Skip to main content
SpringerLink
Log in

Disorders in the Transport of Copper, Iron, Magnesium, Manganese, Selenium and Zinc

  • Chapter
Inborn Metabolic Diseases

  • 3382 Accesses

Zusammenfassung

Metals are indispensable elements of cell biology.They function as cofactors for many specific proteins and are involved in all major metabolic pathways.The number of recognised IEM involving the absorption, transport,or metabolism of metals is rapidly growing. Clinical presentations can involve all organs and systems including the liver and the central nervous system. Deficiency of metals results mostly in loss of function of metal-dependent proteins while excess can result in unregulated oxidation of proteins, lipids and other cellular components.Treatments rely on daily supplementation of the deficient metal at pharmacological doses and on chelating drugs where there is excess.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bie P de, Muller P, Wijmenga C, Klomp LWJ (2007) Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. J Med Genet 44:673–688

    Google Scholar 

  2. EASL (2012) Clinical Practice guidelines: Wilson’s disease. J Hepatol 56: 671–685

    Google Scholar 

  3. Forbes JR, Cox DW (2000) Copper-dependent trafficking of Wilson disease mutant ATP7B proteins. Hum Mol Genet 9:1927–1935

    Google Scholar 

  4. Bull PC, Thomas GR, Rommens JM et al. (1993) The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 5:327–337

    Google Scholar 

  5. Liu XQ, Zhang YF, Liu TT et al. (2004) Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease. World J Gastroenterol 10:590–593

    Google Scholar 

  6. Stapelbroek JM, Bollen CW, Ploos van Amstel JK et al. (2004) The H1069Q mutation in ATP7B is associated with late and neurologic presentation in Wilson disease: results of a meta-analysis. J Hepatol 41:758–763

    Google Scholar 

  7. Wiggelinkhuizen M, Tilanus MEC, Bollen CW, Houwen RHJ (2009) Systematic review: clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease. Aliment Pharmacol Ther 29:947–958

    Google Scholar 

  8. Weiss KH, Thurik F, Gotthardt DN et al. (2013) Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Clin Gastroenterol Hepatol 11:1028–1035

    Google Scholar 

  9. Czlonkowska A, Gajda J, Rodo M (1996) Effects of long-term treatment in Wilson’s disease with D-penicillamine and zinc sulphate. J Neurol 243:269–273

    Google Scholar 

  10. Dhawan A, Taylor RM, Cheeseman P et al. (2005) Wilson’s disease in children: 37-year experience and revised King’s score for liver transplantation. Liver Transplantation 11:441–448

    Google Scholar 

  11. Dahlman T, Hartvig P, Löfholm M et al. (1995) Long-term treatment of Wilson’s disease with triethylene tetramine dihydrochloride (trientine). Q J Med 88:609–616

    Google Scholar 

  12. Lang PA, Schenck M, Nicolay JP et al. (2007) Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nat Med 13:164–170

    Google Scholar 

  13. Kaler SG (1998) Diagnosis and therapy of Menkes syndrome, a genetic form of copper deficiency. Am J Clin Nutr 67:1029S–1034S

    Google Scholar 

  14. Tsukahara M, Imaizumi K, Kawai S, Kajii T (1994) Occipital horn syndrome: report of a patient and review of the literature. Clin Genet 45:32–35

    Google Scholar 

  15. Kennerson ML, Nicholson GA, Kaler SG et al. (2010) Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am J Hum Genet 86:343–352

    Google Scholar 

  16. Tümer Z, Møller LB, Horn N (2003) Screening of 383 unrelated patients affected with Menkes disease and finding of 57 gross deletions in ATP7A. Hum Mutat 22:457–464

    Google Scholar 

  17. Møller LB, Tümer Z, Lund C et al. (2000) Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome. Am J Hum Genet 66:1211–1220

    Google Scholar 

  18. Kaler SG, Holmes CS, Goldstein DS et al. (2008) Neonatal diagnosis and treatment of Menkes disease. N Engl J Med 358:605–614

    Google Scholar 

  19. Tumer Z, Horn N (1998) Menkes disease: underlying genetic defect and new diagnostic possibilities. J Inherit Metab Dis 21:604–612

    Google Scholar 

  20. Kim BE, Smith K, Petris MJ (2003) A copper treatable Menkes disease mutation associated with defective trafficking of a functional Menkes copper ATPase. J Med Genet 40:290–295

