eMedicine Specialties > Neurology > Pediatric Neurology

Menkes Disease: Treatment & Medication

Author: Celia H Chang, MD, Associate Health Sciences Clinical Professor, Department of Neurology, University of California at Davis
Contributor Information and Disclosures

Updated: Nov 24, 2009

Treatment

Consultations

  • Genetics: In families with a previous affected child, genetics consultation and counseling with prenatal testing can be done for future pregnancies.
  • Physical medicine and rehabilitation: The patient may have skeletal deformities and a continued high risk of fractures as well as malformed connective tissues.

Medication

Oral treatment with copper salts such as the sulfate, acetate, or chloride does not alter serum copper and ceruloplasmin levels. Parenteral copper induces synthesis of apoceruloplasmin and the WND gene, resulting in increase of serum copper and ceruloplasmin levels; however, the cerebral copper levels do not change and no clinical improvement ensues.

Treatment with copper chloride and/or L-histidine should be provided by a clinician familiar with their use. Copper chloride and L-histidine solutions of 350-500 µg/d or qod injected intravenously or subcutaneously increase the serum and cerebrospinal fluid copper levels to the normal range after 6 weeks. This treatment seems to improve symptoms related to copper efflux from the cell. Metaphyseal widening and spurring and periosteal thickening regress. Bone maturation progresses, although mineralization is still defective. The ratio of DOPA/DHPG normalizes. However, the connective-tissue defects do not respond to parenteral copper histidine treatment.

Newborns and fetuses treated in utero with copper histidine can avoid neurologic symptoms. Unfortunately, the neurologic symptoms, once present, are less amenable to treatment. Sheela et al reported that a 15-month-old who was treated with subcutaneous copper supplementation for 30 months became seizure free and the skin and hair darkened, but the child continued to have severe developmental delay.12

Early treatment of the brindled mouse prevents neurological symptoms, but if therapy is delayed beyond 10 days of life, the animal dies. The brindled mouse responds to therapy at a stage of brain development that corresponds to the third trimester in humans.

More on Menkes Disease

Overview: Menkes Disease
Differential Diagnoses & Workup: Menkes Disease
Treatment & Medication: Menkes Disease
Follow-up: Menkes Disease
Multimedia: Menkes Disease
References
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References

  1. Hardman B, Michalczyk A, Greenough M, et al. Hormonal regulation of the Menkes and Wilson copper-transporting ATPases in human placental Jeg-3 cells. Biochem J. Mar 1 2007;402(2):241-50. [Medline].

  2. Niciu MJ, Ma XM, El Meskini R, et al. Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment. Neuroscience. 2006;139(3):947-64. [Medline].

  3. Schlief ML, West T, Craig AM, et al. Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity. Proc Natl Acad Sci U S A. Oct 3 2006;103(40):14919-24. [Medline].

  4. Linnebank M, Lutz H, Jarre E, et al. Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells. Neurobiol Dis. Sep 2006;23(3):725-30. [Medline].

  5. Moller LB, Tumer Z, Lund C, et al. Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome. Am J Hum Genet. Apr 2000;66(4):1211-20. [Medline].

  6. Tang J, Donsante A, Desai V, Patronas N, Kaler SG. Clinical outcomes in Menkes disease patients with a copper-responsive ATP7A mutation, G727R. Mol Genet Metab. Nov 2008;95(3):174-81. [Medline].

  7. Bahi-Buisson N, Kaminska A, Nabbout R, et al. Epilepsy in Menkes disease: analysis of clinical stages. Epilepsia. Feb 2006;47(2):380-6. [Medline].

  8. Kaler SG, Holmes CS, Goldstein DS, Tang J, Godwin SC, Donsante A, et al. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med. Feb 7 2008;358(6):605-14. [Medline].

  9. Matsuo M, Tasaki R, Kodama H, Hamasaki Y. Screening for Menkes disease using the urine HVA/VMA ratio. J Inherit Metab Dis. 2005;28(1):89-93. [Medline].

  10. Lee ES, Ryoo JW, Choi DS, Cho JM, Kwon SH, Shin HS. Diffusion-weighted MR imaging of unusual white matter lesion in a patient with Menkes disease. Korean J Radiol. Jan-Feb 2007;8(1):82-5. [Medline].

  11. Geller TJ, Pan Y, Martin DS. Early neuroradiologic evidence of degeneration in Menkes' disease. Pediatr Neurol. Oct 1997;17(3):255-8. [Medline].

  12. Sheela SR, Latha M, Liu P, et al. Copper-replacement treatment for symptomatic Menkes disease: ethical considerations. Clin Genet. Sep 2005;68(3):278-83. [Medline].

  13. Paulsen M, Lund C, Akram Z, Winther JR, Horn N, Møller LB. Evidence that translation reinitiation leads to a partially functional Menkes protein containing two copper-binding sites. Am J Hum Genet. Aug 2006;79(2):214-29. [Medline].

