Genetics of primary progressive multiple sclerosis

Cree, Bruce A.C.

doi:10.1016/b978-0-444-52001-2.00042-x

Cited by 21 publications

(19 citation statements)

References 170 publications

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“…Understanding the role of phenocopies in PPMS has important clinical implications. The finding that PPMS patients are enriched for HSP‐related mutations that cause progressive axonal injury is consistent with the observation that the most common clinical presentation in PPMS is a progressive spastic paraparesis and might help explain why these patients respond poorly to immunomodulatory therapies. Moreover, carrying a pathogenic mutation for a MS phenocopy disorder does not cause MS, but rather modulates the disease course through mechanisms independent of immune‐mediated pathways implicated by reported MS susceptibility loci.…”

Section: Discussionsupporting

confidence: 85%

“…PPMS shares clinical features with specific Mendelian neurological disorders (ie, potential MS phenocopies) that cause progressive neurological disability attributed to injury to the central nervous system (CNS). Examples of genetic disorders that resemble PPMS include hereditary spastic paraplegias (HSPs), inherited leukodystrophies, and mitochondrial disorders …”

mentioning

confidence: 99%

“…PPMS represents an unmet need in the care of neurological patients because of its poor response to MS disease‐modifying therapies and its relentless clinical course that resembles neurodegenerative disorders . Compared to RMS, PPMS patients are older at onset, men and women are equally affected, and the most common clinical presentation is a progressive spastic paraparesis . Moreover, some family studies demonstrate a higher concordance in MS disease course (PPMS versus RMS) within affected siblings than expected by chance .…”

mentioning

confidence: 99%

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Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis

Jia

Madireddy

Caillier

et al. 2018

Annals of Neurology

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Section: Discussionsupporting

confidence: 85%

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confidence: 99%

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confidence: 99%

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Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis

Jia

Madireddy

Caillier

et al. 2018

Annals of Neurology

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“…Factor D Highly specific serine protease cleaves factor B; necessary for the formation of C3 convertase Forneris and Gros (2013) 12. Factor H Essential for regulating alternative pathway; regulates the formation of C3 and C5 convertases; controls complement-mediated damage Ferreira et al (2010) and Cree (2014) 13 (Ling et al 2012). For instance, human pathogenic viruses including HIV, SARS-CoV, Ebola virus, Dengue virus (DENV), and West Nile virus (WNV) have been found to directly interact with MBL (Stoermer and Morrison 2011).…”

Section: C5bmentioning

confidence: 99%

Targeting complement cascade: an alternative strategy for COVID-19

et al. 2020

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The complement system is a stakeholder of the innate and adaptive immune system and has evolved as a crucial player of defense with multifaceted biological effects. Activation of three complement pathways leads to consecutive enzyme reactions resulting in complement components (C3 and C5), activation of mast cells and neutrophils by anaphylatoxins (C3a and C5a), the formation of membrane attack complex (MAC) and end up with opsonization. However, the dysregulation of complement cascade leads to unsolicited cytokine storm, inflammation, deterioration of alveolar lining cells, culminating in acquired respiratory destructive syndrome (ARDS). Similar pathogenesis is observed with the middle east respiratory syndrome (MERS), severe acquired respiratory syndrome (SARS), and SARS-CoV-2. Activation of the lectin pathway via mannose-binding lectin associated serine protease 2 (MASP2) is witnessed under discrete viral infections including COVID-19. Consequently, the spontaneous activation and deposits of complement components were traced in animal models and autopsy of COVID-19 patients. Pre-clinical and clinical studies evidence that the inhibition of complement components results in reduced complement deposits on target and non-target tissues, and aid in recovery from the pathological conditions of ARDS. Complement inhibitors (monoclonal antibody, protein, peptide, small molecules, etc.) exhibit great promise in blocking the activity of complement components and its downstream effects under various pathological conditions including SARS-CoV. Therefore, we hypothesize that targeting the potential complement inhibitors and complement cascade to counteract lung inflammation would be a better strategy to treat COVID-19.

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“…Some dedicated studies describe the natural history of this disease type, 51-53 but aetiological and clinical course studies are frustrated by infrequency, as only 10% of the cases have a PPMS phenotype, 54 and potential reverse causality issues (changes in behaviour/environment due to disease can incorrectly suggest a role for that behavioural/environmental factor in disease aetiology). For these reasons, many studies have focused on genetic, 55 rather than behavioural and environmental factors, despite the latter being a more readily accessible point of intervention. Accordingly, calls are now out for targeted research for progressive MS.…”

Section: Challenging Issues In Ms Epidemiological Researchmentioning

confidence: 99%

The role of epidemiology in MS research: Past successes, current challenges and future potential

2015

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Multiple sclerosis (MS) is a multifaceted condition, with a range of environmental, behavioural and genetic factors implicated in its aetiology and clinical course. Successes in advancing our appreciation of the roles of Epstein-Barr virus, vitamin D/UV and the HLA-DRB1 locus; and our greater understanding of these and related factors' modes of action in MS and other conditions, can be attributed in no small part to the work of generations of epidemiologists. Hardly content to rest on our laurels, however, there are yet a range of unsolved conundrums in MS, including some changes in epidemiological characteristics (e.g. increasing incidence and sex ratio), to say nothing of the unresolved parts regarding what underlies MS risk and its clinical course. There is evidence that epidemiology will continue to play a crucial role in unravelling the architecture of MS causation and clinical course. While classic epidemiological methods are ongoing, novel avenues for research include gene-environment interaction studies, the world of '-omic' research, and the utilisation of mobile and social media tools to both access and track study populations, which means that the epidemiological discoveries of the past century may be but a glimpse of our understanding in the next few decades.

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Genetics of primary progressive multiple sclerosis

Cited by 21 publications

References 170 publications

Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis

Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis

Targeting complement cascade: an alternative strategy for COVID-19

The role of epidemiology in MS research: Past successes, current challenges and future potential

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