    Google Scholar 

  21. Tanner MS (1998) Role of copper in Indian childhood cirrhosis. Am J Clin Nutr 67:1074S–1081S

    Google Scholar 

  22. Müller T, Feichtinger H, Berger H, Müller W (1996) Endemic Tyrolean infantile cirrhosis: an ecogenetic disorder. Lancet 347:877–880

    Google Scholar 

  23. Martinelli D, Travaglini L, Drouin CA et al. (2013) MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy. Brain 136:872–881

    Google Scholar 

  24. Huppke P, Brendel C, Kalscheuer V et al. (2012) Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss and low serum copper and ceruloplasmin. Am J Hum Genet 90:61–68

    Google Scholar 

  25. Huppke P, Brendel C, Korenke GC et al. (2012) Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase. Hum Mutat 33:1207–1215

    Google Scholar 

  26. Harris ZL, Klomp LWJ, Gitlin JD (1998) Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis. Am J Clin Nutr 67:972S–977S

    Google Scholar 

  27. Socha P, Vajro P, Lefeber D, Adamowicz M, Tanner S (2014) Search for rare liver diseases; the case of glycosylation defects mimicking Wilson disease. Clin Res Hepatol Gastroenterol 38:403–406

    Google Scholar 

  28. Pietrangelo A (2015) Genetics, genetic testing, and management of hemochromatosis: 15 years since hepcidin. Gastroenterology 149:1240–1251

    Google Scholar 

  29. Jenkitkasemwong S, Wang CY, Coffey R et al. (2015) SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis. Cell Metab 22:138–50

    Google Scholar 

  30. Pietrangelo A (2010) Hereditary hemochromatosis. Pathogenesis, diagnosis and treatment. Gastroenterology 139:393–408

    Google Scholar 

  31. Grandchamp B, Hetet G, Kannengiesser C et al. (2011) A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene. Blood 118:6660–6666

    Google Scholar 

  32. Jabara HH, Boyden SE, Chou J et al. (2016) A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nature Genetics 48:74–80

    Google Scholar 

  33. Meyer E, Kurian MA, Hayflick SJ (2015) Neurodegeneration with brain iron accumulation: genetic diversity and pathophysiological mechanisms. Annu Rev Genomics Hum Genet 16:257–279

    Google Scholar 

  34. Colombelli C, Aoun M, Tiranti V (2015) Defective lipid metabolism in neurodegeneration with brain iron accumulation (NBIA) syndromes: not only a matter of iron. J Inherit Metab Dis 38:123–136

    Google Scholar 

  35. Jiang P, Mizushima N (2014) Autophagy and human diseases. Cell Res 24:69–79

    Google Scholar 

  36. Franchini M (2006) Hereditary iron overload. Update on pathophysiology, diagnosis and treatment. Am J Hematol 81:202–209

    Google Scholar 

  37. Adams PC, Barton JC (2010) How I treat hemochromatosis. Blood 116:317–325

    Google Scholar 

  38. Pantopoulos K (2015) TfR2 links iron metabolism and erythropoiesis. Blood;125:1055–1056

    Google Scholar 

  39. Rand EB, Karpen SJ, Kelly S et al. (2009) Treatment of neonatal hemochromatosis with exchange transfusions and intravenous immunoglobulin. J Pediatr 155:566–571

    Google Scholar 

  40. Whitington PF, Kelly S (2008) Outcome of pregnancies at risk for neonatal hemochromatosis is improved by treatment with high-dose intravenous immunoglobulin. Pediatrics 121:e1615–e1621

    Google Scholar 

  41. Finberg KE, Heeney MM, Campagna DR et al. (2008) Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 40:569–571

    Google Scholar 

  42. Beutler E, Gelbart T, Lee P, Trevino R, Fernandez MA, Fairbanks VF (2000) Molecular characterization of a case of atransferrinemia. Blood 96:4071–4074

    Google Scholar 

  43. Iolascon A, Camaschella C, Pospisilova D et al. (2008) Natural history of recessive inheritance of DMT1 mutations. J Pediatr 152:136–139

    Google Scholar 

  44. Hayflick SJ, Westaway SK, Levinson B et al. (2003) Genetic, clinical and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 348:33–40

    Google Scholar 

  45. Gregory A, Polster BJ, Hayflick SJ (2009) Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 46:73–80

    Google Scholar 

  46. Kurian MA, Morgan NV, MacPherson L et al. (2008) Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). Neurology 70:1623–1629

