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Journal of Pediatric Neurology 2018; 16(03): 141-147
DOI: 10.1055/s-0037-1604339
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Genetic and Environmental Risk Factors for Pediatric Multiple Sclerosis

Ilena C. George
1   Department of Neurology, Yale School of Medicine, New Haven, Connecticut, United States
,
Naila Makhani
2   Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, United States
› Author Affiliations
Further Information

Publication History

15 January 2017

16 June 2017

Publication Date:
24 July 2017 (online)

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Abstract

Both genetic and environmental risk factors may contribute to risk of multiple sclerosis (MS) in children. Genetic risk factors include the presence of the human leukocyte antigen (HLA)-DRB1*1501 allele and other non-HLA single nucleotide polymorphisms. Environmental risk factors include parental smoking, low serum vitamin D levels, and prior exposure to Epstein–Barr virus. Some of these risk factors not only confer increased susceptibility to MS but may also alter the course of the disease. How different risk factors interact is a growing area of research. In this review, we examine the current literature regarding the genetic and environmental risk factors for MS in children.

Keywords

multiple sclerosis - children - environmental - genetic

Note

Dr. George is a member of the Resident & Fellow Section of Neurology. Dr. Makhani is supported by a Junior Faculty Award from Race to Erase MS.


 

  • References

  • 1 Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol 2017; 13 (01) 25-36
    PubMedGoogle Scholar
  • 2 Küçükali Cİ, Kürtüncü M, Çoban A, Çebi M, Tüzün E. Epigenetics of multiple sclerosis: an updated review. Neuromolecular Med 2015; 17 (02) 83-96
    CrossrefPubMedGoogle Scholar
  • 3 Belbasis L, Bellou V, Evangelou E, Ioannidis JP, Tzoulaki I. Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses. Lancet Neurol 2015; 14 (03) 263-273
    CrossrefPubMedGoogle Scholar
  • 4 Ramagopalan SV, Maugeri NJ, Handunnetthi L. , et al. Expression of the multiple sclerosis-associated MHC class II allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet 2009; 5 (02) e1000369
    CrossrefPubMedGoogle Scholar
  • 5 Boiko AN, Gusev EI, Sudomoina MA. , et al. Association and linkage of juvenile MS with HLA-DR2(15) in Russians. Neurology 2002; 58 (04) 658-660
    CrossrefPubMedGoogle Scholar
  • 6 Disanto G, Magalhaes S, Handel AE. , et al; Canadian Pediatric Demyelinating Disease Network. HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurology 2011; 76 (09) 781-786
    CrossrefPubMedGoogle Scholar
  • 7 Banwell B, Bar-Or A, Arnold DL. , et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lancet Neurol 2011; 10 (05) 436-445
    CrossrefPubMedGoogle Scholar
  • 8 Hafler DA, Compston A, Sawcer S. , et al; International Multiple Sclerosis Genetics Consortium. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007; 357 (09) 851-862
    CrossrefPubMedGoogle Scholar
  • 9 Sawcer S, Hellenthal G, Pirinen M. , et al; International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476 (7359): 214-219
    CrossrefPubMedGoogle Scholar
  • 10 van Pelt ED, Mescheriakova JY, Makhani N. , et al. Risk genes associated with pediatric-onset MS but not with monophasic acquired CNS demyelination. Neurology 2013; 81 (23) 1996-2001
    CrossrefPubMedGoogle Scholar
  • 11 Barcellos LF, Shao X, Rhead B. , et al. First genome-wide analysis in pediatric multiple sclerosis confirms a role for adult MS risk variants and reveals new candidates. Presented at the AAN Annual Meeting, Vancouver, April 15–21, 2016
    PubMedGoogle Scholar
  • 12 Bashinskaya VV, Kulakova OG, Boyko AN, Favorov AV, Favorova OO. A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches. Hum Genet 2015; 134 (11-12): 1143-1162
    CrossrefPubMedGoogle Scholar
