Pediatric Hematology/Oncology and ImmunopathologyPediatric Hematology/Oncology and ImmunopathologyВопросы гематологии/онкологии и иммунопатологии в педиатрии1726-17082414-9314Fund Doctors, Innovations, Science for Children7410.24287/1726-1708-2017-16-3-83-91СтатьиInherited disorders of iron metabolismГенетически обусловленные нарушения обмена железаhttps://orcid.org/0000-0003-4222-2915LohmatovaM. E.ЛохматоваМ.Е.
Russian Federation
https://orcid.org/0000-0003-2756-7325SmetaninaN. S.СметанинаН.С.
Russian Federation

MD, PhD, DSc, pediatric hematologist, Deputy Director of Institute of Hematology, Immunology and Cell Technology, 

Professor at the Department of Hematology, Oncology and Radiation Therapy of Russian National Research University n.a. N.I. Pirogov

Russia, 117997, Moscow, Samory Mashela st., 1

nataliya.smetanina@fnkc.ruDmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, ImmunologyФГБУ «Национальный медицинский исследовательский центр детской гематологии,онкологии и иммунологии им. Дмитрия Рогачева» Минздрава России, МоскваDmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, ImmunologyФГБУ «Национальный медицинский исследовательский центр детской гематологии,онкологии и иммунологии им. Дмитрия Рогачева» Минздрава России, Москва10082017163839110082018Copyright ©; 2017, «D. Rogachev NMRCPHOI»Copyright ©; 2017, ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России2017«D. Rogachev NMRCPHOI»ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава Россииhttps://creativecommons.org/licenses/by/4.0https://hemoncim.com/jour/article/view/74

The presented review provides information about genetic diseases associated with impaired iron metabolism, includes the main aspects of normal iron metabolism, the mechanisms of its disruption for each described pathology. The review also presents information about major clinical manifestation, changes in laboratory parameters and the principles of therapy.

В обзоре представлена информация о генетически обусловленных заболеваниях вследствие нарушения обмена железа, основные аспекты обмена железа в норме, рассмотрены механизмы его нарушений при каждой из описанных патологий. Обзор содержит информацию об основных клинических проявлениях, изменениях лабораторных показателей и принципах терапии.

