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Genetics of Menkes Kinky Hair Disease Medication

  • Author: Stephen G Kaler, MD, MPH; Chief Editor: Maria Descartes, MD  more...
 
Updated: Sep 08, 2015
 

Medication Summary

IV/SC copper in various formulations has been used to treat individuals with Menkes kinky hair disease (MKHD) and occipital horn syndrome (OHS).

L-threo-dihydroxyphenylserine (L-DOPS) is used for amelioration of DBH deficiency.

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Trace metals

Class Summary

IV/SC copper in various formulations has been used to treat individuals with Menkes kinky hair disease (MKHD) and occipital horn syndrome (OHS) over the past 30 years. Whether any particular preparation is superior to another in terms of neurologic outcomes is not clear; the biology of the Menkes transporter suggests that uptake of copper into cells is not dependent on the chemical form in which copper is introduced by SC injection.

Copper chloride, copper histidine, and copper sulfate have been used in humans. IP copper chloride is curative in the brindled mouse mutant. Copper chloride injections have not been reported in the very early treatment of individuals with Menkes kinky hair disease; all experience with very early treatment has been with copper histidine. Therefore, from the evidence available, whether one copper salt conveys superior treatment efficacy is not clear. Copper chloride and copper sulfate are available commercially in the United States, whereas copper histidine is not. Anecdotal evidence reflects that copper sulfate can produce significant injection site inflammation.

Copper (Cupric chloride, Copper trace)

 

Available from Abbott Pharmaceuticals (1-800-937-6100) in a concentration of 2 mg/5 mL. Therefore, SC injection of 500 µL provides 200 mcg of copper.

Proximal renal tubular damage presumably related to exacerbation of natural tendency of kidney in patients with MKHD to sequester copper; clinical significance is minor in most treated patients because renal losses rarely reach the point where replacement (eg, PO bicarbonate) is needed.

Copper histidine

 

For use in NIH Protocol #90-N-0149, a freeze-dried (for enhanced stability) preparation is prepared by the NIH Pharmaceutical Development Service, using the following stepwise procedure:

1. Bubble nitrogen into water for injection for at least 20 min.

2. Weigh 1.345 g CuCl2 dihydrate and 2.45 g L-histidine in separate beakers.

3. Dissolve CuCl2 with water and do the same with L-histidine separately at room temperature; mix well.

4. Add both solutions together; blue color intensifies; mix well.

5. Adjust pH to 7.30-7.4 with 0.1 N NaOH or HCl.

6. Adjust volume to 1000 mL.

7. Filter through a Silo filter U containing a 0.22-micrometer Durapore filter using sterile technique.

8. Aliquot, gravimetrically, 2 g (2 mL) into each 5-mL sterile clear vial and place them on a tray for the freeze-dryer.

9. Freeze to -30° C and then freeze-dry until contents reach room temperature.

10. Stopper vials under vacuum, break off vacuum, and remove trays from freeze-dryer.

11. Seal vials with flip-off aluminum seals.

12. Refrigerate.

The product is stable for at least 1 mo when stored as freeze-dried product at room temperature. However, patients' families typically store vials in their home freezers.

For use in patients, contents of a vial are reconstituted with 2 mL NS, providing a solution of 500 mcg/mL for SC injection.

Dose based on serum copper and ceruloplasmin levels and copper balance studies in treated patients.

Proximal renal tubular damage presumably related to exacerbation of natural tendency of kidney in patients with MKHD to sequester copper; clinical significance is minor in most treated patients because renal losses rarely reach the point where replacement (eg, PO bicarbonate) is needed.

Cupric sulfate

 

Available in Argentina from Farmacologia Argentina de Avanzada (FADA) in a concentration of 2 mg/5 mL (400 mcg/mL); has been used in MKHD there and in Spain.

