Genetics and Natural History of Multiple Sclerosis

ABSTRACT

Recent studies have better defined the association between the human leukocyte antigen (HLA)-DR, cytotoxic T-lymphocyte antigen-4, interleukin-7 receptor, and interferon-gamma polymorphisms and susceptibility to multiple sclerosis (MS), while many more studies have been added to the controversial pool of likely false-positive and false-negative genetic association and linkage studies. Apolipoprotein E alleles may yet play an important role in disease course and cognitive impairment, although largely refuted as being directly associated with ambulatory measures of disease severity. Natural history studies have started to better define the clinical phenotypic heterogeneity of idiopathic inflammatory diseases of the central nervous system, fueling new hypotheses about immunopathogenesis of MS. Our understanding of phenotype measurement tools is improving. However, despite all the ongoing effort, the cause of MS and the determinants of heterogeneity in the clinical phenotype of MS remain largely unknown. As advances in our understanding of the immunobiology of MS start to bridge the gap between pathological and clinical natural history of the disease, biologically relevant phenotypes of MS will hopefully emerge to allow more specific treatment modalities to be developed and brought to practice.

KEYWORDS

Genetic epidemiology - natural history - prognosis - multiple sclerosis

REFERENCES

• 1 Lucchinetti C F, Parisi J, Bruck W. The pathology of multiple sclerosis.  Neurol Clin. 2005;  23(1) 77-105
• 2 Kantarci O H, Weinshenker B G. Natural history of multiple sclerosis.  Neurol Clin. 2005;  23(1) 17-38
• 3 McDonald W I, Compston A, Edan G et al.. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis.  Ann Neurol. 2001;  50(1) 121-127
• 4 Poser C M, Paty D W, Scheinberg L et al.. New diagnostic criteria for multiple sclerosis: guidelines for research protocols.  Ann Neurol. 1983;  13(3) 227-231
• 5 Kantarci O H, de Andrade M, Weinshenker B G. Identifying disease modifying genes in multiple sclerosis.  J Neuroimmunol. 2002;  123(1-2) 144-159
• 6 Oksenberg J R, Barcellos L F. The complex genetic aetiology of multiple sclerosis.  J Neurovirol. 2000;  6(S2) S10-S14
• 7 Ebers G C, Sadovnick A D, Risch N J. A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group [see comment].  Nature. 1995;  377(6545) 150-151
• 8 Weinshenker B G. Epidemiology of multiple sclerosis.  Neurol Clin. 1996;  14(2) 291-308
• 9 Ebers G C. A twin consensus in MS [see comment].  Mult Scler. 2005;  11(5) 497-499
• 10 Kantarci O H, Barcellos L F, Atkinson E J et al.. Men transmit MS more often to their children vs women: the Carter effect.  Neurology. 2006;  67(2) 305-310
• 11 Ebers G C, Sadovnick A D, Dyment D A et al.. Parent-of-origin effect in multiple sclerosis: observations in half-siblings.  Lancet. 2004;  363(9423) 1773-1774
• 12 Herrera B M, Ramagopalan S V, Orton S et al.. Parental transmission of MS in a population-based Canadian cohort [see comment].  Neurology. 2007;  69(12) 1208-1212
• 13 Hensiek A E, Seaman S R, Barcellos L F et al.. Familial effects on the clinical course of multiple sclerosis.  Neurology. 2007;  68(5) 376-383
• 14 Weiss K M, Terwilliger J D. How many diseases does it take to map a gene with SNPs?.  Nat Genet. 2000;  26(2) 151-157
• 15 GAMES; Transatlantic Multiple Sclerosis Genetics Cooperative . A meta-analysis of whole genome linkage screens in multiple sclerosis.  J Neuroimmunol. 2003;  143(1-2) 39-46
