EPIDEMIOLOGY AND GENETICS OF MULTIPLE SCLEROSIS

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CHAPTER 74 EPIDEMIOLOGY AND GENETICS OF MULTIPLE SCLEROSIS

Jan D. Lünemann, Roland Martin

Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS) that usually begins in early adulthood and is characterized by demyelination, gliosis, a varying degree of axonal pathology, and episodic or progressive neurological disability. More than 1 million people worldwide and at least 350,000 individuals in the United States alone are affected with multiple sclerosis, which is second only to trauma as a cause of acquired disability in young adults in most white populations.1,2

DISEASE HETEROGENEITY

The heterogeneous nature of multiple sclerosis is reflected by its variable clinical phenotype, its nonuniform neuropathology, and its heterogeneous molecular pathogenesis. Both genetic and environmental factors are believed to have an effect either in modulating susceptibility or influencing the development of the disease. Autoreactive T cells are considered to play a key role in mediating the disease process. Evidence for a role of autoreactive T cells stems from the composition of inflammatory infiltrates in the CNS, which consist mainly of lymphocytes and monocytes, and from data from its animal model, experimental allergic (autoimmune) encephalomyelitis. The injection of myelin components into susceptible animals leads to a CD4+ T cell–mediated autoimmune disease resembling multiple sclerosis and can be adoptively transferred from sick to healthy animals via encephalitogenic CD4+ T cells. A role of autoaggressive T cells in multiple sclerosis is further supported by the therapeutic, although limited, efficacy of immunosuppressive and immunomodulatory agents and by the fact that certain major histocompatibility complex (MHC) class II alleles represent the strongest genetic risk factor, presumably because of their role as antigen-presenting molecules to pathogenic CD4+ T cells.

Inflammatory events are considered to initiate and drive the disease process during early stages. The myelin damage and axonal injury that account for the permanent neurological deficit seen during later phases of multiple sclerosis probably result from a complex sequence of events, including processes intrinsic to the CNS, such as increased vulnerability to tissue injury and/or poor repair, which might progress independently of immune factors. Multiple sclerosis is therefore not solely a disease of the immune system; CNS-specific components, although largely overlooked in their potential pathogenetic role, are presumably equally important for its pathogenesis.3

The clinical pattern of multiple sclerosis is generally divided into two major forms. The first, most frequent (85% to 90%) subtype follows a relapsing-remitting course and is characterized by separate episodes of neurological deficits involving different sites of the CNS, each lasting for at least 24 hours and separated by intervals of at least 1 month. Relapsing-remitting multiple sclerosis usually evolves over decades and in most cases transforms into a secondary progressive course. About 10% to 15% of patients present with insidious disease onset and steady progression, termed primary progressive multiple sclerosis. There is heterogeneity in morphological alterations of the brain, as visualized by either magnetic resonance imaging (MRI) or histopathological evaluation, but also in clinical presentation, such as which CNS system and areas are primarily affected and whether a patient responds to treatment. The factors underlying the different disease courses and the disease heterogeneity are incompletely understood but presumably include a complex genetic trait that translates into different immune abnormalities and/or increased vulnerability of CNS tissue to inflammatory insult or reduced ability to repair damage.

Current knowledge about how certain genes confer risk for multiple sclerosis or any other autoimmune disease at the molecular level is incomplete. However, numerous studies on the genetic epidemiology of multiple sclerosis, which are described in the following sections, provide compelling evidence that the susceptibility to the disease is inherited, although additional environmental triggers might be necessary to translate disease susceptibility into the clinical phenotype.

POPULATION PREVALENCE

The disease prevalence varies between 60 and 200 per 100,000 in North America and northern Europe and generally follows a north-to-south decreasing gradient on the northern hemisphere and the opposite on the southern hemisphere, with very low rates or virtual absence of the disease near the equator (Fig. 74-1).

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Figure 74-1 Worldwide distribution of multiple sclerosis. Multiple sclerosis is most common in parts of the world with cooler climates. Europe, North America, and parts of Australia and New Zealand have multiple sclerosis prevalence rates (60 to 200 per 100,000) that are much higher than rates in countries clustered around the equator.

(Adapted from Marrie RA: Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol 2004; 12:709-718.)

This geographical distribution can be attributed to both environmental factors and genetic effects. For many years, an infectious etiology of multiple sclerosis has been suspected, because it is consistent with a number of epidemiological observations and with immunopathological characteristics of the disease. Migration studies showed that individuals who migrate from high-risk to low-risk areas after the age of 15 tend to retain their risk of multiple sclerosis, whereas individuals who migrate from high-risk to low-risk areas before the age of 15 acquire a lower risk; this indicates that childhood exposure to an environmental factor increases disease susceptibility. Supportive data for an infectious agent also come from reports of endemic clusters of multiple sclerosis. After the British occupation of the Faroe Islands, off the coast of Denmark, where no cases of multiple sclerosis had been reported before, several islanders developed the disease between 1940 and the end of World War II, and the affected areas were found to be locations of British troop encampments after 1940. Other examples of multiple sclerosis epidemics have been described in northern America and Europe. These observations suggest that an environmental factor is relevant for the initiation of the disease process, and in the established disease, infections are additionally known to be capable of triggering exacerbations.

No specific transmissible agent has so far been linked convincingly to multiple sclerosis. The most consistent evidence of a potential role in the disease exists for Epstein-Barr virus and human herpesvirus 6, as a result of the detection of viral DNA in brain specimens derived from multiple sclerosis lesions (in the case of human herpesvirus 6) and by convincing seroepidemiological studies. Both are ubiquitous viruses that act at the population level and produce latent, recurrent infections. Generally conceptualized as a trigger for the manifestation of the disease in genetically susceptible individuals, the mechanisms by which these viruses and other potential candidates initiate, exacerbate, and perpetuate the disease are, however, far from understood.

Arguing for a genetic basis of multiple sclerosis is the fact that the disease prevalence differs strikingly between geographically close but genetically distinct populations. Ethnic groups such as the Lapps in Scandinavia, Gypsies in Hungary, Maoris in New Zealand, or Aborigines in Australia are rarely if ever affected by multiple sclerosis, although the disease is otherwise common in these latitudes. Furthermore, multiple sclerosis is rare among Japanese and Chinese populations, African Blacks, North and South Amerindians, and the native populations in southern countries of the former Soviet Union (Turkmen, Uzbeks, Kazakhs, Kyrgyzis), but it occurs notably more frequently among Whites living in the same area. Further examples are the different prevalence rates in genetically distant populations living on the same island, as reported for Sardinia, Cyprus, and Ireland.

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