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whom one of each pair is known to have MS In the most extensive of these studies (Ebers et al), the diagnosis was veri ed in 12 of 35 pairs of monozygotic twins (34 percent) and in only 2 of 49 pairs of dizygotic twins (4 percent) Furthermore, in two additional sets of monozygotic twins who were clinically normal, lesions were detected by MRI The concordance rate in dizygotic pairs is similar to that in nontwin siblings Despite these provocative ndings, no consistent pattern of mendelian inheritance has emerged (Of course, one must not assume that all diseases with an increased familial incidence are hereditary in that instances of the same condition in several members of a family may simply re ect an exposure to a common environmental agent Paralytic poliomyelitis, for example, was about eight times more common in immediate family members than in the population at large) Nonetheless, further evidence of a genetic factor in the causation of MS is the nding that certain histocompatibility locus antigens (HLAs) are more frequent in patients with MS than in control subjects The strongest association is with the DR locus on the sixth chromosome Other HLA haplotypes that are overrepresented in MS (HLA-DR2 and, to a lesser extent, -DR3, -B7, and -A3) are thought to be markers for an MS susceptibility gene possibly an immune response gene The presence of one of these markers increases the risk that an individual will develop MS by a factor of 3 to 5 These antigens may indeed prove to be related to the frequency of the disease, but their presence is not invariable and their exact role is far from clear (see Compston) The low conjugal incidence of MS, on the other hand, indicates that any common exposure to an inciting infection or environmental agent must occur early in life In order to test this hypothesis, Schapira and coworkers determined the periods of common exposure (common habitation periods) in members of families with two or more cases From this they calculated the mean common exposure to have happened before 14 years of age, with a latency of about 21 years gures that are in general agreement with those derived from the migration studies quoted above The incidence of MS is two or three times higher in women than in men, but the signi cance of this fact is unclear, the best current explanation being that women are generally more susceptible to immune and in ammatory conditions The incidence in children is very low; only 03 to 04 percent of all cases appear during the rst decade In an analysis of three childhood-onset cases, Hauser and colleagues found no phenotypic differences between childhood and adult cases Beyond childhood, the risk of rst developing symptoms of the disease rises steeply with age, reaching a peak at about 30 years, remaining high in the fourth decade, then falling off sharply and becoming low in the sixth decade It has been pointed out that MS has a unimodal age-speci c onset curve, similar to the age-speci c onset curves of many infectious and connective tissue diseases About two-thirds of cases of MS have their onset between 20 and 40 years of age Of the remainder, most cases begin before the age of 20; in a smaller number, the disease appears to develop in late adult life (late fties and sixties) In the latter patients, early symptoms may have been forgotten or may never have declared themselves clinically (we have several times found the typical lesions of MS in aged autopsied individuals who had no history of neurologic illness) Gilbert and Sadler report ve such cases and from their pathologic ndings declare that the true incidence of MS may be three times higher than stated gures Several studies from northern Europe and Canada have suggested that the likelihood of developing MS is somewhat greater.

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among rural than among urban dwellers; studies of American army personnel indicate the opposite (Beebe et al) A number of surveys in Great Britain have intimated that the disease is more frequent in the higher socioeconomic groups than in the lower ones Yet in the United States, no clear relationship has been established to the poverty or social deprivations that are part of a low socioeconomic status Numerous other environmental factors [surgical operations, trauma, anesthesia, exposure to household pets (small dogs), mercury in silver amalgam llings in teeth] have been proposed but are unsupported by rm evidence and probably are mostly spurious associations

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