  • 13 Sawcer S, Franklin RJ, Ban M. Multiple sclerosis genetics. Lancet Neurol 2014; 13 (07) 700-709
    CrossrefPubMedGoogle Scholar
  • 14 Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006; 296 (23) 2832-2838
    CrossrefPubMedGoogle Scholar
  • 15 Gianfrancesco MA, Stridh P, Rhead B. , et al; Network of Pediatric Multiple Sclerosis Centers. Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology 2017; 88 (17) 1623-1629
    CrossrefPubMedGoogle Scholar
  • 16 Brenton JN, Koenig S, Goldman MD. Vitamin D status and age of onset of demyelinating disease. Mult Scler Relat Disord 2014; 3 (06) 684-688
    CrossrefPubMedGoogle Scholar
  • 17 Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000; 72 (03) 690-693
    CrossrefPubMedGoogle Scholar
  • 18 Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011; 11 (02) 85-97
    CrossrefPubMedGoogle Scholar
  • 19 Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology 2013; 80 (06) 548-552
    CrossrefPubMedGoogle Scholar
  • 20 Hedström AK, Lima Bomfim I, Hillert J, Olsson T, Alfredsson L. Obesity interacts with infectious mononucleosis in risk of multiple sclerosis. Eur J Neurol 2015; 22 (03) 578-e38
    CrossrefPubMedGoogle Scholar
  • 21 Ahn JJ, O'Mahony J, Moshkova M. , et al. Puberty in females enhances the risk of an outcome of multiple sclerosis in children and the development of central nervous system autoimmunity in mice. Mult Scler 2015; 21 (06) 735-748
    CrossrefPubMedGoogle Scholar
  • 22 Kaplowitz PB. Link between body fat and the timing of puberty. Pediatrics 2008; 121 (Suppl. 03) S208-S217
    CrossrefPubMedGoogle Scholar
  • 23 Banwell B, Krupp L, Kennedy J. , et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 2007; 6 (09) 773-781
    CrossrefPubMedGoogle Scholar
  • 24 Chitnis T, Graves J, Weinstock-Guttman B. , et al; U.S. Network of Pediatric MS Centers. Distinct effects of obesity and puberty on risk and age at onset of pediatric MS. Ann Clin Transl Neurol 2016; 3 (12) 897-907
    CrossrefPubMedGoogle Scholar
  • 25 Huppke B, Ellenberger D, Rosewich H, Friede T, Gärtner J, Huppke P. Clinical presentation of pediatric multiple sclerosis before puberty. Eur J Neurol 2014; 21 (03) 441-446
    CrossrefPubMedGoogle Scholar
  • 26 Lulu S, Graves J, Waubant E. Menarche increases relapse risk in pediatric multiple sclerosis. Mult Scler 2016; 22 (02) 193-200
    CrossrefPubMedGoogle Scholar
  • 27 Langer-Gould A, Zhang JL, Chung J, Yeung Y, Waubant E, Yao J. Incidence of acquired CNS demyelinating syndromes in a multiethnic cohort of children. Neurology 2011; 77 (12) 1143-1148
    CrossrefPubMedGoogle Scholar
  • 28 Belman AL, Krupp LB, Olsen CS. , et al; US Network of Pediatric MS Centers. Characteristics of children and adolescents with multiple sclerosis. Pediatrics 2016; 138 (01) e20160120
    CrossrefPubMedGoogle Scholar
  • 29 Kennedy J, O'Connor P, Sadovnick AD, Perara M, Yee I, Banwell B. Age at onset of multiple sclerosis may be influenced by place of residence during childhood rather than ancestry. Neuroepidemiology 2006; 26 (03) 162-167
    CrossrefPubMedGoogle Scholar
  • 30 Dean G, McLoughlin H, Brady R, Adelstein AM, Tallett-Williams J. Multiple sclerosis among immigrants in Greater London. BMJ 1976; 1 (6014): 861-864
    CrossrefPubMedGoogle Scholar
  • 31 Waubant E, Mowry EM, Krupp L. , et al; US Pediatric MS Network. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology 2011; 76 (23) 1989-1995
    CrossrefPubMedGoogle Scholar
  • 32 Makhani N, Banwell B, Tellier R. , et al; Canadian Pediatric Demyelinating Disease Network. Viral exposures and MS outcome in a prospective cohort of children with acquired demyelination. Mult Scler 2016; 22 (03) 385-388
    CrossrefPubMedGoogle Scholar
  • 33 Bager P, Nielsen NM, Bihrmann K. , et al. Childhood infections and risk of multiple sclerosis. Brain 2004; 127 (Pt 11): 2491-2497
    CrossrefPubMedGoogle Scholar