  14. Donsante A, Tang J, Godwin SC, Holmes CS, Goldstein DS, Bassuk A, et al. Differences in ATP7A gene expression underlie intrafamilial variability in Menkes disease/occipital horn syndrome. J Med Genet. Aug 2007;44(8):492-7. [Medline].

  15. Adaletli I, Omeroglu A, Kurugoglu S, Elicevik M, Cantasdemir M, Numan F. Lumbar and iliac artery aneurysms in Menkes' disease: endovascular cover stent treatment of the lumbar artery aneurysm. Pediatr Radiol. Oct 2005;35(10):1006-9. [Medline].

  16. Ambrosini L, Mercer JF. Defective copper-induced trafficking and localization of the Menkes protein in patients with mild and copper-treated classical Menkes disease. Hum Mol Genet. Aug 1999;8(8):1547-55. [Medline].

  17. Aoki T. Wilson's disease and Menkes disease. Pediatr Int. Aug 1999;41(4):403-4. [Medline].

  18. Barnes N, Tsivkovskii R, Tsivkovskaia N, Lutsenko S. The copper-transporting ATPases, Menkes and Wilson disease proteins, have distinct roles in adult and developing cerebellum. J Biol Chem. Mar 11 2005;280(10):9640-5. [Medline].

  19. Borm B, Moller LB, Hausser I, et al. Variable clinical expression of an identical mutation in the ATP7A gene for Menkes disease/occipital horn syndrome in three affected males in a single family. J Pediatr. Jul 2004;145(1):119-21. [Medline].

  20. Ferreira RC, Heckenlively JR, Menkes JH, Bateman JB. Menkes disease. New ocular and electroretinographic findings. Ophthalmology. Jun 1998;105(6):1076-8. [Medline].

  21. Gasch AT, Kaler SG, Kaiser-Kupfer M. Menkes disease. Ophthalmology. Mar 1999;106(3):442-3. [Medline].

  22. Gerard-Blanluet M, Birk-Moller L, Caubel I, et al. Early development of occipital horns in a classical Menkes patient. Am J Med Genet A. Oct 1 2004;130(2):211-3. [Medline].

  23. Godwin SC, Shawker T, Chang B, Kaler SG. Brachial artery aneurysms in Menkes disease. J Pediatr. Sep 2006;149(3):412-5. [Medline].

  24. Goodyer ID, Jones EE, Monaco AP, Francis MJ. Characterization of the Menkes protein copper-binding domains and their role in copper-induced protein relocalization. Hum Mol Genet. Aug 1999;8(8):1473-8. [Medline].

  25. Grange DK, Kaler SG, Albers GM, et al. Severe bilateral panlobular emphysema and pulmonary arterial hypoplasia: unusual manifestations of Menkes disease. Am J Med Genet A. Dec 1 2005;139(2):151-5. [Medline].

  26. Gu YH, Kodama H, Shiga K, et al. A survey of Japanese patients with Menkes disease from 1990 to 2003: incidence and early signs before typical symptomatic onset, pointing the way to earlier diagnosis. J Inherit Metab Dis. 2005;28(4):473-8. [Medline].

  27. Hsi G, Cox DW. A comparison of the mutation spectra of Menkes disease and Wilson disease. Hum Genet. Jan 2004;114(2):165-72. [Medline].

  28. Kaler SG. Metabolic and molecular bases of Menkes disease and occipital horn syndrome. Pediatr Dev Pathol. Jan-Feb 1998;1(1):85-98. [Medline].

  29. Kim BE, Smith K, Petris MJ. A copper treatable Menkes disease mutation associated with defective trafficking of a functional Menkes copper ATPase. J Med Genet. Apr 2003;40(4):290-5. [Medline].

  30. Kim OH, Suh JH. Intracranial and extracranial MR angiography in Menkes disease. Pediatr Radiol. Oct 1997;27(10):782-4. [Medline].

  31. Kodama H, Gu YH, Mizunuma M. Drug targets in Menkes disease - prospective developments. Expert Opin Ther Targets. Oct 2001;5(5):625-635. [Medline].

  32. Kodama H, Murata Y. Molecular genetics and pathophysiology of Menkes disease. Pediatr Int. Aug 1999;41(4):430-5. [Medline].

  33. Kodama H, Murata Y, Kobayashi M. Clinical manifestations and treatment of Menkes disease and its variants. Pediatr Int. Aug 1999;41(4):423-9. [Medline].

  34. Kodama H, Sato E, Yanagawa Y, et al. Biochemical indicator for evaluation of connective tissue abnormalities in Menkes' disease. J Pediatr. Jun 2003;142(6):726-8. [Medline].