Proximal renal tubular damage presumably related to exacerbation of natural tendency of kidney in patients with MKHD to sequester copper; clinical significance is minor in most treated patients because renal losses rarely reach the point where replacement (eg, PO bicarbonate) is needed.

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L-threo-dihydroxyphenylserine (L-DOPS)

Class Summary

This agent is used to ameliorate dopamine-beta-hydroxylase (DBH) deficiency.

L-threo-dihydroxyphenylserine (L-DOPS)

 

Synthetic amino acid converted to NE by enzyme aromatic-L-amino acid decarboxylase. Provision to patients with MKHD should increase levels of NE and DHPG (deaminated metabolite of NE) because block in DBH is bypassed. L-DOPS should correct typical neurochemical abnormalities in plasma of patients with MKHD (and theoretically in CSF, if L-DOPS crosses blood-brain barrier, which is not known).

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Contributor Information and Disclosures
Author

Stephen G Kaler, MD, MPH Head, Unit On Pediatric Genetics, Laboratory of Clinical Genomics and Clinical Director, Intramural Research Program, National Institute of Child Health & Human Development (NICHD), National Institutes of Health

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Christian J Renner, MD Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany

Disclosure: Nothing to disclose.

Acknowledgements

I thank deeply the patients and families who have participated in our clinical trials and the members of my Section for their hard work and dedication to the aims of our laboratory.

References
  1. Møller LB, Hicks JD, Holmes CS, Goldstein DS, Brendl C, Huppke P, et al. Diagnosis of copper transport disorders. Curr Protoc Hum Genet. 2011 Jul. Chapter 17:Unit17.9. [Medline]. [Full Text].

  2. Kim YH, Lee R, Yoo HW, Yum MS, Bae SH, Chung SC, et al. Identification of a novel mutation in the ATP7A gene in a Korean patient with Menkes disease. J Korean Med Sci. 2011 Jul. 26(7):951-3. [Medline]. [Full Text].

  3. Datta AK, Ghosh T, Nayak K, Ghosh M. Menkes kinky hair disease: A case report. Cases J. 2008 Sep 18. 1(1):158. [Medline].

  4. Aldecoa V, Escofet-Soteras C, Artuch R, Ormazabal A, Gabau-Vila E, Martin-Martinez C. [Menkes disease: its clinical, biochemical and molecular diagnosis]. Rev Neurol. 2008 Apr 1-15. 46(7):446-7. [Medline].

  5. Danks DM, Campbell PE, Walker-Smith J, et al. Menkes' kinky-hair syndrome. Lancet. 1972 May 20. 1(7760):1100-2. [Medline].

  6. Danks DM, Cartwright E, Stevens BJ, Townley RR. Menkes' kinky hair disease: further definition of the defect in copper transport. Science. 1973 Mar 16. 179(78):1140-2. [Medline].

  7. Menkes JHM, Alter M, Steigleder GK. A sex-linked recessive disorder with retardation of growth, peculiar hair and focal cerebellar degeneration. Pediatrics. 1962. 29:764-769.

  8. Chelly J, Tumer Z, Tonnesen T, et al. Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nat Genet. 1993 Jan. 3(1):14-9. [Medline].

  9. Baerlocher K, Nadal D. [Menkes syndrome]. Ergeb Inn Med Kinderheilkd. 1988. 57:77-144. [Medline].

  10. Kaler SG. Menkes disease. Adv Pediatr. 1994. 41:263-304. [Medline].

  11. Kaler SG, Tang J, Donsante A, Kaneski CR. Translational read-through of a nonsense mutation in ATP7A impacts treatment outcome in Menkes disease. Ann Neurol. 2009 Jan. 65(1):108-13. [Medline].

  12. Donsante A, Yi L, Zerfas PM, Brinster LR, Sullivan P, Goldstein DS, et al. ATP7A gene addition to the choroid plexus results in long-term rescue of the lethal copper transport defect in a Menkes disease mouse model. Mol Ther. 2011 Dec. 19(12):2114-23. [Medline]. [Full Text].

