Abstract
In this Review (Part I), we investigate the scientific evidence that multiple sclerosis (MS) is caused by the death of oligodendrocytes, the cells that synthesize myelin, due to a lack of biochemical and nutritional factors involved in mitochondrial energy production in these cells. In MS, damage to the myelin sheaths surrounding nerve axons causes disruption of signal transmission from the brain to peripheral organs, which may lead to disability. However, the extent of disability is not deterred by the use of MS medication, which is based on the autoimmune hypothesis of MS. Rather, disability is associated with the loss of brain volume, which is related to the loss of grey and white matter. A pathology-supported genetic testing (PSGT) method, developed for personalized assessment and treatment to prevent brain volume loss and disability progression in MS is discussed. This involves identification of MS-related pathogenic pathways underpinned by genetic variation and lifestyle risk factors that may converge into biochemical abnormalities associated with adverse expanded disability status scale (EDSS) outcomes and magnetic resonance imaging (MRI) findings during patient follow-up. A Metabolic Model is presented which hypothesizes that disability may be prevented or reversed when oligodendrocytes are protected by nutritional reserve. Evidence for the validity of the Metabolic Model may be evaluated in consecutive test cases following the PSGT method. In Part II of this Review, two cases are presented that describe the PSGT procedures and the clinical outcomes of these individuals diagnosed with MS.
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References
Adams RA, Schachtrup C, Davalos D, Tsigelny I, Akassoglou K (2007) Fibrinogen signal transduction as a mediator and therapeutic target in inflammation: lessons from multiple sclerosis. Curr Med Chem 14:2925–2936. https://doi.org/10.2174/092986707782360015
Al-Serri A, Alroughani R, Al-Temaimi RA (2019) The FTO gene polymorphism rs9939609 is associated with obesity and disability in multiple sclerosis patients. Sci Rep 9:19071. https://doi.org/10.1038/s41598-019-55742-2
Argaw AT, Zhang Y, Snyder BJ, Zhao ML, Kopp N, Lee SC, Raine CS, Brosnan CF, John GR (2006) IL-1beta regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. J Immunol 177:5574–5584. https://doi.org/10.4049/jimmunol.177.8.5574
Armon-Omer A, Waldman C, Simaan N, Neuman H, Tamir S, Shahien R (2019) New insights on the nutrition status and antioxidant capacity in multiple sclerosis patients. Nutrients 11. Pii: E427. doi: https://doi.org/10.3390/nu11020427
Azary S, Schreiner T, Graves J, Waldman A, Belman A, Weinstock Guttman B, Aaen G, Tillema J-M, Mar S, Hart J, Ness J, Harris Y, Krupp L, Gorman M, Benson L, Rodriguez M, Chitnis T, Rose J, Barcellos LF, Lotze T, Carmichael SL, Roalstad S, Casper CT, Waubant E (2018) Contribution of dietary intake to relapse rate in early paediatric multiple sclerosis. J Neurol Neurosurg Psychiatry 89:28–33. https://doi.org/10.1136/jnnp-2017-315936
Bakhuraysah MM, Siatskas C, Petratos S (2016) Hematopoietic stem cell transplantation for multiple sclerosis: is it a clinical reality? Stem Cell Res Ther 7:12. https://doi.org/10.1186/s13287-015-0272-1
Banwell B, Giovannoni G, Hawkes C, Lublin F (2013) Editors' welcome and a working definition for a multiple sclerosis cure. Mult Scler Relat Disord 2:65–67. https://doi.org/10.1016/j.msard.2012.12.001
Baranzini SE, Mudge J, van Velkinburgh JC, Khankhanian P, Khrebtukova I, Miller NA, Zhang L, Farmer AD, Bell CJ, Kim RW, May GD, Woodward JE, Caillier SJ, McElroy JP, Gomez R, Pando MJ, Clendenen LE, Ganusova EE, Schilkey FD, Ramaraj T, Khan OA, Huntley JJ, Luo S, Kwok PY, Wu TD, Schroth GP, Oksenberg JR, Hauser SL, Kingsmore SF (2010) Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464:1351–1356. https://doi.org/10.1038/nature08990
Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55:458–468. https://doi.org/10.1002/ana.20016
