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Published on: December 9, 2015
Identification of an iron-responsive subtype in two children diagnosed with relapsing-remitting multiple sclerosis
Susan J van Rensburg1, Armand V Peeters2, Ronald van Toorn3
1Division of Chemical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
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.
Insights
Genetic variants affecting iron metabolism may cause a subtype of childhood multiple sclerosis (MS). Supplementation normalized iron levels, leading to a decade of remission in two boys with relapsing-remitting MS (RRMS).
Area of Science:
- Genetics and Neurology
- Metabolic disorders
- Pediatric autoimmune diseases
Background:
- Multiple Sclerosis (MS) involves demyelination; iron is crucial for myelin synthesis.
- Previous observations noted remission in two boys with relapsing-remitting MS (RRMS) through iron supplementation.
- A potential genetic defect in iron metabolism was hypothesized, prompting further genetic investigation.
Purpose of the Study:
- To identify causal genetic pathways in pediatric MS through whole exome sequencing (WES).
- To evaluate the long-term efficacy of iron supplementation in managing pediatric MS.
- To explore the role of iron metabolism defects in the pathophysiology of childhood MS.
Main Methods:
- Whole exome sequencing (WES) was employed to identify genetic variants.
- Long-term monitoring of blood iron levels over 10 years during supplementation.
- Regular clinical assessments by a pediatric neurologist and schoolteacher feedback.
Main Results:
- WES identified variants in genes related to iron absorption/transport (TMPRSS6, TF, CUBN, SLC25A37, CD163) and mitochondrial function (COQ3).
- Neither child possessed the common HLA-DRB1*1501 allele, suggesting a distinct genetic etiology.
- Both children achieved 10 years of stable RRMS remission with normalized iron levels via supplementation.
Conclusions:
- WES can reveal heritable factors causing sustained iron loss via renal reabsorption defects.
- These defects, alongside impaired vitamin B12/D absorption and mitochondrial iron transport, suggest an iron-deficient MS subtype in children.
- This supports a model where mitochondrial dysfunction due to iron deficiency contributes to oligodendrocyte damage and impaired myelination in pediatric MS.
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