June 30, 2003
J. Willliam Lindsey, MD, Jerry S. Wolinsky, MD, University of Texas Health Science Center at Houston
WebMD Scientific American® Medicine
Genetic Aspects of Multiple Sclerosis
A Complication of Sodium Repletion
Genetic Aspects of Multiple Sclerosis
The suspicion that susceptibility to MS is at least partly familial has been confirmed in extensive studies. The risk of MS occurring in a monozygotic twin of an MS patient was found to be 31%, whereas the risk of MS occurring in a dizygotic twin was determined to be about 5%. The risk for a sibling or parent of an affected person was 2% to 5%, compared with a risk in the general population of only 0.1%. Further studies in adopted siblings and half-siblings demonstrated that this increased familial risk was entirely attributable to genetic rather than environmental factors. These findings imply that several interacting genes influence susceptibility to MS.
The genetic factors that confer susceptibility to MS are only partly known. The only locus reproducibly shown to be associated with MS is human leukocyte antigen (HLA) class II; the DRB1*1501 extended haplotype is associated with MS in white patients.[2,3] In an attempt to identify additional loci that contribute to MS, independent research groups conducted genome-wide screens on large groups of families with multiplex MS but found no genome regions with particularly strong linkage to MS.
The diagnosis of MS is made on the basis of the clinical signs and symptoms; MRI and other laboratory tests play a supporting role. Diagnosis requires evidence of the dissemination of lesions in time and space and the careful exclusion of other causes. The patient should have had more than one episode of neurologic dysfunction and should have evidence of white matter lesions in more than one part of the CNS. Because there is no pathognomonic sign or symptom or definitive laboratory test result, diagnosis requires careful clinical judgment and should be made only by an experienced neurologist. Common differential diagnostic considerations include structural lesions, inherited demyelinating or degenerative diseases, vasculitides, vascular disease, chronic infections (e.g., syphilis, Lyme disease, and human T cell lymphotropic virus type I), vitamin B12 deficiency, and neurosarcoidosis.
Several sets of established diagnostic criteria for MS are available, and an international panel has recently proposed a revised set of diagnostic criteria that utilizes both clinical presentation and laboratory data (see Table 1). The criteria require the objective demonstration of dissemination of lesions in space and time. This can be achieved with clinical evidence alone or with a combination of clinical and laboratory evidence. The types of laboratory evidence considered are MRI, CSF examination, and evoked responses.
Central pontine myelinolysis (CPM) is a syndrome in which neurologic deficits occur after rapid correction of hyponatremia. CPM usually occurs in young to middle-aged adults and is often associated with alcohol abuse or malnutrition. Signs and symptoms usually begin 3 days after the start of sodium replacement and consist of changes in mental status, dysarthria and other signs of corticobulbar dysfunction, and spastic quadriplegia. Improvement usually begins about 2 weeks after the onset of symptoms, but the degree of recovery is variable. The most striking finding on pathologic examination is the presence of symmetrical demyelinated lesions in the central pons. Demyelinated lesions may also occur in a relatively symmetrical pattern in the basal ganglia, thalamus, internal capsule, subcortical white matter, and cerebellum. T2-weighted MRI usually demonstrates the presence of hyperintense lesions. These lesions usually cannot be enhanced with contrast. CPM may also occur after liver transplantation. There is no specific treatment once symptoms have developed. Long duration and rapid correction of hyponatremia increase the risk of CPM; the recommended rate for correction of hyponatremia is no faster than 10 to 12 mEq in 24 hours.
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