Bartosik-Psujek H, Psujek M (2019) Vitamin D as an immune modulator in multiple sclerosis. Neurol Neurochir Pol 53:113–122. https://doi.org/10.5603/PJNNS.a2019.0015
Bartzokis G (2011) Neuroglialpharmacology: white matter pathophysiologies and psychiatric treatments. Front Biosci (Landmark Ed) 16:2695–2733. https://doi.org/10.2741/3881
Bejaoui K, Rolak LA (2010) What is the risk of permanent disability from a multiple sclerosis relapse? Neurology 74:900–902. https://doi.org/10.1212/WNL.0b013e3181d55ee9
Bengtsson SL, Nagy Z, Skare S, Forsman L, Forssberg H, Ullén F (2005) Extensive piano practicing has regionally specific effects on white matter development. Nat Neurosci 8:1148–1150. https://doi.org/10.1038/nn1516
Bosler A, Greene D (2017) How to practice effectively for just about anything. TED-Ed 27 Feb 2017. https://youtu.be/f2O6mQkFiiw. Accessed 26 Sept 2020
Boster A, Caon C, Perumal J, Hreha S, Zabad R, Zak I, Tselis A, Lisak R, Khan O (2008) Failure to develop multiple sclerosis in patients with neurologic symptoms without objective evidence. Mult Scler 14:804–808. https://doi.org/10.1177/1352458507088156
Brand MD (2016) Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic Biol Med 100:14–31. https://doi.org/10.1016/j.freeradbiomed.2016.04.001
Burt RK, Balabanov R, Han X, Sharrack B, Morgan A, Quigley K, Yaung K, Helenowski IB, Jovanovic B, Spahovic D, Arnautovic I, Lee DC, Benefield BC, Futterer S, Oliveira MC, Burman J (2015) Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA 313:275–284. https://doi.org/10.1001/jama.2014.17986
Burtchell J (2019) Should Multiple Sclerosis Drugs Cost $62,000 a Year? https://www.healthline.com/health-news/ms-why-are-ms-drug-prices-so-high-071913#Medications-as-Commodities. Accessed 15 February 2021
Chaudhuri A, Behan PO (2013) Lessons from clinical trials of alemtuzumab in multiple sclerosis. Mult Scler Relat Disord 2:92–95. https://doi.org/10.1016/j.msard.2012.08.005
Chiou B, Neal EH, Bowman AB, Lippmann ES, Simpson IA, Connor JR (2018) Endothelial cells are critical regulators of iron transport in a model of the human blood-brain barrier. J Cereb Blood Flow Metab 39:2117–2131. https://doi.org/10.1177/0271678X18783372
Claflin SB, Tan B, Taylor BV (2019) The long-term effects of disease modifying therapies on disability in people living with multiple sclerosis: a systematic review and meta-analysis. Mult Scler Relat Disord 36:101374. https://doi.org/10.1016/j.msard.2019.08.016
Cobine PA, Pierrel F, Winge DR (2006) Copper trafficking to the mitochondrion and assembly of copper metalloenzymes. Biochim Biophys Acta 1763:759–772. https://doi.org/10.1016/j.bbamcr.2006.03.002
Confavreux C, Vukusic S, Moreau T, Adeleine P (2000) Among patients with multiple sclerosis, relapses do not significantly influence the progression of irreversible disability. N Engl J Med 343:1430–1438. https://doi.org/10.1056/NEJM200011163432001
Connor JR, Menzies SL (1996) Relationship of iron to oligodendrocytes and myelination. Glia 17:83–93. https://doi.org/10.1002/(SICI)1098-1136(199606)17:2<83::AID-GLIA1>3.0.CO;2-7
Davis W, van Rensburg SJ, Cronje FJ, Whati L, Fisher LR, van der Merwe L, Geiger D, Hassan MS, Matsha T, Erasmus RT, Kotze MJ (2014) The fat mass and obesity-associated FTO rs9939609 polymorphism is associated with elevated homocysteine levels in patients with multiple sclerosis screened for vascular risk factors. Metab Brain Dis 29:409–419. https://doi.org/10.1007/s11011-014-9486-7
de la Fuente AG, Errea O, van Wijngaarden P, Gonzalez GA, Kerninon C, Jarjour AA, Lewis HJ, Jones CA, Nait-Oumesmar B, Zhao C, Huang JK, Ffrench-Constant C, Franklin RJ (2015) Vitamin D receptor-retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation. J Cell Biol 211:975–985. https://doi.org/10.1083/jcb.201505119
De Riccardis L, Buccolieri A, Muci M, Pitotti E, De Robertis F, Trianni G, Manno D, Maffia M (2018) Copper and ceruloplasmin dyshomeostasis in serum and cerebrospinal fluid of multiple sclerosis subjects. Biochim Biophys Acta Mol Basis Dis 1864(5 Pt A):1828–1838. https://doi.org/10.1016/j.bbadis.2018.03.007
