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

Abstract

BackgroundMultiple 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.MethodsWhole 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.ResultsWES 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.ConclusionOur 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.

Cerebral Iron Deposition in Neurodegeneration

“…In pediatric MS with profound Fe deficit, patients stabilized after Fe supplementation. Authors speculated that oligodendroglial Fe deficiency leading to impaired ATP synthesis might have resulted in inefficient myelination and fragility of oligodendrocytes [374]. In line with this finding, mild association between decreasing transferrin saturation and increasing disability was shown in another study [375].…”

White matter lesion volumes on 3-T MRI in people with MS who had followed a diet- and lifestyle program for more than 10 years

“…22 Sufficient iron and vitamin B12-folate methylation capacity is required by the mitochondria for this excessive energy generation. 6,23 If the oligodendrocytes experience energy blackouts they perish. 6,24 2.…”

Ferroptosis: a new regulatory mechanism in neuropathic pain

“…In oligodendrocytes, the amount of iron is 20 times higher than in astrocytes, and since iron is a cofactor required for myelin synthesis, an excessive amount of intracellular iron will contribute to the development of ferroptosis ( Thorburne and Juurlink, 2002 ; Van Rensburg et al, 2019 ; She et al, 2021 ). Also, the investigators observed that oligodendrocyte precursor cells (OPCs) are more easily susceptible to the effects of extracellular free iron and intracellular cysteine depletion, which leads to an increase in lipid peroxidation, a blockage of oligodendrocyte differentiation, and cell death.…”