• 16 Sawcer S, Compston A. The genetic analysis of multiple sclerosis in Europeans: concepts and design [see comment].  J Neuroimmunol. 2003;  143(1-2) 13-16
• 17 Sawcer S, Ban M, Maranian M et al.. A high-density screen for linkage in multiple sclerosis.  Am J Hum Genet. 2005;  77 454-467
• 18 Oksenberg J R, Barcellos L F, Cree B A et al.. Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans.  Am J Hum Genet. 2004;  74(1) 160-167
• 19 Lincoln M R, Montpetit A, Cader M Z et al.. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis.  Nat Genet. 2005;  37(10) 1108-1112
• 20 Barcellos L F, Sawcer S, Ramsay P P et al.. Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis.  Hum Mol Genet. 2006;  15(18) 2813-2824
• 21 Reich D, Patterson N, De Jager P L et al.. A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility.  Nat Genet. 2005;  37(10) 1113-1118
• 22 Gough S C, Walker L S, Sansom D M. CTLA4 gene polymorphism and autoimmunity.  Immunol Rev. 2005;  204 102-115
• 23 Harbo H F, Celius E G, Vartdal F, Spurkland A. CTLA4 promoter and exon 1 dimorphisms in multiple sclerosis.  Tissue Antigens. 1999;  53(1) 106-110
• 24 Ligers A, Xu C, Saarinen S, Hillert J, Olerup O. The CTLA-4 gene is associated with multiple sclerosis.  J Neuroimmunol. 1999;  97(1-2) 182-190
• 25 Fukazawa T, Yanagawa T, Kikuchi S et al.. CTLA-4 gene polymorphism may modulate disease in Japanese multiple sclerosis patients.  J Neurol Sci. 1999;  171(1) 49-55
• 26 Kantarci O H, Hebrink D D, Achenbach S J et al.. CTLA4 is associated with susceptibility to multiple sclerosis.  J Neuroimmunol. 2003;  134(1-2) 133-141
• 27 Suppiah V, Alloza I, Heggarty S et al.. The CTLA4 + 49 A/G*G-CT60*G haplotype is associated with susceptibility to multiple sclerosis in Flanders.  J Neuroimmunol. 2005;  164(1-2) 148-153
• 28 Dincic E, Zivkovic M, Stankovic A et al.. Association of polymorphisms in CTLA-4, IL-1ra and IL-1beta genes with multiple sclerosis in Serbian population.  J Neuroimmunol. 2006;  177(1-2) 146-150
• 29 Malferrari G, Stella A, Monferini E et al.. Ctla4 and multiple sclerosis in the Italian population.  Exp Mol Pathol. 2005;  78(1) 55-57
• 30 Alizadeh M, Babron M C, Birebent B et al.. Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients.  Ann Neurol. 2003;  54(1) 119-122
• 31 Roxburgh R H, Sawcer S, Maranian M et al.. No evidence of a significant role for CTLA-4 in multiple sclerosis.  J Neuroimmunol. 2006;  171(1-2) 193-197
• 32 Fukazawa T, Kikuchi S, Miyagishi R et al.. CTLA-4 gene polymorphism is not associated with conventional multiple sclerosis in Japanese.  J Neuroimmunol. 2005;  159(1-2) 225-229
• 33 Teutsch S M, Booth D R, Bennetts B H, Heard R N, Stewart G J. Association of common T cell activation gene polymorphisms with multiple sclerosis in Australian patients.  J Neuroimmunol. 2004;  148(1-2) 218-230
• 34 Lorentzen A R, Celius E G, Ekstrom P O et al.. Lack of association with the CD28/CTLA4/ICOS gene region among Norwegian multiple sclerosis patients.  J Neuroimmunol. 2005;  166(1-2) 197-201
• 35 Masterman T, Ligers A, Zhang Z et al.. CTLA4 dimorphisms and the multiple sclerosis phenotype.  J Neuroimmunol. 2002;  131(1-2) 208-212
• 36 Barcellos L F, Kamdar B B, Ramsay P P et al.. Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a descriptive study [see comment].  Lancet Neurol. 2006;  5(11) 924-931
• 37 Goris A, Heggarty S, Marrosu M G et al.. Linkage disequilibrium analysis of chromosome 12q14-15 in multiple sclerosis: delineation of a 118-kb interval around interferon-gamma (IFNG) that is involved in male versus female differential susceptibility.  Genes Immun. 2002;  3(8) 470-476