disorders of iron metabolismhemochromatosisIRIDAsideroblastic anemiasferroportinhepcidinatransferrinemiaaceruloplasminemiaнарушения обмена железагемохроматозIRIDAсидеробластные анемииферропортингепсидинатрансферринемияацеруллоплазминемия1. Ganz T. Hepcidin and iron regulation, 10 years later. Blood 2011; 117: 4425-33.Ganz T. Hepcidin and iron regulation, 10 years later. Blood 2011; 117: 4425-33.2. Brissot P., et al. Current approach to hemochromatosis. Blood Rev 2008; 22: 195-210.Brissot P., et al. Current approach to hemochromatosis. Blood Rev 2008; 22: 195-210.3. Camaschella C., Poggiali E. Inherited disorders of iron metabolism. Curr Opin Pediatr 2011; 23: 14-20.Camaschella C., Poggiali E. Inherited disorders of iron metabolism. Curr Opin Pediatr 2011; 23: 14-20.4. Andrews N.C. Forging a field: the golden age of iron biology. Blood 2008; 112: 219-30.Andrews N.C. Forging a field: the golden age of iron biology. Blood 2008; 112: 219-30.5. Hentze M.W., Muckenthaler M.U., Andrews N.C. Balancing Acts: Molecular Control of Mammalian Iron Metabolism. Cell 2004; 117: 285-97.Hentze M.W., Muckenthaler M.U., Andrews N.C. Balancing Acts: Molecular Control of Mammalian Iron Metabolism. Cell 2004; 117: 285-97.6. De Falco L., Sanchez M., Silvestri L., Kannengiesser C., Muckenthaler M.U., Iolascon A., Gouya L., et al. C. Iron refractory iron deficiency anemia. Haematol 2013; 98 (6): 845-53.De Falco L., Sanchez M., Silvestri L., Kannengiesser C., Muckenthaler M.U., Iolascon A., Gouya L., et al. C. Iron refractory iron deficiency anemia. Haematol 2013; 98 (6): 845-53.7. Pippard M.J. Iron deficiency anemia, anemia of chronic disorders and iron overload / In Porwit A., McCullough J., Erber W.N., editors. Blood and bone marrow pathology. 2nd ed. Edinburgh: Churchill Livingstone, 2011. p. 173-95.Pippard M.J. Iron deficiency anemia, anemia of chronic disorders and iron overload / In Porwit A., McCullough J., Erber W.N., editors. Blood and bone marrow pathology. 2nd ed. Edinburgh: Churchill Livingstone, 2011. p. 173-95.8. Aguilar-Martinez P., Grandchamp B., Cunat S., Cadet E., Blanc F., Nourrit M., Lassoued K., et al. Iron overload in HFE C282Y heterozygotes at first genetic testing: a strategy for identifying rare HFE variants. Haematol 2011; 96: 507-14.Aguilar-Martinez P., Grandchamp B., Cunat S., Cadet E., Blanc F., Nourrit M., Lassoued K., et al. Iron overload in HFE C282Y heterozygotes at first genetic testing: a strategy for identifying rare HFE variants. Haematol 2011; 96: 507-14.9. Camaschella C. Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood 2005; 106 (12): 3710-7.Camaschella C. Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood 2005; 106 (12): 3710-7.10. Lyon E., Frank E. Hereditary hemochromatosis since discovery of the HFE gene. Clin Chemistry 2001; 47 (7): 1147-56.Lyon E., Frank E. Hereditary hemochromatosis since discovery of the HFE gene. Clin Chemistry 2001; 47 (7): 1147-56.11. Wallace D.F., Subramanian V.N. Non-HFE haemochromatosis. World J Gastroenterol 2007; 13 (35): 4690-98.Wallace D.F., Subramanian V.N. Non-HFE haemochromatosis. World J Gastroenterol 2007; 13 (35): 4690-98.12. Lanzara C., Roetto A., Daraio F., Rivard S., Ficarella R., Simard H., Cox T.M., et al. Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 2004; 103 (11): 4317-21.Lanzara C., Roetto A., Daraio F., Rivard S., Ficarella R., Simard H., Cox T.M., et al. Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 2004; 103 (11): 4317-21.13. De Domenico I., McVey Ward D., Langelier C., Vaughn M.B., Nemeth E., Sundquist W.I., Ganz T., et al. The Molecular Mechanism of Hepcidin-mediated Ferroportin Down-Regulation. Mol Biol Cell 2007; 18: 2569-70.De Domenico I., McVey Ward D., Langelier C., Vaughn M.B., Nemeth E., Sundquist W.I., Ganz T., et al. The Molecular Mechanism of Hepcidin-mediated Ferroportin Down-Regulation. Mol Biol Cell 2007; 18: 2569-70.14. Montosi G., Donovan A., Totaro A., Garuti C., Pignatti E., Cassanelli S., et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 2001; 108: 619-23.Montosi G., Donovan A., Totaro A., Garuti C., Pignatti E., Cassanelli S., et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 2001; 108: 619-23.15. Pietrangelo A. The ferroportin disease. Blood Cell Mol Dis 2004; 32: 131-8.Pietrangelo A. The ferroportin disease. Blood Cell Mol Dis 2004; 32: 131-8.16. De Domenico I., McVey Ward D., Langelier C., Vaughn M.B., Nemeth E., Sundquist W.I., Ganz T., et al. The Molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell 2007; 18: 2569-78 .De Domenico I., McVey Ward D., Langelier C., Vaughn M.B., Nemeth E., Sundquist W.I., Ganz T., et al. The Molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell 2007; 18: 2569-78 .17. Pietrangelo A. The ferroportin disease. Clin Liv Dis 2014; 3 (5): 98-100.Pietrangelo A. The ferroportin disease. Clin Liv Dis 2014; 3 (5): 98-100.18. Kato J., Fujikawa K., Kanda M., Fukuda N., Sasaki K., Takayama T., Kobune M., et al. A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload. Am J Hum Genet 2001; 69 (1): 191-7.Kato J., Fujikawa K., Kanda M., Fukuda N., Sasaki K., Takayama T., Kobune M., et al. A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload. Am J Hum Genet 2001; 69 (1): 191-7.19. Brissot P. Current appoaches to the management of hemochromatosis. Am Soc Hematol Education Book, 2006, pp. 36-41.Brissot P. Current appoaches to the management of hemochromatosis. Am Soc Hematol Education Book, 2006, pp. 36-41.20. Du X., She E., Gelbart T., Thiksa J., Lee P., Xia Y., Khovananth K., et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science 2008, 320 (5879): 1088-92.Du X., She E., Gelbart T., Thiksa J., Lee P., Xia Y., Khovananth K., et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science 2008, 320 (5879): 1088-92.21. Folgueras A.R., de Lara F.M., PendSs A.M., Garabaya C., Rodrfguez F., Astudijlo A., Bernal T., et al. Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood 2008, 112: 2539-45.Folgueras A.R., de Lara F.M., PendSs A.M., Garabaya C., Rodrfguez F., Astudijlo A., Bernal T., et al. Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood 2008, 112: 2539-45.22. Ramsay A.J., Hooper J.D., Folgueras A.R., Velasco G., Lopez-Otin C. Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis. Haematol 2009; 94: 840-9.Ramsay A.J., Hooper J.D., Folgueras A.R., Velasco G., Lopez-Otin C. Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis. Haematol 2009; 94: 840-9.23. Melis M.A., Cau M., Congiu R., et al. A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron. Haematol 2008; 93: 1473-9.Melis M.A., Cau M., Congiu R., et al. A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron. Haematol 2008; 93: 1473-9.24. Finberg K.E., Heeney M.M., Campagna D.R., et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 2008; 40: 569-71.Finberg K.E., Heeney M.M., Campagna D.R., et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 2008; 40: 569-71.25. Finberg K.E. Iron-refractory iron deficiency anemia. Semin Hematol 2009; 46 (4): 378-8.Finberg K.E. Iron-refractory iron deficiency anemia. Semin Hematol 2009; 46 (4): 378-8.26. Camaschella С., Poggiali E. Inherited disorders of iron metabolism. Current opinion in pediatrics 2011; 23: 14-20.Camaschella С., Poggiali E. Inherited disorders of iron metabolism. Current opinion in pediatrics 2011; 23: 14-20.27. Camaschella С. State of the Art - How I manage patients with atypical microcytic anaemia. British Journal of Haematology 2013; 160 (1): 12-24.Camaschella С. State of the Art - How I manage patients with atypical microcytic anaemia. British Journal of Haematology 2013; 160 (1): 12-24.28. Cau M., Galanello R., Giagu N., Melis M.A. Responsiveness to oral iron and ascorbic acid in a patient with IRIDA. Blood Cells Mol Dis 2012; 48 (2): 121-3.Cau M., Galanello R., Giagu N., Melis M.A. Responsiveness to oral iron and ascorbic acid in a patient with IRIDA. Blood Cells Mol Dis 2012; 48 (2): 121-3.29. Sasu B.J., Cooke K.S., Arvedson T.L., Plewa C., Ellison A.R., Sheng J., et al. Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. Blood 2010; 115 (17): 3616-24.Sasu B.J., Cooke K.S., Arvedson T.L., Plewa C., Ellison A.R., Sheng J., et al. Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. Blood 2010; 115 (17): 3616-24.30. Hohlbaum A.M., Trentman S., Gille H., Allersdorfer A., Belaiba R.S., Huelsmeyer M., et al. Discovery and Preclinical Characterization of a Novel Hepcidin Antagonist with Tunable PK/PD Properties for the Treatment of Anemia in Different Patient Populations. ASH Annual Meeting Abstracts 2011; 118 (21): 687.Hohlbaum A.M., Trentman S., Gille H., Allersdorfer A., Belaiba R.S., Huelsmeyer M., et al. Discovery and Preclinical Characterization of a Novel Hepcidin Antagonist with Tunable PK/PD Properties for the Treatment of Anemia in Different Patient Populations. ASH Annual Meeting Abstracts 2011; 118 (21): 687.31. Akinc A., Chan-Daniels A., Sehgal A., Foster D., Bettencourt B.R., Hettinger J., et al. Targeting the Hepcidin Pathway with RNAi Therapeutics for the Treatment of Anemia. ASH Annual Meeting Abstracts. 