  13. Sato R, Okutani K, Higashi T, Satou M, Fujimoto K, Okazaki K. [Case report : respiratory care for anesthesia in a patient with Menkes syndrome and micrognathia]. Masui. 2009 Jan. 58(1):103-5. [Medline].

  14. Passariello M, Almenrader N, Pietropaoli P. Anesthesia for a child with Menkes disease. Paediatr Anaesth. 2008 Dec. 18(12):1225-6. [Medline].

  15. Yamashita J, Yamakage M, Kawana S, Namiki A. Two cases of Menkes disease: airway management and dental fragility. Anaesth Intensive Care. 2009 Mar. 37(2):332-3. [Medline].

  16. [Guideline] Cunniff C. Prenatal screening and diagnosis for pediatricians. Pediatrics. 2004 Sep. 114(3):889-94. [Medline].

  17. Amaravadi R, Glerum DM, Tzagoloff A. Isolation of a cDNA encoding the human homolog of COX17, a yeast gene essential for mitochondrial copper recruitment. Hum Genet. 1997 Mar. 99(3):329-33. [Medline].

  18. Bennetts HW, Chapman FE. Copper deficiency in sheep in Western Australia: a preliminary account of the aetiology of enzootic ataxia of lambs and an anemia of ewes. Aust Vet J. 1937. 13:138-49.

  19. Camakaris J, Voskoboinik I, Mercer JF. Molecular mechanisms of copper homeostasis. Biochem Biophys Res Commun. 1999 Aug 2. 261(2):225-32. [Medline].

  20. Francis MJ, Jones EE, Levy ER, et al. A Golgi localization signal identified in the Menkes recombinant protein. Hum Mol Genet. 1998 Aug. 7(8):1245-52. [Medline].

  21. 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. 2005 Dec 1. 139(2):151-5. [Medline].

  22. Guitet M, Campistol J, Medina M. [Menkes disease: experience in copper salts therapy]. Rev Neurol. 1999 Jul 16-31. 29(2):127-30. [Medline].

  23. Kaler SG. ATP7A-related copper transport diseases-emerging concepts and future trends. Nat Rev Neurol. 2011 Jan. 7(1):15-29. [Medline].

  24. Kaler SG. Diagnosis and therapy of Menkes syndrome, a genetic form of copper deficiency. Am J Clin Nutr. 1998 May. 67(5 Suppl):1029S-1034S. [Medline].

  25. Kaler SG. Menkes disease mutations and response to early copper histidine treatment. Nat Genet. 1996 May. 13(1):21-2. [Medline].

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

  27. Kaler SG, Buist NR, Holmes CS, et al. Early copper therapy in classic Menkes disease patients with a novel splicing mutation. Ann Neurol. 1995 Dec. 38(6):921-8. [Medline].

  28. Kaler SG, Das S, Levinson B, et al. Successful early copper therapy in menkes disease associated with a mutant transcript containing a small In-frame deletion. Biochem Mol Med. 1996 Feb. 57(1):37-46. [Medline].

  29. Kaler SG, Gahl WA, Berry SA, et al. Predictive value of plasma catecholamine levels in neonatal detection of Menkes disease. J Inherit Metab Dis. 1993. 16(5):907-8. [Medline].

  30. Kaler SG, Gallo LK, Proud VK, et al. Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus. Nat Genet. 1994 Oct. 8(2):195-202. [Medline].

  31. Kaler SG, Goldstein DS, Holmes C, et al. Plasma and cerebrospinal fluid neurochemical pattern in Menkes disease. Ann Neurol. 1993 Feb. 33(2):171-5. [Medline].

  32. 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. 2008 Feb 7. 358(6):605-14. [Medline]. [Full Text].

  33. Kaler SG, Schwartz JP. Expression of the Menkes disease homolog in rodent neuroglial cells. Neurosci Res Commun. 1998. 23:61-66.