• 38 Reboul J, Mertens C, Levillayer F et al.. Cytokines in genetic susceptibility to multiple sclerosis: a candidate gene approach.  French Multiple Sclerosis Genetics Group . J Neuroimmunol. 2000;  102(1) 107-112
• 39 Vandenbroeck K, Cunningham S, Goris A et al.. Polymorphisms in the interferon-gamma/interleukin-26 gene region contribute to sex bias in susceptibility to rheumatoid arthritis.  Arthritis Rheum. 2003;  48(10) 2773-2778
• 40 Kantarci O H, Goris A, Hebrink D D et al.. IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis.  Genes Immun. 2005;  6(2) 153-161
• 41 Dai Y, Masterman T, Huang W X et al.. Analysis of an interferon-gamma gene dinucleotide-repeat polymorphism in Nordic multiple sclerosis patients.  Mult Scler. 2001;  7(3) 157-163
• 42 Goris A, Epplen C, Fiten P et al.. Analysis of an IFN-gamma gene (IFNG) polymorphism in multiple sclerosis in Europe: effect of population structure on association with disease.  J Interferon Cytokine Res. 1999;  19(9) 1037-1046
• 43 Schrijver H M, Hooper-van Veen T, van Belzen M J et al.. Polymorphisms in the genes encoding interferon-gamma and interferon-gamma receptors in multiple sclerosis.  Eur J Immunogenet. 2004;  31(3) 133-140
• 44 Bergkvist M, Olsson M, Sandberg-Wollheim M. No evidence for genetic linkage between development of multiple sclerosis and components of the IFN system and the JAK-STAT pathway.  Mult Scler. 2004;  10(1) 87-88
• 45 Gee J R, Keller J N. Astrocytes: regulation of brain homeostasis via apolipoprotein E.  Int J Biochem Cell Biol. 2005;  37(6) 1145-1150
• 46 Laskowitz D T, Horsburgh K, Roses A D. Apolipoprotein E and the CNS response to injury.  J Cereb Blood Flow Metab. 1998;  18(5) 465-471
• 47 Enzinger C, Ropele S, Strasser-Fuchs S et al.. Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele [see comment].  Arch Neurol. 2003;  60(1) 65-70
• 48 Schmidt S, Barcellos L F, DeSombre K et al.. Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis.  Am J Hum Genet. 2002;  70(3) 708-717
• 49 Kantarci O H, Hebrink D D, Achenbach S J et al.. Association of APOE polymorphisms with disease severity in MS is limited to women [see comment].  Neurology. 2004;  62(5) 811-814
• 50 Cocco E, Sotgiu A, Costa G et al.. HLA-DR, DQ and APOE genotypes and gender influence in Sardinian primary progressive MS.  Neurology. 2005;  64(3) 564-566
• 51 Savettieri G, Messina D, Andreoli V et al.. Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis.  J Neurol. 2004;  251(10) 1208-1214
• 52 Burwick R M, Ramsay P P, Haines J L et al.. APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers.  Neurology. 2006;  66(9) 1373-1383
• 53 Koutsis G, Panas M, Giogkaraki E et al.. APOE epsilon4 is associated with impaired verbal learning in patients with MS.  Neurology. 2007;  68(8) 546-549
• 54 Ebers G C, Kukay K, Bulman D E et al.. A full genome search in multiple sclerosis [see comment].  Nat Genet. 1996;  13(4) 472-476
• 55 Zhang Z, Duvefelt K, Svensson F et al.. Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis.  Genes Immun. 2005;  6(2) 145-152
• 56 Hafler D A, Compston A, Sawcer S International Multiple Sclerosis Genetics Consortium et al.. Risk alleles for multiple sclerosis identified by a genomewide study.  N Engl J Med. 2007;  357(9) 851-862
• 57 Lundmark F, Salter H, Hillert J. An association study of two functional promotor polymorphisms in the myeloperoxidase (MPO) gene in multiple sclerosis.  Mult Scler. 2007;  13(6) 697-700
• 58 Lucchinetti C, Bruck W, Parisi J et al.. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination [see comment].  Ann Neurol. 2000;  47(6) 707-717
