Autoimmune encephalitis: the first observational study from Iran.

BACKGROUND: Even within the most populous countries in the Middle East, such as Iran, autoimmune encephalitis cases have been rarely reported. OBJECTIVE: We aimed to describe the demographic, clinical, and paraclinical characteristics of Iranian patients with autoimmune encephalitis positive for anti-neuronal autoantibodies. METHODS: This cross-sectional study included all patients diagnosed with autoimmune encephalitis and referred to our hospital, in Isfahan, Iran, from March 2016 to May 2020. Patients' demographic, clinical, laboratory, radiological, and electroencephalographic features were obtained from their medical records. RESULTS: We identified a total of 39 (21 females, 53.8%) patients with autoimmune encephalitis (mean age = 34.9 ± 12.8 years). The most commonly detected antibody was anti-NMDAR (n = 26, 66.7%), followed by anti-GABABR (n = 8, 20.5%), anti-Zic4 (n = 4, 10.3%), and anti-GAD65 (n = 1, 2.6%) antibodies, in descending order of frequency. Two anti-NMDAR-positive patients had a history of systemic lupus erythematosus (SLE), and four had a prior history of herpes simplex encephalitis. Clinical presentations in patients positive for anti-Zic4 antibodies included cognitive decline (n = 4, 100%), seizures (n = 3, 75%), parkinsonism (n = 1, 25%), and stiff-person syndrome (n = 1, 25%). CONCLUSION: This was the first case series of Iranian patients with autoimmune encephalitis with some interesting observations, including SLE-associated anti-NMDAR encephalitis, as well as an unusual concurrence of anti-Zic4 antibody positivity and cognitive problems, seizures, parkinsonism, and stiff-person syndrome.

Analysis of alternative lengthening of telomere markers in BRCA1 defective cells.

Telomeres are specialized structures responsible for the chromosome end protection. Previous studies have revealed that defective BRCA1 may lead to elevated telomere fusions and accelerated telomere shortening. In addition, BRCA1 associates with promyelocytic leukemia (PML) bodies in alternative lengthening of telomeres (ALTs) positive cells. We report here elevated recombination rates at telomeres in cells from human BRCA1 mutation carriers and in mouse embryonic stem cells lacking both copies of functional Brca1. An increased recombination rate at telomeres is one of the signs of ALT. To investigate this possibility further we employed the C-circle assay that identifies ALT unequivocally. Our results revealed elevated levels of ALT activity in Brca1 defective mouse cells. Similar results were obtained when the same cells were assayed for the presence of another ALT marker, namely the frequency of PML bodies. These results suggest that BRCA1 may act as a repressor of ALT. © 2016 The Authors Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

Conus medullaris involvement in demyelinating disorders of the CNS: A comparative study.

BACKGROUND: Differentiation of the demyelinating disorders of the CNS seems challenging in practice. Conus medullaris, the cone-shaped end of the spinal cord, is more involved in anti-MOG patients based on preliminary studies, a possibly helpful detail in its differentiation. Nevertheless, the evidence is still limited and the underlying cause is unclear and undiscussed in previous studies. OBJECTIVE: To contribute to preliminary studies by comparing conus involvement among patients with MS, anti-AQP4, and anti-MOG diseases using larger sample size. METHODS: More than a thousand MS, anti-AQP4, and anti-MOG patients were followed up for a maximum of five years, scanned for conus medullaris involvement. Data regarding each cohort were then analyzed and compared using statistical methods. RESULTS: The rate of conus medullaris involvement was significantly higher in anti-MOG patietns (OR = 27.109, P < 0.001), followed by anti-AQP4 (OR = 4.944, P = 0.004), and MS patients (OR = reference). Survival analysis showed higher pace and cumulative incidence of conus attacks in anti-MOG patients. Conus-involved patients, showed no significant difference regarding age, sex, concurrent brain lesions, and their partial recovery. Predictive values show that the probability of being diagnosed with anti-MOG is roughly 13 times higher in conus-involved patients (25.93% vs. 1.97%), although this probability was still higher for MS, as it has a much higher incidence. CONCLUSION: Despite minor differences, the results were in line with previous studies, confirming the higher rate of conus medullaris involvement among anti-MOG patients. Potential underlying causes are proposed and remain to be investigated in future studies.

MRI signs of CNS demyelinating diseases.