    Google Scholar 

  47. Venco P, Bonora M, Giorgi C et al. (2015) Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca²+. Front Genet 6:185

    Google Scholar 

  48. Shalev H, Phillip M, Galil A, Carmi R, Landau D (1998) Clinical presentation and outcome in primary familial hypomagnesaemia. Arch Dis Child 78:127–130

    Google Scholar 

  49. Milla PJ, Aggett PJ, Wolff OH, Harries JT (1979) Studies in primary hypomagnesaemia: evidence for defective carrier-mediated small intestinal transport of magnesium. Gut 20:1028–1033

    Google Scholar 

  50. Schlingmann KP, Sassen MC, Weber S et al. (2005) Novel TRPM6 mutations in 21 families with primary hypomagnesemia and secondary hypocalcemia. J Am Soc Nephrol 16:3061–3069

    Google Scholar 

  51. Lainez S, Schlingmann KP, van der Wijst J et al. (2014) New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia. Eur J Hum Genet 22:497–504

    Google Scholar 

  52. Walder RY, Landau D, Meyer P et al. (2002) Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 31:171–174

    Google Scholar 

  53. Schlingmann KP, Weber S, Peters M et al. (2002). Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 31:166–170

    Google Scholar 

  54. Godron A, Harambat J, Boccio V et al. (2012) Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations. Clin J Am Soc Nephrol 7:801–809

    Google Scholar 

  55. Claverie-Martin F, Garcia-Nieto V, Loris C et al. (2013) Claudin-19 mutations and clinical phenotype in Spanish patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Plos One 8:e53151

    Google Scholar 

  56. Weber S, Schneider L, Peters M et al. (2001) Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. J Am Soc Nephrol 12:1872–1881

    Google Scholar 

  57. Claverie-Martin F, Vargas-Poussou R, Mueller D, Garcia-Nieto V (2015) Clinical utility genecard for familial hypomagnesemia with hypercalciuria and nephrocalcinosis with/without severe ocular involvement. Eur J Hum Genet 23: doi:10.1038

    Google Scholar 

  58. Stuiver M, Lainez S, Will C et al. (2011). CNNM2, encoding a basolateral protein required for renal Mg2+ handling is mutated in dominant hypomagnesemia. Am J Hum Genet 88:333–343

    Google Scholar 

  59. Meij IC, Koenderink JB, van Bokhoven H et al. (2000) Dominant isolated renal magnesium loss is caused by misrouting of the Na+K+-ATPase γ-subunit. Nat Genet 26:265–266

    Google Scholar 

  60. Glaudemans B, van der Wijst J, Scola RH et al. (2009) A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia. J Clin Invest 119:936–942

    Google Scholar 

  61. Geven WB, Monnens LAH, Willems JL, Buijs W, Hamel CJ (1987) Isolated autosomal recessive renal magnesium loss in two sisters. Clin Genet 32:398–402

    Google Scholar 

  62. Tiel Groenestege WM, Thebault S, van der Wijst J et al. (2007) Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J Clin Invest 117:2260–2267

    Google Scholar 

  63. Tuschl A, Clayton PT, Gospe SM et al. (2012) Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man. Am J Hum Genet 90:457–466

    Google Scholar 

  64. Quadri M, Federico A, Zhao T et al. (2012) Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease. Am J Hum Genet 90:467–477

    Google Scholar 

  65. Tuschl K, Mills PB, Clayton PT (2013) Manganese and the brain. Int Rev Neurobiol 110:277–312

    Google Scholar 

  66. Schoenmakers E, Agostini M, Mitchell C et al. (2010) Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans. J Clin Invest 120:4220–4235

    Google Scholar 

  67. Dumitrescu AM, Liao XH, Abdullah MSY et al. (2005) Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nature Genet 37:1247–1252

    Google Scholar 

  68. Agamy O, Zeev BB, Lev D et al. (2010) Mutations disrupting selenocysteine formation cause progressive cerebello-cerebral atrophy. Am J Hum Genet 87:538–544

    Google Scholar 

  69. Anttonen AK, Hilander T, Linnankivi T et al. (2015) Selenoprotein biosynthesis defect causes progressive encephalopathy with elevated lactate. Neurology 85:306–315

