Identification of an iron-responsive subtype in two children diagnosed with relapsing-remitting multiple sclerosis using whole exome sequencing

Susan J van Rensburg; Armand V Peeters; Ronald van Toorn; Johan Schoeman; Kelebogile E Moremi; Carel J van Heerden; Maritha J Kotze

doi:10.1016/j.ymgmr.2019.100465

Identification of an iron-responsive subtype in two children diagnosed with relapsing-remitting multiple sclerosis using whole exome sequencing

Mol Genet Metab Rep. 2019 Mar 23:19:100465. doi: 10.1016/j.ymgmr.2019.100465. eCollection 2019 Jun.

Authors

Susan J van Rensburg¹, Armand V Peeters², Ronald van Toorn³, Johan Schoeman³, Kelebogile E Moremi¹, Carel J van Heerden⁴, Maritha J Kotze⁵

Affiliations

¹ Division of Chemical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
² Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
³ Paediatric Medicine and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
⁴ Central Analytical Facility (CAF), DNA Sequencing Unit, Stellenbosch University, Stellenbosch, South Africa.
⁵ Division of Chemical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, National Health Laboratory Service (NHLS), Cape Town, South Africa.

Abstract

Background: Multiple sclerosis is a disorder related to demyelination of axons. Iron is an essential cofactor in myelin synthesis. Previously, we described two children (males of mixed ancestry) with relapsing-remitting multiple sclerosis (RRMS) where long-term remission was achieved by regular iron supplementation. A genetic defect in iron metabolism was postulated, suggesting that more advanced genetic studies could shed new light on disease pathophysiology related to iron.

Methods: Whole exome sequencing (WES) was performed to identify causal pathways. Blood tests were performed over a 10 year period to monitor the long-term effect of a supplementation regimen. Clinical wellbeing was assessed quarterly by a pediatric neurologist and regular feedback was obtained from the schoolteachers.

Results: WES revealed gene variants involved in iron absorption and transport, in the transmembrane protease, serine 6 (TMPRSS6) and transferrin (TF) genes; multiple genetic variants in CUBN, which encodes cubilin (a receptor involved in the absorption of vitamin B12 as well as the reabsorption of transferrin-bound iron and vitamin D in the kidneys); SLC25A37 (involved in iron transport into mitochondria) and CD163 (a scavenger receptor involved in hemorrhage resolution). Variants were also found in COQ3, involved with synthesis of Coenzyme Q10 in mitochondria. Neither of the children had the HLA-DRB1*1501 allele associated with increased genetic risk for MS, suggesting that the genetic contribution of iron-related genetic variants may be instrumental in childhood MS. In both children the RRMS has remained stable without activity over the last 10 years since initiation of nutritional supplementation and maintenance of normal iron levels, confirming the role of iron deficiency in disease pathogenesis in these patients.

Conclusion: Our findings highlight the potential value of WES to identify heritable risk factors that could affect the reabsorption of transferrin-bound iron in the kidneys causing sustained iron loss, together with inhibition of vitamin B12 absorption and vitamin D reabsorption (CUBN) and iron transport into mitochondria (SLC25A37) as the sole site of heme synthesis. This supports a model for RRMS in children with an apparent iron-deficient biochemical subtype of MS, with oligodendrocyte cell death and impaired myelination possibly caused by deficits of energy- and antioxidant capacity in mitochondria.

Keywords: CNS, central nervous system; CoQ, Coenzyme Q; DFO, desferroxamine mesylate; DIS, dissemination in space; DIT, dissemination in time; DMT, disease modifying therapy; EDSS, Expanded Disability Status Scale; ETC, electron transport chain; GWAS, genome-wide association study; Genetic variants; HDL, high density lipoprotein; HERV-W, human endogenous retrovirus W; HLA, human leukocyte antigen; HREC, human research ethics committee; IPMSSG, International Pediatric Multiple Sclerosis Study Group; IRE, iron-response element; Iron deficiency; MGA1, juvenile hereditary megaloblastic anemia 1; MRI, magnetic resonance imaging; MS, Multiple sclerosis; MSRV, MS-associated retrovirus; MST1R, macrophage stimulating-1 receptor; Mitochondria; Oxidative stress; PSGT, pathology supported genetic testing; Pediatric onset multiple sclerosis; ROS, reactive oxygen species; RRMS, relapsing-remitting MS; SAMe, S-adenosyl methionine; SDHB, iron-protein subunit of Complex II; TF, transferrin; TMPRSS6, transmembrane protease, serine 6; WES, whole exome sequencing; Whole exome sequencing.