Although it has proven difficult to identify non-HLA susceptibility genes in MS, or even to determine the precise location of the well-established HLA association, there is little doubt that the risk of developing MS is at least in part genetically determined. In addition, there is now growing evidence that MS expressivity—the variability of the MS phenotype—is also influenced by heritable factors. Intrafamilial concordance in MS has been reported with regard to disease course (88), rate of progression (89), and ultimate disability (90,91), as well as age (92) and clinical manifestations (93) at disease onset.

Moreover, Weinshenker (94) has argued that MS is merely the arbitrarily demarcated prototype for a motley collection of ''idiopathic inflammatory demyeli-nating diseases of the CNS'' of varying severity and chronicity—including, at one end of the spectrum, monophasic, multifocal entities such as Devic's syndrome and, at the other, bout-less myelopathies of dubious dissemination in space or time. Although these ''IIDDs'' share many features, including presumed immunemediated pathogenesis, the propensity to develop one rather than the other seems, in some cases, to depend on ethnic background or immunogenetic phenotype; e.g., Devic's syndrome is more common in Orientals than in Caucasians (95,96), while acute monosymptomatic optic neuritis is more likely to be a manifestation of ''proto-typic MS'' in carriers of HLA-DR15 than in noncarriers (97,98). {The genes encoding the p chain of HLA-DR and other classical HLA proteins do not appear to influence MS prognosis, although the results of the innumerable studies that have investigated this phenomenon during the past three decades have been somewhat discordant [reviewed in (99)]}.

As Kantarci et al. (100) have pointed out, the hunt for disease-modifying genes in MS should make use of long-term outcome measures—such as the ''conversion''

from one IIDD to another, or the radiological or histopathological assessment of ultimate disease burden—which are more likely to be influenced by genetic factors than short-term, clinical measures of "stochastic" variables such as relapse frequency or early disability. Indeed, Fazekas et al. (101) have demonstrated the superiority of magnetic resonance imaging (MRI)-related outcome measures, in the context of genetic studies of MS expressivity, to measures based on clinical disability scales: in their initial dataset of 83 patients, the APOE e4 allele was significantly associated with greater lesion burden on MRI, whereas a significant effect on disability as assessed by the Expanded Disability Status Scale was not observed until the dataset was expanded to include 374 patients (102). Indeed, in the 25 studies examining the effect of APOE e4 on MS prognosis published to date (Table 3), 10 of the 18 studies employing clinical measures of disease severity have been negative (102-112,115118,122,124,125), while four of seven studies incorporating radiological measures have been positive (101,113,114,119,120,122,123).

APOE encodes apolipoprotein E, a molecule synthesized and secreted by glial cells that serves as a ligand mediating the uptake of plasma lipoproteins, which are vital for membrane repair. The e4 allele is associated, clinically, with susceptibility to, and lower age at onset in, both familial and sporadic Alzheimer's disease (AD) (126) and adverse outcome following head trauma and stroke (127); pathologically, with less efficient dendritic remodeling in brains from AD patients (128); and, radi-ologically, with greater T1-weighted lesion load on MRI in patients with MS (101). APOE alleles could conceivably influence clinical outcome in MS through the differential effects of the isoforms they encode on remyelination or axonal degeneration. Chapman et al. (129) have hypothesized that such effects could be the mechanism behind both the progression-hastening impact of APOE s4 in neurodegenerative disorders diagnosed early in life, such as MS and Creuzfeldt-Jakob disease (130) and the allele's onset-hastening impact in neurodegenerative disorders diagnosed late in life, such as AD and Wilson's disease (131).

When all the evidence is weighed (Table 3), polymorphism of APOE appears to explain at least a portion of the radiological and clinical heterogeneity of MS. Still, the most meaningful form of heterogeneity in MS may prove to be that described by Lucchinetti et al. (132), who observed four distinct patterns of MS pathology—with each pattern occurring alone in a given subject—in biopsy or autopsy material from 83 patients. These pathological patterns may represent "proximal phenotypes''— upstream biological determinants of an indeterminate clinical phenotype—of the type whose identification and analysis (133) have been advocated by Terwilliger and Goring (133) for the successful genetic dissection of etiologically heterogeneous complex diseases. As Kantarci et al. (100) remark, however, only after laboratory or neuroimaging correlates of the patterns are defined will it become possible to routinely analyze the contribution of genetic factors to the pathological heterogeneity of MS. In the meantime, most MS expressivity studies to date (100) have had to content themselves with more distal clinical and paraclinical surrogates.

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