  • 34 Mowry EM, James JA, Krupp LB, Waubant E. Vitamin D status and antibody levels to common viruses in pediatric-onset multiple sclerosis. Mult Scler 2011; 17 (06) 666-671
    CrossrefPubMedGoogle Scholar
  • 35 Mikaeloff Y, Caridade G, Tardieu M, Suissa S. ; KIDSEP study group. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain 2007; 130 (Pt 10): 2589-2595
    CrossrefPubMedGoogle Scholar
  • 36 Tremlett H, Fadrosh DW, Faruqi AA. , et al; US Network of Pediatric MS Centers. Gut microbiota in early pediatric multiple sclerosis: a case-control study. Eur J Neurol 2016; 23 (08) 1308-1321
    CrossrefPubMedGoogle Scholar
  • 37 Tremlett H, Fadrosh DW, Faruqi AA. , et al; US Network of Pediatric MS Centers. Associations between the gut microbiota and host immune markers in pediatric multiple sclerosis and controls. BMC Neurol 2016; 16 (01) 182
    CrossrefPubMedGoogle Scholar
  • 38 Kleinewietfeld M, Manzel A, Titze J. , et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 2013; 496 (7446): 518-522
    CrossrefPubMedGoogle Scholar
  • 39 Wu C, Yosef N, Thalhamer T. , et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 2013; 496 (7446): 513-517
    CrossrefPubMedGoogle Scholar
  • 40 Fitzgerald K, Munger K, Freedman M. , et al. Increased sodium intake is not associated with MS activity or progression in BENEFIT. Presented at the AAN Annual Meeting, Vancouver, April 15–21, 2016
    PubMedGoogle Scholar
  • 41 McDonald J, Graves J, Waldman A. , et al. A case-control study of dietary salt intake in pediatric-onset multiple sclerosis. Mult Scler Relat Disord 2016; 6: 87-92
    CrossrefPubMedGoogle Scholar
  • 42 Langer-Gould A, Qian L, Tartof SY. , et al. Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases. JAMA Neurol 2014; 71 (12) 1506-1513
    CrossrefPubMedGoogle Scholar
  • 43 Farez MF, Correale J. Immunizations and risk of multiple sclerosis: systematic review and meta-analysis. J Neurol 2011; 258 (07) 1197-1206
    CrossrefPubMedGoogle Scholar
  • 44 Mikaeloff Y, Caridade G, Rossier M, Suissa S, Tardieu M. Hepatitis B vaccination and the risk of childhood-onset multiple sclerosis. Arch Pediatr Adolesc Med 2007; 161 (12) 1176-1182
    CrossrefPubMedGoogle Scholar
  • 45 Mikaeloff Y, Caridade G, Suissa S, Tardieu M. Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood. Neurology 2009; 72 (10) 873-880
    CrossrefPubMedGoogle Scholar
  • 46 Pellegrino P, Carnovale C, Pozzi M. , et al. On the relationship between human papilloma virus vaccine and autoimmune diseases. Autoimmun Rev 2014; 13 (07) 736-741
    CrossrefPubMedGoogle Scholar
  • 47 Hedström AK, Lima Bomfim I, Barcellos L. , et al. Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis. Neurology 2014; 82 (10) 865-872
    CrossrefPubMedGoogle Scholar
  • 48 Boster AL, Endress CF, Hreha SA, Caon C, Perumal JS, Khan OA. Pediatric-onset multiple sclerosis in African-American black and European-origin white patients. Pediatr Neurol 2009; 40 (01) 31-33
    CrossrefPubMedGoogle Scholar
  • 49 Mowry EM, Krupp LB, Milazzo M. , et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol 2010; 67 (05) 618-624
    PubMedGoogle Scholar
  • 50 Tremlett H, Fadrosh DW, Faruqi AA. , et al; US Network of Pediatric MS Centers. Gut microbiota composition and relapse risk in pediatric MS: a pilot study. J Neurol Sci 2016; 363: 153-157
    CrossrefPubMedGoogle Scholar
  • 51 Farez MF, Fiol MP, Gaitán MI, Quintana FJ, Correale J. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 2015; 86 (01) 26-31
    CrossrefPubMedGoogle Scholar
  • 52 Nourbakhsh B, Graves J, Casper TC. , et al; Network of Pediatric Multiple Sclerosis Centers. Dietary salt intake and time to relapse in paediatric multiple sclerosis. J Neurol Neurosurg Psychiatry 2016; 87 (12) 1350-1353
    CrossrefPubMedGoogle Scholar
  • 53 Graves JS, Barcellos LF, Shao X. , et al; U.S. Network of Pediatric MS Centers. Genetic predictors of relapse rate in pediatric MS. Mult Scler 2016; 22 (12) 1528-1535
    CrossrefPubMedGoogle Scholar