Ebers G, De Luca G (2010) Faculty opinions recommendation of [Bejaoui K and Rolak LA, Neurology 2010 74(11):900–902] In Faculty Opinions, 30 Dec 2010; https://doi.org/10.3410/f.7180957.7433059
Ernster L, Dallner G (1995) Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta 1271:195–204. https://doi.org/10.1016/0925-4439(95)00028-3
Exley C, Mamutse G, Korchazhkina O, Pye E, Strekopytov S, Polwart A, Hawkins C (2006) Elevated urinary excretion of aluminium and iron in multiple sclerosis. Mult Scler J 12(5):533–540. https://doi.org/10.1177/1352458506071323
Field J, Browning SR, Johnson LJ, Danoy P, Varney MD, Tait BD, Gandhi KS, Charlesworth JC, Heard RN, Australia and New Zealand Multiple Sclerosis Genetics Consortium, Stewart GJ, Kilpatrick TJ, Foote SJ, Bahlo M, Butzkueven H, Wiley J, Booth DR, Taylor BV, Brown MA, Rubio JP, Stankovich J (2010) A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis. PLoS One 5(10):e13454. https://doi.org/10.1371/journal.pone.0013454
Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, Drexhage J, Mahad D, Bradl M, van Horssen J, Lassmann H (2012) NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain 135(Pt 3):886–899. https://doi.org/10.1093/brain/aws012
Frau J, Carai M, Coghe G, Fenu G, Lorefice L, La Nasa G, Mamusa E, Vacca A, Marrosu MG, Cocco E (2018) Long-term follow-up more than 10 years after HSCT: a monocentric experience. J Neurol 265:410–416. https://doi.org/10.1007/s00415-017-8718-2
Freeman JA, Playford ED (2012) Rehabilitation therapy in MS; a short-term, expensive, placebo. Mult Scler 18:1379–1381. https://doi.org/10.1177/1352458512459692
French HM, Reid M, Mamontov P, Simmons RA, Grinspan JB (2009) Oxidative stress disrupts oligodendrocyte maturation. J Neurosci Res 87:3076–3087. https://doi.org/10.1002/jnr.22139
Gaitán MI, Correale J (2019) Multiple sclerosis misdiagnosis: a persistent problem to solve. Front Neurol 10:466. https://doi.org/10.3389/fneur.2019.00466 eCollection 2019
Gemmati D, Zeri G, Orioli E, De Gaetano FE, Salvi F, Bartolomei I, D'Alfonso S, Dall'osso C, Leone MA, Singh AV, Asselta R, Zamboni P (2012) Polymorphisms in the genes coding for iron binding and transporting proteins are associated with disability, severity, and early progression in multiple sclerosis. BMC Med Genet 13:70. https://doi.org/10.1186/1471-2350-13-70
Giovannoni G (2018) Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 31:233–243. https://doi.org/10.1097/WCO.0000000000000561
Graumann U, Reynolds R, Steck AJ, Schaeren-Wiemers N (2003) Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult. Brain Pathol 13:554–573. https://doi.org/10.1111/j.1750-3639.2003.tb00485.x
Hartung DM, Bourdette DN, Ahmed SM, Whitham RH (2015) The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: too big to fail? Neurology 84:2185–2192. https://doi.org/10.1212/WNL.0000000000001608
Hauser SL (2015) Hematopoietic stem cell transplantation for MS: extraordinary evidence still needed. JAMA 313:251–252. https://doi.org/10.1001/jama.2014.18150
Healey KM, Pavletic SZ, Al-Omaishi J, Leuschen MP, Pirruccello SJ, Filipi ML, Enke C, Ursick MM, Hahn F, Bowen JD, Nash RA (2004) Discordant functional and inflammatory parameters in multiple sclerosis patients after autologous haematopoietic stem cell transplantation. Mult Scler 10:284–289. https://doi.org/10.1191/1352458504ms1022oa
Herbert E, Engel-Hills P, Hattingh C, Fouche JP, Kidd M, Lochner C, Kotze MJ, van Rensburg SJ (2018) Fractional anisotropy of white matter, disability and blood iron parameters in multiple sclerosis. Metab Brain Dis 33:545–557. https://doi.org/10.1007/s11011-017-0171-5
Hibbits N, Pannu R, Wu TJ, Armstrong RC (2009) Cuprizone demyelination of the corpus callosum in mice correlates with altered social interaction and impaired bilateral sensorimotor coordination. ASN Neuro 1. Pii: e00013. doi: https://doi.org/10.1042/AN20090032
Hohlfeld R (2010) 'Gimme five': future challenges in multiple sclerosis. ECTRIMS lecture 2009. Mult Scler 16:3–14. https://doi.org/10.1177/1352458509357355
