Albertine Donker

General Discussion 321 9 of exercise capacity, clinical status and quality of life, irrespective of concomitant anemia, 92 supporting the idea that ID on the muscular and cellular level plays a role in the symptomatology of IRIDA, independent of IDA. An important question is whether ID and IDA affect central nervous development and neurocognitive functioning of IRIDA patients. As reviewed earlier in this thesis ( Chapter 2 ), iron is essential for the development of the central nervous system. Iron and iron-containing enzymes are indispensable for neuronal and glial energy metabolism, myelin and neurotransmitter synthesis and degradation. 88,93 According to both animal and human studies, ID and IDA in fetal life and infancy are associated with longlasting and possibly irreversible neurocognitive impairment. 94 However, anecdotal data do not report neuropsychological consequences of IRIDA, even in the presence of a severe phenotype. 95 This corroborates the observations in our IRIDA patients, with the remark that we did not perform neuropsychological assessment and thus might have overlooked minor neurocognitive deficits. Taken together, the effect of TMPRSS6 defects and subsequent ID on multiple organs and physiologic systems, including the muscular system, the thyroid gland and the central nervous needs further elucidation in longitudinal clinical studies of IRIDA patients. Insights in the degree and the effect of ID regarding the different iron- demanding tissues might help in tailoring treatment to the individual IRIDA patient, weighing the benefits of (parenteral) iron treatment on the health and wellbeing against the risks of iron loading, especially of the reticulo-endothelial (RES) system. Balancing between adequate treatment of iron deficiency (anemia) and risk of iron loading of the reticulo-endothelial system is a challenge in IRIDA As described in this thesis ( Chapter 4 2 ), and also observed by others ( Chapter 3 1 ), most IRIDA patients due to TMPRSS6 defects require parenteral iron in order to correct anemia to a tolerable level. However, response to parenteral iron is still sluggish and incomplete since the inappropriately high serumhepcidin levels keep the iron trapped inside the RES in especially the spleen and liver. Therefore, intravenous iron supplementation poses the IRIDA patient at risk for iron loading of the macrophages. This pattern of iron loading is also characteristic for patients with loss of function variants in SLC40A1 encoding ferroportin, but differs from observations in patients with hereditary hemochromatosis due to variants in HFE, TfR2, HJV and HAMP and gain of function variants in SLC40A1 , which are conversely associated with inappropriately low serum hepcidin levels,