The differential diagnosis of the central nervous system (CNS) demyelinating diseases can be greatly facilitated by visualization and appreciation of pathognomonic radiological signs, visualized on magnetic resonance imaging (MRI) sequences. Given the distinct therapeutic approaches for each of these diseases, a decisive and reliable diagnosis in patients presenting with demyelination-associated symptoms is of crucial value. Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are major examples of such conditions, each possessing a number of MRI signs, closely associated with the disorder. This pictorial review aims to describe seventeen pathognomonic MRI signs associated with several CNS demyelinating disorders including MS, NMOSD, myelin oligodendrocyte glycoprotein-associated disease, Baló's concentric sclerosis, metachromatic leukodystrophy, progressive multifocal leukoencephalopathy, and neurosarcoidosis.

COVID-19 and the Risk of Relapse in Multiple Sclerosis Patients: A Fight with No Bystander Effect?

BACKGROUND: COVID-19 is speculated to increase the likelihood of relapsing-remitting multiple sclerosis (RRMS) exacerbation. OBJECTIVE: To investigate the association between contraction of COVID-19 and incidence of acute MS attacks in RRMS patients six months post-infection. METHODS: This retrospective cohort study compares the risk of relapse in RRMS patients with (n=56) and without COVID-19 (n=69). Incidence of relapse was recorded for six-month following contraction of COVID-19. Incidence of RRMS exacerbation in patients with COVID-19 was compared to patients without COVID-19 (the independent control group) and the same patients six months prior to the COVID-19 pandemic. RESULTS: A lower incidence rate of RRMS exacerbation was observed in patients that contracted COVID-19 than in patients who did not contract COVID-19 (incidence rate ratio: 0.275; p=0.026). Self-controlled analysis showed no significant difference in relapse rates before the COVID-19 pandemic and after contracting COVID-19 (p=0.222). The relapse risk was not different between patients who had been hospitalized due to COVID-19 severity and those who had not (p=0.710). CONCLUSION: COVID-19 contraction may not increase the risk of acute MS attacks shortly following contraction. We hypothesize that COVID-19-associated lymphopenia may partly preclude the autoreactive memory cells from expansion and initiating relapses through a so-called bystander effect of COVID-19 infection.

Mitochondrial Medicine: Genetic Underpinnings and Disease Modeling Using Induced Pluripotent Stem Cell Technology.

Mitochondrial medicine is an exciting and rapidly evolving field. While the mitochondrial genome is small and differs from the nuclear genome in that it is circular and free of histones, it has been implicated in neurodegenerative diseases, type 2 diabetes, aging and cardiovascular disorders. Currently, there is a lack of efficient treatments for mitochondrial diseases. This has promoted the need for developing an appropriate platform to investigate and target the mitochondrial genome. However, developing these therapeutics requires a model system that enables rapid and effective studying of potential candidate therapeutics. In the past decade, induced pluripotent stem cells (iPSCs) have become a promising technology for applications in basic science and clinical trials, and have the potential to be transformative for mitochondrial drug development. Engineered iPSC-derived cardiomyocytes (iPSC-CM) offer a unique tool to model mitochondrial disorders. Additionally, these cellular models enable the discovery and testing of novel therapeutics and their impact on pathogenic mtDNA variants and dysfunctional mitochondria. Herein, we review recent advances in iPSC-CM models focused on mitochondrial dysfunction often causing cardiovascular diseases. The importance of mitochondrial disease systems biology coupled with genetically encoded NAD+/NADH sensors is addressed toward developing an in vitro translational approach to establish effective therapies.

Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a prevalent and untreatable cardiovascular disease with a highly complex clinical and genetic causation. HCM patients bearing similar sarcomeric mutations display variable clinical outcomes, implying the involvement of gene modifiers that regulate disease progression. As individuals exhibiting mutations in mitochondrial DNA (mtDNA) present cardiac phenotypes, the mitochondrial genome is a promising candidate to harbor gene modifiers of HCM. Herein, we sequenced the mtDNA of isogenic pluripotent stem cell-cardiomyocyte models of HCM focusing on two sarcomeric mutations. This approach was extended to unrelated patient families totaling 52 cell lines. By correlating cellular and clinical phenotypes with mtDNA sequencing, potentially HCM-protective or -aggravator mtDNA variants were identified. These novel mutations were mostly located in the non-coding control region of the mtDNA and did not overlap with those of other mitochondrial diseases. Analysis of unrelated patients highlighted family-specific mtDNA variants, while others were common in particular population haplogroups. Further validation of mtDNA variants as gene modifiers is warranted but limited by the technically challenging methods of editing the mitochondrial genome. Future molecular characterization of these mtDNA variants in the context of HCM may identify novel treatments and facilitate genetic screening in cardiomyopathy patients towards more efficient treatment options.