Hutchinson M (2012) Do not treat from CIS onset: evaluate disease course and prognosis first--commentary. Mult Scler 18:396–397. https://doi.org/10.1177/135245851244060
Kaisey M, Solomon AJ, Luu M, Giesser BS, Sicotte NL (2019) Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord 30:51–56. https://doi.org/10.1016/j.msard.2019.01.048
Kallaur AP, Reiche EMV, Oliveira SR, Simão ANC, Pereira WLCJ, Alfieri DF, Flauzino T, Proença CM, Lozovoy MAB, Kaimen-Maciel DR, Maes M (2017) Genetic, immune-inflammatory, and oxidative stress biomarkers as predictors for disability and disease progression in multiple sclerosis. Mol Neurobiol 54:31–44. https://doi.org/10.1007/s12035-015-9648-6
Katz Sand I (2018) The role of diet in multiple sclerosis: mechanistic connections and current evidence. Curr Nutr Rep 7:150–160. https://doi.org/10.1007/s13668-018-0236-z
Katz Sand I, Benn EKT, Fabian M, Fitzgerald KC, Digga E, Deshpande R, Miller A, Gallo S, Arab L (2019) Randomized-controlled trial of a modified Mediterranean dietary program for multiple sclerosis: a pilot study. Mult Scler Relat Disord 36:101403. https://doi.org/10.1016/j.msard.2019.101403
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM, Diabetes Prevention Program Research Group (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403. https://doi.org/10.1056/NEJMoa012512
Kotze MJ, van Velden DP, Botha K, Badenhorst CH, Avenant H, van Rensburg SJ, Cronjé F (2013) Pathology-supported genetic testing directed at shared disease pathways for optimized health in later life. Per Med 10:497–507. https://doi.org/10.2217/pme.13.43
Kotze MJ, Lückhoff HK, Peeters AV, Baatjes K, Schoeman M, van der Merwe L, Grant KA, Fisher LR, van der Merwe N, Pretorius J, van Velden DP, Myburgh EJ, Pienaar FM, van Rensburg SJ, Yako YY, September AV, Moremi KE, Cronje FJ, Tiffin N, Bouwens CS, Bezuidenhout J, Apffelstaedt JP, Hough FS, Erasmus RT, Schneider JW (2015) Genomic medicine and risk prediction across the disease spectrum. Crit Rev Clin Lab Sci 52:120–137. https://doi.org/10.3109/10408363.2014.997930
Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis an expanded disability status scale (EDSS). Neurology 33:1444–1452
Lassmann H, van Horssen J (2016) Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions. Biochim Biophys Acta 1862:506–510. https://doi.org/10.1016/j.bbadis.2015.09.018
Lublin FD, Reingold SC (1996) Defining the clinical course of multi- ple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46:907–911
Marrie RA, Rudick R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T (2010) Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis. Neurology 74:1041–1047. https://doi.org/10.1212/WNL.0b013e3181d6b125
Martinez Sosa S, Smith KJ (2017) Understanding a role for hypoxia in lesion formation and location in the deep and periventricular white matter in small vessel disease and multiple sclerosis. Clin Sci (Lond) 131:2503–2524. https://doi.org/10.1042/CS20170981
Metz I, Lucchinetti CF, Openshaw H, Garcia-Merino A, Lassmann H, Freedman MS, Atkins HL, Azzarelli B, Kolar OJ, Brück W (2007) Autologous haematopoietic stem cell transplantation fails to stop demyelination and neurodegeneration in multiple sclerosis. Brain 130(Pt 5):1254–1262. https://doi.org/10.1093/brain/awl370
McGregor R, Li G, Penny H, Lombardi G, Afzali B, Goldsmith DJ (2014) Vitamin D in renal transplantation - from biological mechanisms to clinical benefits. Am J Transplant 14:1259–1270. https://doi.org/10.1111/ajt.12738
Miller A, Korem M, Almog R, Galboiz Y (2005) Vitamin B12, demyelination, remyelination and repair in multiple sclerosis. J Neurol Sci 233:93–97. https://doi.org/10.1016/j.jns.2005.03.009
Moir D, Rickert WS, Levasseur G, Larose Y, Maertens R, White P, Desjardins S (2008) A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions. Chem Res Toxicol 21:494–502. https://doi.org/10.1021/tx700275p
Morrison BM, Lee Y, Rothstein JD (2013) Oligodendroglia: metabolic supporters of axons. Trends Cell Biol 23:644–651. https://doi.org/10.1016/j.tcb.2013.07.007