• 59 CHAMPS Group Study . Interferon beta-1a for optic neuritis patients at high risk for multiple sclerosis.  Am J Ophthalmol. 2001;  132(4) 463-471
• 60 Beck R W, Chandler D L, Cole S R et al.. Interferon beta-1a for early multiple sclerosis: CHAMPS trial subgroup analyses.  Ann Neurol. 2002;  51(4) 481-490
• 61 Beck R W, Trobe J D, Moke P S et al.. High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial [see comment].  Arch Ophthalmol. 2003;  121(7) 944-949
• 62 Cordonnier C, de Seze J, Breteau G et al.. Prospective study of patients presenting with acute partial transverse myelopathy.  J Neurol. 2003;  250(12) 1447-1452
• 63 Ford B, Tampieri D, Francis G. Long-term follow-up of acute partial transverse myelopathy [see comment].  Neurology. 1992;  42 250-252
• 64 Weinshenker B G, Wingerchuk D M, Vukusic S et al.. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis.  Ann Neurol. 2006;  59(3) 566-569
• 65 Weinshenker B G. Plasma exchange for severe attacks of inflammatory demyelinating diseases of the central nervous system.  J Clin Apher. 2001;  16(1) 39-42
• 66 Keegan M, Konig F, McClelland R et al.. Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange [see comment].  Lancet. 2005;  366(9485) 579-582
• 67 Wingerchuk D M. Neuromyelitis optica: current concepts.  Front Biosci. 2004;  9 834-840
• 68 Kantarci O, Siva A, Eraksoy M et al.. Survival and predictors of disability in Turkish MS patients.  Turkish Multiple Sclerosis Study Group (TUMSSG) . Neurology. 1998;  51(3) 765-772
• 69 Rodriguez M, Siva A, Ward J et al.. Impairment, disability, and handicap in multiple sclerosis: a population-based study in Olmsted County, Minnesota.  Neurology. 1994;  44(1) 28-33
• 70 Frohman E M, Filippi M, Stuve O et al.. Characterizing the mechanisms of progression in multiple sclerosis: evidence and new hypotheses for future directions [see comment].  Arch Neurol. 2005;  62(9) 1345-1356
• 71 Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up.  Brain. 1993;  116(Pt 1) 117-134
• 72 Riise T, Gronning M, Fernandez O et al.. Early prognostic factors for disability in multiple sclerosis, a European multicenter study.  Acta Neurol Scand. 1992;  85(3) 212-218
• 73 Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis [see comment].  N Engl J Med. 2000;  343(20) 1430-1438
• 74 Trojano M, Avolio C, Manzari C et al.. Multivariate analysis of predictive factors of multiple sclerosis course with a validated method to assess clinical events.  J Neurol Neurosurg Psychiatry. 1995;  58(3) 300-306
• 75 Bergamaschi R, Berzuini C, Romani A, Cosi V. Predicting secondary progression in relapsing-remitting multiple sclerosis: a Bayesian analysis [see comment].  J Neurol Sci. 2001;  189(1-2) 13-21
• 76 Ann Marrie R, Rudick R A. Drug insight: interferon treatment in multiple sclerosis.  Nat Clin Pract Neurol. 2006;  2(1) 34-44
• 77 Fox E J. Management of worsening multiple sclerosis with mitoxantrone: a review.  Clin Ther. 2006;  28(4) 461-474
• 78 Kurtzke J F. Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS).  Neurology. 1983;  33(11) 1444-1452
• 79 Rao S M, Leo G J, Haughton V M, St Aubin-Faubert P, Bernardin L. Correlation of magnetic resonance imaging with neuropsychological testing in multiple sclerosis.  Neurology. 1989;  39(2 Pt 1) 161-166
• 80 Rudick R A. Clinical outcomes assessment in multiple sclerosis: Part I.  Mult Scler. 1996;  2(5) 244-246
• 81 Fischer J S, Rudick R A, Cutter G R, Reingold S C. The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force.  Mult Scler. 1999;  5(4) 244-250