  35. Krajacic P, Qian Y, Hahn P, et al. Retinal localization and copper-dependent relocalization of the Wilson and Menkes disease proteins. Invest Ophthalmol Vis Sci. Jul 2006;47(7):3129-34. [Medline].

  36. Lane C, Petris MJ, Benmerah A, et al. Studies on endocytic mechanisms of the Menkes copper-translocating P-type ATPase (ATP7A; MNK). Endocytosis of the Menkes protein. Biometals. Feb 2004;17(1):87-98. [Medline].

  37. Mandelstam SA, Fisher R. Menkes disease: a rare cause of bilateral inguinal hernias. Australas Radiol. Apr 2005;49(2):192-5. [Medline].

  38. Menkes JH. Menkes disease and Wilson disease: two sides of the same copper coin. Part I: Menkes disease. Eur J Paediatr Neurol. 1999;3(4):147-58. [Medline].

  39. Mercer JF, Ambrosini L, Horton S, et al. Animal models of Menkes disease. Adv Exp Med Biol. 1999;448:97-108. [Medline].

  40. Munakata M, Sakamoto O, Kitamura T, et al. The effects of copper-histidine therapy on brain metabolism in a patient with Menkes disease: a proton magnetic resonance spectroscopic study. Brain Dev. Jun 2005;27(4):297-300. [Medline].

  41. Muz' NI, Matvienko AV. [Local injection of fraxiparine for the treatment of the lower extremity trophic ulcer]. Klin Khir. Nov-Dec 2002;51-2. [Medline].

  42. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: {309400}: {1/10/00}. [Full Text].

  43. Pedespan JM, Jouaville LS, Cances C, et al. Menkes disease: study of the mitochondrial respiratory chain in three cases. Eur J Paediatr Neurol. 1999;3(4):167-70. [Medline].

  44. Petris MJ, Mercer JF. The Menkes protein (ATP7A; MNK) cycles via the plasma membrane both in basal and elevated extracellular copper using a C-terminal di-leucine endocytic signal. Hum Mol Genet. Oct 1999;8(11):2107-15. [Medline].

  45. Petris MJ, Mercer JF, Camakaris J. The cell biology of the Menkes disease protein. Adv Exp Med Biol. 1999;448:53-66. [Medline].

  46. Poulsen L, Moller LB, Plunkett K, et al. X-linked Menkes disease: first documented report of germ-line mosaicism. Genet Test. 2004;8(3):286-91. [Medline].

  47. Sasaki G, Ishii T, Sato S, et al. Multiple polypoid masses in the gastrointestinal tract in patient with Menkes disease on copper-histidinate therapy. Eur J Pediatr. Dec 2004;163(12):745-6. [Medline].

  48. Suzuki M, Gitlin JD. Intracellular localization of the Menkes and Wilson's disease proteins and their role in intracellular copper transport. Pediatr Int. Aug 1999;41(4):436-42. [Medline].

  49. Tang J, Robertson S, Lem KE, et al. Functional copper transport explains neurologic sparing in occipital horn syndrome. Genet Med. Nov 2006;8(11):711-8. [Medline].

  50. Tumer Z, Birk Moller L, Horn N. Screening of 383 unrelated patients affected with Menkes disease and finding of 57 gross deletions in ATP7A. Hum Mutat. Dec 2003;22(6):457-64. [Medline].

  51. Tumer Z, Moller LB, Horn N. Mutation spectrum of ATP7A, the gene defective in Menkes disease. Adv Exp Med Biol. 1999;448:83-95. [Medline].

  52. Waggoner DJ, Bartnikas TB, Gitlin JD. The role of copper in neurodegenerative disease. Neurobiol Dis. Aug 1999;6(4):221-30. [Medline].

  53. Zaffanello M, Fanos V. Rare urological abnormalities in 2 cases of Menkes' syndrome. J Urol. Oct 2003;170(4 Pt 1):1335. [Medline].

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Further Reading

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Keywords

Menkes disease, neurodegenerative disease, impaired copper transport, abnormal copper metabolism, kinky hair disease, dietary copper, occipital horn syndrome, X-linked cutis laxa, Ehlers-Danlos type 9, Xq13.3 gene

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Contributor Information and Disclosures

Author

Celia H Chang, MD, Associate Health Sciences Clinical Professor, Department of Neurology, University of California at Davis
Celia H Chang, MD is a member of the following medical societies: American Academy of Neurology and Child Neurology Society
Disclosure: Nothing to disclose.

Medical Editor

Beth A Pletcher, MD, Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey
Beth A Pletcher, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Kenneth J Mack, MD, PhD, Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic
Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, and Society for Neuroscience
Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD, Assistant Professor, Department of Pediatrics, Division of Pediatric Neurology, Department of Neurology, Oregon Health and Science University; Consulting Staff, Shriners Hospital for Children
Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society
Disclosure: Nothing to disclose.

 
 
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