Munger KL, Zhang SM, O'Reilly E, Hernán MA, Olek MJ, Willett WC, Ascherio A (2004) Vitamin D intake and incidence of multiple sclerosis. Neurology 62:60–65. https://doi.org/10.1212/01.wnl.0000101723.79681.38
Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A (2006) Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296:2832–2838. https://doi.org/10.1001/jama.296.23.2832
Nakahara J, Maeda M, Aiso S, Suzuki N (2012) Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy. Clin Rev Allergy Immunol 42:26–34. https://doi.org/10.1007/s12016-011-8287-6
Nortje K (2019) Interview https://www.youtube.com/watch?v=6aPo5quNOUk. Accessed 13 October 2020
Nelson MC, Isaacs F, Hassan MS, Kidd M, Cronje FJ, Van Rensburg SJ (2014) Prevalence of abnormal bloodflow patterns and effects of biochemistry and lifestyle factors on the major neck vessels in patients with multiple sclerosis in the Western cape, South Africa. Medical Technology SA 28:28–33
Nylander A, Hafler DA (2012) Multiple sclerosis. J Clin Invest 122:1180–1188. https://doi.org/10.1172/JCI58649
Oberholser K, Hodis E, Harel M, Berchansky A, Prilusky J, Proteopedia Page Contributors and Editors (2016) Complex III of Electron transport chain. http://proteopediaorg/wiki/indexphp/Complex_III_of_Electron_Transport_Chain Accessed 11 Nov 2020
Oliveira SR, Flauzino T, Sabino BS, Kallaur AP, Alfieri DF, Kaimen-Maciel DR, Morimoto HK, de Almeida ERD, Lozovoy MAB, Reiche EMV, Dichi I, Simão ANC (2018) Elevated plasma homocysteine levels are associated with disability progression in patients with multiple sclerosis. Metab Brain Dis 33:1393–1399. https://doi.org/10.1007/s11011-018-0224-4
Ontaneda D, Cohen JA (2012) EDSS improvement: recovery of function or noise? Mult Scler 18:1520–1521. https://doi.org/10.1177/1352458512441689
Pakpoor J, Seminatore B, Graves JS, Schreiner T, Waldman AT, Lotze TE, Belman A, Greenberg BM, Weinstock-Guttman B, Aaen G, Tillema JM, McDonald JC, Hart J, Ness JM, Harris Y, Rubin J, Candee M, Krupp L, Gorman M, Benson L, Rodriguez M, Chitnis T, Mar S, Kahn I, Rose J, Carmichael SL, Roalstad S, Waltz M, Casper TC, Waubant E, US Network of Pediatric Multiple Sclerosis Centers (2018) Dietary factors and pediatric multiple sclerosis: A case-control study. Mult Scler 24:1067–1076. https://doi.org/10.1177/1352458517713343
Palace J, Duddy M, Lawton M, Bregenzer T, Zhu F, Boggild M, Piske B, Robertson NP, Oger J, Tremlett H, Tilling K, Ben-Shlomo Y, Lilford R, Dobson C (2019) Assessing the long-term effectiveness of interferon-beta and glatiramer acetate in multiple sclerosis: final 10-year results from the UK multiple sclerosis risk-sharing scheme. J Neurol Neurosurg Psychiatry 90:251–260. https://doi.org/10.1136/jnnp-2018-318360
Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Brück W, Lucchinetti C, Lassmann H (2006) Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129(Pt 12):3165–3172
Pittock SJ, McClelland RL, Mayr WT, Jorgensen NW, Weinshenker BG, Noseworthy J, Rodriguez M (2004) Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study. Ann Neurol 56:303–306. https://doi.org/10.1002/ana.20197
Podbielska M, Banik NL, Kurowska E, Hogan EL (2013) Myelin recovery in multiple sclerosis: the challenge of remyelination. Brain Sci 3:1282–1324. https://doi.org/10.3390/brainsci3031282
Popper KR (1959) The logic of scientific discovery. Julius Springer, Hutchinson & Co. Berlin
Prineas JW, Parratt JDE (2018) Multiple sclerosis: Serum anti-CNS autoantibodies. Mult Scler 24:610–622. https://doi.org/10.1177/1352458517706037
Rinholm JE, Vervaeke K, Tadross MR, Tkachuk AN, Kopek BG, Brown TA, Bergersen LH, Clayton DA (2016) Movement and structure of mitochondria in oligodendrocytes and their myelin sheaths. Glia 64:810–825. https://doi.org/10.1002/glia.22965
Robertson RN (1983) The lively membranes. Cambridge University Press, Cambridge
Rodriguez M (2009) Have we finally identified an autoimmune demyelinating disease? Ann Neurol 66:572–573. https://doi.org/10.1002/ana.21838