    Google Scholar 

  70. Aggett PJ (1983) Acrodermatitis enteropathica. J Inherit Metab Dis 6:39S–43S

    Google Scholar 

  71. Van Wouwe JP (1989) Clinical and laboratory diagnosis of acrodermatitis enteropathica. Eur J Pediatr 149:2–8

    Google Scholar 

  72. Atherton DJ, Muller DPR, Aggett PJ, Harries JT (1979) A defect in zinc uptake by jejunal biopsies in acrodermatitis enteropathica. Clin Sci 56:505–507

    Google Scholar 

  73. Küry S, Dréno B, Bézieau S et al. (2002) Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet 31:239–240

    Google Scholar 

  74. Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J (2002) A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet 71:66–73

    Google Scholar 

  75. Kasana S, Din J, Maret W (2015) Genetic causes and gene-nutrient interactions in mammalian zinc deficiencies: Acrodermatitis enteropathica and transient neonatal zinc deficiency as examples. J Trace Elem Med Biol 29:47–62

    Google Scholar 

  76. Wessels KR, King JC, Brown KH (2014) Development of a plasma zinc concentration cutoff to identify individuals with severe zinc deficiency based on results from adults undergoing experimental severe dietary zinc restriction and individuals with acrodermatitis enteropathica. J Nutr 144:1204–1210

    Google Scholar 

  77. Anttila PH, Von Willebrand E, Simell O (1986) Abnormal immune responses during hypozincaemia in acrodermatitis enteropathica. Acta Paediatr Scand 75:988–992

    Google Scholar 

  78. Neldner KH, Hambidge KM (1975) Zinc therapy of acrodermatitis enteropathica. N Engl J Med 292:879–882

    Google Scholar 

  79. Stevens J, Lubitz L (1998) Symptomatic zinc deficiency in breast-fed term and premature infants. J Paed Child Health 34:97–100

    Google Scholar 

  80. Chowanadisai W, Lönnerdal B, Kelleher SL (2006) Identification of a mutation in SLC30A2 (ZnT-2) in women with low milk zinc concentration that results in transient neonatal zinc deficiency. J Biol Chem 281:39699–39707

    Google Scholar 

  81. Sampsom B, Fagerhol MK, Sunderkötter C et al. (2002) Hyperzincaemia and hypercalprotectinaemia: a new disorder of zinc metabolism. Lancet 360:1742–1745

    Google Scholar 

  82. Isidor B, Poignant S, Corradini N et al. (2009) Hyperzincemia and hypercalprotectinemia: unsuccessful treatment with tacrolimus. Acta Paediatr 98:410–412

    Google Scholar 

  83. Smith JC, Zeller JA, Brown ED, Ong SC (1976) Elevated plasma zinc: a heritable anomaly. Science 193:496–498

    Google Scholar 

  84. Tuschl K, Meyer E, Valdivia LE et al (2016) Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia. Nat. Commun. 7:11601 doi: 10.1038/ncomms11601

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics Metabolic Unit, University Medical Center Utrecht, Wilhelmina Children’s Hospital, Lundlaan 6, 3584 EA, Utrecht, Netherlands

    Peter M. van Hasselt

  2. Genetics and Genomic Medicine, UCL Institute of Child Health, Great Ormond Street Hospital for Children, 30 Guilford Street, WC1N 1EH, London, UK

    Peter T. Clayton

  3. Department of Paediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Lundlaan 6, 3584 EA, Utrecht, Netherlands

    Roderick H. J. Houwen

Authors
  1. Peter M. van Hasselt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter T. Clayton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roderick H. J. Houwen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Peter M. van Hasselt , Peter T. Clayton or Roderick H. J. Houwen .

Editor information

Editors and Affiliations

  1. Department of Neurology, Neurometabolic Unit, Hôpital Pitié Salpêtrière, Paris, France

    Jean-Marie Saudubray

  2. Division of Metabolism, University Children’s Hospital, Zurich, Switzerland

    Matthias R. Baumgartner

  3. Willink Biochemical Genetics Unit Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK

    John Walter

  4. Central Manchester University Hospitals NHS Foundation Trust, St Mary‘s Hospital, Manchester, UK

    John Walter

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

van Hasselt, P.M., Clayton, P.T., Houwen, R.H.J. (2016). Disorders in the Transport of Copper, Iron, Magnesium, Manganese, Selenium and Zinc. In: Saudubray, JM., Baumgartner, M., Walter, J. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-49771-5_37

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-49771-5_37

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-49769-2

  • Online ISBN: 978-3-662-49771-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation