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ABSTRACT

Multiple sclerosis (MS) is an autoimmune disease with central nervous system pathology. An underlying genetic contribution to MS pathogenesis is suggested by familial clustering of cases and the frequent occurrence of MS in specific groups with a common ancestral history (particularly those of northern European origin) compared with others. Recurrence risk estimates in multi-case families, combined with observations of twin concordance and empirical data predict that the MS-prone genotype results primarily from multiple independent or interacting polymorphic genes, each exerting a small or moderate effect. Equally significant, it is also likely that genetic heterogeneity exists, meaning that specific genes influence susceptibility and pathogenesis in some affected but not in others. Genes encoding antigen-presenting molecules within the HLA region in chromosome 6p21, account for the largest part of the genetic risk for MS and until recently, the rest of MS genetics constituted an impenetrable black box. The past few years have seen real progress in the development of laboratory and analytical approaches to study non-Mendelian complex genetic disorders and, as a result, multiple non-HLA allelic variants affecting MS susceptibility were identified and convincingly replicated. Their incomplete penetrance and moderate individual effect probably reflects interactions with other genes, post-transcriptional regulatory mechanisms, and significant environmental influences.

INTRODUCTION

Multiple sclerosis (MS, OMIM# 126200; HGNC# 7314) is a serious, debilitating disease of the central nervous system (CNS) characterized by chronic inflammation, myelin loss, gliosis, axonal and oligodendrocyte pathology, and progressive neurological dysfunction.1 MS is a common cause of non traumatic neurological disability in young adults, affecting approximately 2 million people worldwide, with prevalence rates reaching up to 2 in 1,000 in some parts of the world.2 The incidence of MS seems to have increased considerably over the last century, and this increase may have occurred primarily in women.3,4 Although the exact etiology of MS remains unknown, a broadly accepted model of pathogenesis supports the occurrence of two overlapping processes, inflammatory and neurodegenerative.5,6 Despite important advances in therapeutics for MS, long-term prognosis remains generally poor; 15 years after diagnosis, over 80% of patients have functional or cognitive limitations and 50–60% require assistance to walk. The reduced life expectancy with respect to that of the general population ranges between 10 and 12 years. As with many common diseases, MS is characterized by modest disease risk heritability, polygenic inheritance, multifaceted gene-gene and gene-environment interactions, and clinically variable phenotypic presentation. The demonstration of even a small effect of a gene on the development of MS could fundamentally change our understanding of its underlying biology and potentially create novel opportunities for treatment or prevention.

CLINICAL SYMPTOMS OF MS

Symptoms of MS result from interruption of the myelinated tracts in the CNS and ensuing axonal injury. Early clinical features commonly include episodes of visual involvement (optic neuritis, diplopia, nystagmus), loss of movement or weakness in the limbs, sensory loss, and/or ataxia. As the disease progresses ...

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