Rooney RN, Kotze MJ, de Villiers JN, Hillermann R, Cohen JA (1999) Multiple sclerosis, porphyria-like symptoms, and a history of iron deficiency anemia in a family of Scottish descent. Am J Med Genet 86:194–196. https://doi.org/10.1002/(sici)1096-8628(19990910)86:2<194::aid-ajmg21>3.0.co;2-c
Rotstein DL, Healy BC, Malik MT, Chitnis T, Weiner HL (2015) Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol 72:152–158. https://doi.org/10.1001/jamaneurol.2014.3537
Rovaris M, Filippi M (2003) Interventions for the prevention of brain atrophy in multiple sclerosis: current status. CNS Drugs 17:563–575. https://doi.org/10.2165/00023210-200317080-00002
Saiz A, Carreras E, Berenguer J, Yagüe J, Martínez C, Marín P, Rovira M, Pujol T, Arbizu T, Graus F (2001) MRI and CSF oligoclonal bands after autologous hematopoietic stem cell transplantation in MS. Neurology 56:1084–1089. https://doi.org/10.1212/wnl.56.8.1084
Schmithorst VJ, Wilke M (2002) Differences in white matter architecture between musicians and non-musicians: a diffusion tensor imaging study. Neurosci Lett 321:57–60. https://doi.org/10.1016/S0304-3940(02)00054-X
Schweitzer F, Laurent S, Fink GR, Barnett MH, Reddel S, Hartung H-P, Warnke C (2019) Age and the risks of high-efficacy disease modifying drugs in multiple sclerosis. Curr Opin Neurol Jun 32(3):305–312. https://doi.org/10.1097/WCO.0000000000000701
Selzer RR, Rosenblatt DS, Laxova R, Hogan K (2003) Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydrofolate reductase deficiency. N Engl J Med 349:45–50. https://doi.org/10.1056/NEJMoa021867
Shinzawa-Itoh K, Aoyama H, Muramoto K, Terada H, Kurauchi T, Tadehara Y, Yamasaki A, Sugimura T, Kurono S, Tsujimoto K, Mizushima T, Yamashita E, Tsukihara T, Yoshikawa S (2007) Structures and physiological roles of 13 integral lipids of bovine heart cytochrome c oxidase. EMBO J 26:1713–17125. https://doi.org/10.1038/sj.emboj.7601618
Simpson IA, Ponnuru P, Klinger ME, Myers RL, Devraj K, Coe CL, Lubach GR, Carruthers A, Connor JR (2015) A novel model for brain iron uptake: introducing the concept of regulation. J Cereb Blood Flow Metab 35:48–57. https://doi.org/10.1038/jcbfm.2014.168
Sintzel MB, Rametta M, Reder AT (2018) Vitamin D and multiple sclerosis: a comprehensive review. Neurol Ther 7:59–85. https://doi.org/10.1007/s40120-017-0086-4
Smith EM, Alvarez JA, Kearns MD, Hao L, Sloan JH, Konrad RJ, Ziegler TR, Zughaier SM, Tangpricha V (2017) High-dose vitamin D3 reduces circulating hepcidin concentrations: a pilot, randomized, double-blind, placebo-controlled trial in healthy adults. Clin Nutr 36:980–985. https://doi.org/10.1016/j.clnu.2016.06.015
Soilu-Hänninen M, Aivo J, Lindström B-M, Elovaara I, Sumelahti M-L, Färkkilä M, Tienari P, Atula S, Sarasoja T, Herrala L, Keskinarkaus I, Kruger J, Kallio T, Rocca MA, Filippi M (2012) A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 83:565–571. https://doi.org/10.1136/jnnp-2011-301876
Solomon AJ, Corboy JR (2017) The tension between early diagnosis and misdiagnosis of multiple sclerosis. Nat Rev Neurol 13:567–572. https://doi.org/10.1038/nrneurol.2017.106
Solomon AJ, Bourdette DN, Cross AH, Applebee A, Skidd PM, Howard DB, Spain RI, Cameron MH, Kim E, Mass MK, Yadav V, Whitham RH, Longbrake EE, Naismith RT, Wu GF, Parks BJ, Wingerchuk DM, Rabin BL, Toledano M, Tobin WO, Kantarci OH, Carter JL, Keegan BM, Weinshenker BG (2016) The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology 87:1393–1399. https://doi.org/10.1212/WNL.0000000000003152
Spencer J, Bell JS, DeLuca GC (2018) Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier. J Neurol Neurosurg Psychiatry 89:42–52. https://doi.org/10.1136/jnnp-2017-316011
Stefely JA, Pagliarini DJ (2017) Biochemistry of mitochondrial coenzyme Q biosynthesis. Trends Biochem Sci 42(10):824–843. https://doi.org/10.1016/j.tibs.2017.06.008
Surtees R, Leonard J, Austin S (1991) Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet 338:1550–1554. https://doi.org/10.1016/0140-6736(91)92373-a
Swank RL, Lerstad O, Strøm A, Backer J (1952) Multiple sclerosis in rural Norway its geographic and occupational incidence in relation to nutrition. N Engl J Med 246:722–728
Syed S, Michalski ES, Tangpricha V, Chesdachai S, Kumar A, Prince J, Ziegler TR, Suchdev PS, Kugathasan S (2017) Vitamin D status is associated with Hepcidin and hemoglobin concentrations in children with inflammatory bowel disease. Inflamm Bowel Dis 23:1650–1658. https://doi.org/10.1097/MIB.0000000000001178
Teunissen CE, Killestein J, Kragt JJ, Polman CH, Dijkstra CD, Blom HJ (2008) Serum homocysteine levels in relation to clinical progression in multiple sclerosis. J Neurol Neurosurg Psychiatry 79:1349–1353. https://doi.org/10.1136/jnnp.2008.151555
Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintoré M, Traboulsee AL, Trojano M, Uitdehaag BMJ, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA (2018) Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 17:162–173. https://doi.org/10.1016/S1474-4422(17)30470-2
Torkildsen O, Brunborg LA, Myhr K-M, Bø L (2008) The cuprizone model for demyelination. Acta Neurol Scand Suppl 188:72–76. https://doi.org/10.1111/j.1600-0404.2008.01036.x
Tremlett H, Zhu F, Petkau J, Oger J, Zhao Y, BC MS Clinic Neurologists (2012) Natural, innate improvements in multiple sclerosis disability. Mult Scler 8:1412–1421
Van der Walt A, Stankovich J, Bahlo M, Taylor BV, Van der Mei IA, Foote SJ, Rubio JP, Kilpatrick TJ, Butzkueven H (2011) Heterogeneity at the HLA-DRB1 allelic variation locus does not influence multiple sclerosis disease severity, brain atrophy or cognition. Mult Scler 17:344–352. https://doi.org/10.1177/1352458510389101
Van Munster CE, Uitdehaag BM (2017) Outcome measures in clinical trials for multiple sclerosis. CNS Drugs 31:217–236. https://doi.org/10.1007/s40263-017-0412-5
Van Rensburg SJ, Kotze MJ, Hon D, Haug P, Kuyler J, Hendricks M, Botha J, Potocnik FC, Matsha T, Erasmus RT (2006) Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis. Metab Brain Dis 21:121–137
van Rensburg SJ, Kotze MJ, van Toorn R (2012) The conundrum of iron in multiple sclerosis -time for an individualised approach. Metab Brain Dis 27:239–253. https://doi.org/10.1007/s11011-012-9290-1
van Rensburg SJ, van Toorn R, Moremi KE, Peeters AV, Oguniyi A, Kotze MJ (2016) Multiple sclerosis-like diagnosis as a complication of previously treated malaria in an iron and vitamin D deficient Nigerian patient. Metab Brain Dis 31:197–204. https://doi.org/10.1007/s11011-015-9788-4
van Rensburg SJ, Peeters AV, van Toorn R, Schoeman J, Moremi KE, van Heerden CJ, Kotze MJ (2019) Identification of an iron-responsive subtype in two children diagnosed with relapsing-remitting multiple sclerosis using whole exome sequencing. Mol genet Metab rep 19:100465. Doi: https://doi.org/10.1016/j.ymgmr.2019.100465. eCollection 2019 Jun.
van Rensburg SJ, Hattingh C, Johannes C, Moremi KE, Peeters AV, van Heerden CJ, Erasmus RTE, Zemlin AE, Kemp MC, Jaftha M, Khine AA, Potocnik FCV, Whati L, Engel-Hills P, van Toorn R, Kotze MJ (2021) Pathology-supported genetic testing as a method for disability prevention in multiple sclerosis (MS). Part II. Insights from two MS cases. Metab Brain Dis. https://doi.org/10.1007/s11011-021-00712-9
van Toorn R, Schoeman JF, Solomons R, Rensburg MA, van Rensburg SJ (2010) Iron status in children with recurrent episodes of tumefactive cerebral demyelination. J Child Neurol 25:1401–1407. https://doi.org/10.1177/0883073810366179
Vilariño-Güell C, Zimprich A, Martinelli-Boneschi F, Herculano B, Wang Z, Matesanz F, Urcelay E, Vandenbroeck K, Leyva L, Gris D, Massaad C, Quandt JA, Traboulsee AL, Encarnacion M, Bernales CQ, Follett J, Yee IM, Criscuoli MG, Deutschländer A, Reinthaler EM, Zrzavy T, Mascia E, Zauli A, Esposito F, Alcina A, Izquierdo G, Espino-Paisán L, Mena J, Antigüedad A, Urbaneja-Romero P, Ortega-Pinazo J, Song W, Sadovnick AD (2019) Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease. PLoS Genet; 15(6):e1008180 doi: 101371/journalpgen1008180 eCollection 2019 Jun.
