Barre Syndrome is described in an adult patient with SARS-COV-2 infection. CASE PRESENTATION: The clinical course of a 45-year-old immunosuppressed man is summarized as a patient who developed ataxia, ophthalmoplegia, and areflexia after upper respiratory infection symptoms began. A nasopharyngeal swab was positive for COVID-19 polymerase chain reaction. He progressed to acute hypoxemic and hypercapnic respiratory failure requiring intubation and rapidly developed tetraparesis. Magnetic resonance imaging of the spine was consistent with Guillain Barre Syndrome. However, the clinical symptoms, along with positive anti-GQ1B antibodies, were consistent with Miller Fisher Syndrome and Guillain Barre Syndrome overlap. The patient required tracheostomy and had limited improvement in his significant neurological symptoms after several months. CONCLUSIONS: The case demonstrates the severe neurological implications, prolonged recovery and implications in the concomitant respiratory failure of COVID-19 patients with neurological symptoms on the spectrum of disorders of Guillain Barre Syndrome.