• 82 Goodkin D E, Hertsgaard D, Seminary J. Upper extremity function in multiple sclerosis: improving assessment sensitivity with box-and-block and nine-hole peg tests.  Arch Phys Med Rehabil. 1988;  69(10) 850-854
• 83 Miller D M, Rudick R A, Cutter G, Baier M, Fischer J S. Clinical significance of the multiple sclerosis functional composite: relationship to patient-reported quality of life.  Arch Neurol. 2000;  57(9) 1319-1324
• 84 Deloire M S, Salort E, Bonnet M et al.. Cognitive impairment as marker of diffuse brain abnormalities in early relapsing remitting multiple sclerosis.  J Neurol Neurosurg Psychiatry. 2005;  76(4) 519-526
• 85 Achiron A, Polliack M, Rao S M et al.. Cognitive patterns and progression in multiple sclerosis: construction and validation of percentile curves.  J Neurol Neurosurg Psychiatry. 2005;  76(5) 744-749
• 86 Roxburgh R HSR, Seaman S R, Mastermann T et al.. Multiple Sclerosis Severity Score. Using disability and disease duration to rate disease severity.  Neurology. 2005;  64 1144-1151
• 87 Weinshenker B G, Bass B, Rice G P et al.. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability.  Brain. 1989;  112(Pt 1) 133-146
• 88 Weinshenker B G, Bass B, Rice G P et al.. The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course.  Brain. 1989;  112(Pt 6) 1419-1428
• 89 Pittock S J, McClelland R L, Mayr W T et al.. Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study.  Ann Neurol. 2004;  56(2) 303-306
• 90 Pittock S J. Does benign multiple sclerosis today imply benign multiple sclerosis tomorrow?: implications for treatment [see comment].  Neurology. 2007;  68 480-481
• 91 Langer-Gould A, Popat R A, Huang S M et al.. Clinical and demographic predictors of long-term disability in patients with relapsing-remitting multiple sclerosis: a systematic review.  Arch Neurol. 2006;  63(12) 1686-1691
• 92 Confavreux C, Hutchinson M, Hours M M, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group [see comment].  N Engl J Med. 1998;  339(5) 285-291
• 93 Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process [see comment].  Brain. 2003;  126(Pt 4) 770-782
• 94 Cottrell D A, Kremenchutzky M, Rice G P et al.. The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis [see comment].  Brain. 1999;  122(Pt 4) 625-639
• 95 Tremlett H, Paty D, Devonshire V. The natural history of primary progressive MS in British Columbia, Canada.  Neurology. 2005;  65 1919-1923
• 96 Sadovnick A D, Eisen K, Ebers G C, Paty D W. Cause of death in patients attending multiple sclerosis clinics [see comment].  Neurology. 1991;  41(8) 1193-1196
• 97 Phadke J G. Survival pattern and cause of death in patients with multiple sclerosis: results from an epidemiological survey in north-east Scotland.  J Neurol Neurosurg Psychiatry. 1987;  50(5) 523-531
• 98 Riise T, Grønning M, Aarli J A, Nyland H, Larsen J P, Edland A. Prognostic factors for life expectancy in multiple sclerosis analysed by Cox-models.  J Clin Epidemiol. 1988;  41(10) 1031-1036
• 99 Poser S, Kurtzke J F, Poser W, Schlaf G. Survival in multiple sclerosis.  J Clin Epidemiol. 1989;  42(2) 159-168
• 100 Bronnum-Hansen H, Koch-Henriksen N, Hyllested K. Survival of patients with multiple sclerosis in Denmark: a nationwide, long-term epidemiologic survey.  Neurology. 1994;  44(10) 1901-1907
• 101 Pekmezovic T, Jarebinski M, Drulovic J, Stojsavljevic N, Levic Z. Survival of multiple sclerosis patients in the Belgrade population.  Neuroepidemiology. 2002;  21(5) 235-240
• 102 Wallin M T, Page W F, Kurtzke J F. Epidemiology of multiple sclerosis in US veterans. VIII. Long-term survival after onset of multiple sclerosis.  Brain. 2000;  123(Pt 8) 1677-1687