Vollmann H, Ragert P, Conde V, Villringer A, Classen J, Witte OW, Steele CJ (2014) Instrument specific use-dependent plasticity shapes the anatomical properties of the corpus callosum: a comparison between musicians and non-musicians. Front Behav Neurosci 8:245. https://doi.org/10.3389/fnbeh.2014.00245
Vollmer T, Signorovitch J, Huynh L, Galebach P, Kelley C, DiBernardo A, Sasane R (2015) The natural history of brain volume loss among patients with multiple sclerosis: a systematic literature review and meta-analysis. J Neurol Sci 357:8–18. https://doi.org/10.1016/j.jns.2015.07.014
Wahls T, Scott MO, Alshare Z, Rubenstein L, Darling W, Carr L, Smith K, Chenard CA, LaRocca N, Snetselaar L (2018) Dietary approaches to treat MS-related fatigue: comparing the modified Paleolithic (Wahls elimination) and low saturated fat (Swank) diets on perceived fatigue in persons with relapsing-remitting multiple sclerosis: study protocol for a randomized controlled trial. Trials 19:309. https://doi.org/10.1186/s13063-018-2680-x
Wakefield AJ, More LJ, Difford J, McLaughlin JE (1994) Immunohistochemical study of vascular injury in acute multiple sclerosis. J Clin Pathol 47:129–133
Wallin MT, Culpepper WJ, Nichols E, Bhutta ZA, Gebrehiwot TT, Hay SI, Khalil IA, Krohn KJ, Liang X, Naghavi M, Mokdad AH, Nixon MR, Reiner RC, Sartorius B, Smith M, Topor-Madry R, Werdecker A, Vos T, Feigin VL, Murray CJL, GBD (2016) Multiple sclerosis collaborators (2019) global, regional, and national burden of multiple sclerosis 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol 18:269–285. https://doi.org/10.1016/S1474-4422(18)30443-5
Weiss G, Ganz T, Goodnough LT (2019) Anemia of inflammation. Blood 133:40–50. https://doi.org/10.1182/blood-2018-06-856500
White KN, Conesa C, Sánchez L, Amini M, Farnaud S, Lorvoralak C, Evans RW (2012) The transfer of iron between ceruloplasmin and transferrins. Biochim Biophys Acta 1820:411–416. https://doi.org/10.1016/j.bbagen.2011.10.006
Wojtovich AP, Smith CO, Haynes CM, Nehrke KW, Brookes PS (2013) Physiological consequences of complex II inhibition for aging, disease, and the mKATP channel. Biochim Biophys Acta 1827:598–611. https://doi.org/10.1016/j.bbabio.2012.12.007
Yankovskaya V, Horsefield R, Törnroth S, Luna-Chavez C, Miyoshi H, Léger C, Byrne B, Cecchini G, Iwata S (2003) Architecture of succinate dehydrogenase and reactive oxygen species generation. Science 299:700–704. https://doi.org/10.1126/science.1079605
Yoon YS, Byun HO, Cho H, Kim BK, Yoon G (2003) Complex II defect via down-regulation of iron-sulfur subunit induces mitochondrial dysfunction and cell cycle delay in iron chelation-induced senescence-associated growth arrest. J Biol Chem 278:51577–51586. https://doi.org/10.1074/jbc.M308489200
Yoshikawa S, Muramoto K, Shinzawa-Itoh K, Mochizuki M (2012) Structural studies on bovine heart cytochrome c oxidase. Biochim Biophys Acta 1817:579–589. https://doi.org/10.1016/j.bbabio.2011.12.012
Zickermann V, Wirth C, Nasiri H, Siegmund K, Schwalbe H, Hunte C, Brandt U (2015) Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I. Science 347:44–49. https://doi.org/10.1126/science.1259859
Zhornitsky S, McKay KA, Metz LM, Teunissen CE, Rangachari M (2016) Cholesterol and markers of cholesterol turnover in multiple sclerosis: relationship with disease outcomes. Mult Scler Relat Disord 5:53–65. https://doi.org/10.1016/j.msard.2015.10.005
Acknowledgments
We acknowledge Stellenbosch University, the National Health Laboratory Service (NHLS) and the MS Care Trust, Cape Town, South Africa for their support of the MS Project.
Funding
This study was funded by the National Health Laboratory Service Award Number 94139 and the South African BioDesign Initiative of the Department of Science and Innovation and the Technology Innovation Agency, South Africa (Grant number 401/01). SJ van Rensburg, C Hattingh, ME Kemp and KE Moremi were supported by Winetech, South Africa (Grant Number N07/09/203). Publication fees for Open Access are supported by the University of Stellenbosch, South Africa. The funding bodies had no role in the design of the study, collection, analysis, and interpretation of data or in writing of the manuscript.
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SJVR and MJK designed the PSGT Method. SJVR had the idea for the article, performed the literature search and drafted the manuscript. RVT, RTE, CJH, PEH and MJK critically reviewed the manuscript. KEM, CJ and MCK collected and evaluated the data which provided the idea for the manuscript. SJVR did the artwork with professional input. All authors approved the final manuscript.
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SJVR and MJK are listed as inventors on patent number 2010/ 00058 filed by Stellenbosch University. MJK is also a director and shareholder of Gknowmix (Pty) Ltd., a spin out company of the South African Medical Research Council. The remaining authors declared no conflict of interest. No writing assistance was utilised in the preparation of this manuscript.
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van Rensburg, S.J., van Toorn, R., Erasmus, R.T. et al. Pathology-supported genetic testing as a method for disability prevention in multiple sclerosis (MS). Part I. Targeting a metabolic model rather than autoimmunity. Metab Brain Dis 36, 1151–1167 (2021). https://doi.org/10.1007/s11011-021-00711-w
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DOI: https://doi.org/10.1007/s11011-021-00711-w