2011; 118 (21): 688.Akinc A., Chan-Daniels A., Sehgal A., Foster D., Bettencourt B.R., Hettinger J., et al. Targeting the Hepcidin Pathway with RNAi Therapeutics for the Treatment of Anemia. ASH Annual Meeting Abstracts. 2011; 118 (21): 688.32. Trombini P., Coliva T., Nemeth E., Mariani R., Ganz T., Biondi A., Piperno A. Effects of plasma transfusion on hepcidin production in human congenital hypotransferrinemia. Haematol 2007; 92 (10): 1407-10.Trombini P., Coliva T., Nemeth E., Mariani R., Ganz T., Biondi A., Piperno A. Effects of plasma transfusion on hepcidin production in human congenital hypotransferrinemia. Haematol 2007; 92 (10): 1407-10.33. Grandchamp B., Hetet G., Kannengiesser C., Oudin C., Beaumont C., Rodrigues-Fcrreira S., et al. A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene. Blood 2011; 118: 6660-6.Grandchamp B., Hetet G., Kannengiesser C., Oudin C., Beaumont C., Rodrigues-Fcrreira S., et al. A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene. Blood 2011; 118: 6660-6.34. Lolascon A., Camaschella C., Pospisilova D., Piscopo C., Tchernia G., Beaumont C. Natural history of recessive inheritance of DMTI mutations. J pediatr 2008, 152: 136-9.Lolascon A., Camaschella C., Pospisilova D., Piscopo C., Tchernia G., Beaumont C. Natural history of recessive inheritance of DMTI mutations. J pediatr 2008, 152: 136-9.35. Beaumont C., Delaunay J., Hetet G., Grandchamp B., de Montalembert M., Tchernia G. Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload. Blood 2006, 107: 4168-70.Beaumont C., Delaunay J., Hetet G., Grandchamp B., de Montalembert M., Tchernia G. Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload. Blood 2006, 107: 4168-70.36. Fleming M.D. Congenital sideroblastic anemias: iron and heme lost in mitochondrial translation. American Society of Hematology. Hematology Education Book, 2011, pp. 525-31.Fleming M.D. Congenital sideroblastic anemias: iron and heme lost in mitochondrial translation. American Society of Hematology. Hematology Education Book, 2011, pp. 525-31.37. Camaschella C. Recent advances in the understanding of inherited sideroblastic anaemia. Br J Haematol 2008; 143 (1): 27-38.Camaschella C. Recent advances in the understanding of inherited sideroblastic anaemia. Br J Haematol 2008; 143 (1): 27-38.38. Camaschella C., Campanella A., De Falco L., Boschetto L., Merlini R., Silvestri L., Levi S., et al. The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload. Blood 2007, 110 (4): 1353-8.Camaschella C., Campanella A., De Falco L., Boschetto L., Merlini R., Silvestri L., Levi S., et al. The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload. Blood 2007, 110 (4): 1353-8.39. Wingert R.A., Galloway J.L., Barut B., Foott H., Fraenkel P., Axe J.L., Weber G.J., et al. Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis. Nature 2005; 436 (7053): 1035-39.Wingert R.A., Galloway J.L., Barut B., Foott H., Fraenkel P., Axe J.L., Weber G.J., et al. Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis. Nature 2005; 436 (7053): 1035-39.40. Iolascon A., De Falco L., Beaumont C. Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis. Haematol 2009; 94 (3): 395-408.Iolascon A., De Falco L., Beaumont C. Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis. Haematol 2009; 94 (3): 395-408.41. Loreal O., Turlin B., Pigeon C., Moisan A., Ropert M., Morice P., et al. Aceruloplasminemia: new clinical, pathophysiological and therapeutic insights. J Hepatol 2002; 36 (6): 85-6.Loreal O., Turlin B., Pigeon C., Moisan A., Ropert M., Morice P., et al. Aceruloplasminemia: new clinical, pathophysiological and therapeutic insights. J Hepatol 2002; 36 (6): 85-6.42. Nittis T., Gitlin J.D. The copper-iron connection: hereditary aceruloplasminemia. Semin Hematol 2002; 39 (4): 282-9.Nittis T., Gitlin J.D. The copper-iron connection: hereditary aceruloplasminemia. Semin Hematol 2002; 39 (4): 282-9.43. Kono S. Aceruloplasminemia: An update. Inter Rev Neurobiol 2013; 125-51.Kono S. Aceruloplasminemia: An update. Inter Rev Neurobiol 2013; 125-51.44. Tai M., Matsuhashi N., Ichii O., Suzuki T., Ejiri Y., Kono S., Terada T., et al. Epub 2014; 44 (12): 1253-8.Tai M., Matsuhashi N., Ichii O., Suzuki T., Ejiri Y., Kono S., Terada T., et al. Epub 2014; 44 (12): 1253-8.45. Miyajima H. Aceruloplasminemia. Neuropathol 2015; 35: 83-90.Miyajima H. Aceruloplasminemia. Neuropathol 2015; 35: 83-90.