  34. Kaler SG, Tumer Z. Prenatal diagnosis of Menkes disease. Prenat Diagn. 1998 Mar. 18(3):287-9. [Medline].

  35. Klomp LW, Lin SJ, Yuan DS et al. Identification and functional expression of HAH1, a novel human gene involved in copper homeostasis. J Biol Chem. 1997 Apr 4. 272(14):9221-6. [Medline].

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

  37. La Fontaine SL, Firth SD, Camakaris J, et al. Correction of the copper transport defect of Menkes patient fibroblasts by expression of the Menkes and Wilson ATPases. J Biol Chem. 1998 Nov 20. 273(47):31375-80. [Medline].

  38. Levinson B, Conant R, Schnur R, et al. A repeated element in the regulatory region of the MNK gene and its deletion in a patient with occipital horn syndrome. Hum Mol Genet. 1996 Nov. 5(11):1737-42. [Medline].

  39. Mercer JF, Livingston J, Hall B, et al. Isolation of a partial candidate gene for Menkes disease by positional cloning. Nat Genet. 1993 Jan. 3(1):20-5. [Medline].

  40. 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. 2000 Apr. 66(4):1211-20. [Medline].

  41. Payne AS, Gitlin JD. Functional expression of the menkes disease protein reveals common biochemical mechanisms among the copper-transporting P-type ATPases. J Biol Chem. 1998 Feb 6. 273(6):3765-70. [Medline].

  42. 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. 1999 Oct. 8(11):2107-15. [Medline].

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

  44. Petris MJ, Strausak D, Mercer JF. The Menkes copper transporter is required for the activation of tyrosinase. Hum Mol Genet. 2000 Nov 22. 9(19):2845-51. [Medline].

  45. Prohaska JR, Tamura T, Percy AK, Turnlund JR. In vitro copper stimulation of plasma peptidylglycine alpha-amidating monooxygenase in Menkes disease variant with occipital horns. Pediatr Res. 1997 Dec. 42(6):862-5. [Medline].

  46. Pufahl RA, Singer CP, Peariso KL, et al. Metal ion chaperone function of the soluble Cu(I) receptor Atx1. Science. 1997 Oct 31. 278(5339):853-6. [Medline].

  47. Robertson D, Goldberg MR, Onrot J, et al. Isolated failure of autonomic noradrenergic neurotransmission. Evidence for impaired beta-hydroxylation of dopamine. N Engl J Med. 1986 Jun 5. 314(23):1494-7. [Medline].

  48. Sarkar B, Lingertat-Walsh K, Clarke JT. Copper-histidine therapy for Menkes disease. J Pediatr. 1993 Nov. 123(5):828-30. [Medline].

  49. Schaefer M, Gitlin JD. Genetic disorders of membrane transport. IV. Wilson's disease and Menkes disease. Am J Physiol. 1999 Feb. 276(2 Pt 1):G311-4. [Medline].

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

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

  52. Tumer Z, Horn N, Tonnesen T, et al. Early copper-histidine treatment for Menkes disease. Nat Genet. 1996 Jan. 12(1):11-3. [Medline].

  53. Tumer Z, Lund C, Tolshave J, et al. Identification of point mutations in 41 unrelated patients affected with Menkes disease. Am J Hum Genet. 1997 Jan. 60(1):63-71. [Medline].

  54. 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].

  55. Valentine JS, Gralla EB. Delivering copper inside yeast and human cells. Science. 1997 Oct 31. 278(5339):817-8. [Medline].

  56. Voskoboinik I, Strausak D, Greenough M, et al. Functional analysis of the N-terminal CXXC metal-binding motifs in the human menkes copper-transporting P-type ATPase expressed in cultured mammalian cells. J Biol Chem. 1999 Jul 30. 274(31):22008-12. [Medline].

  57. Vulpe C, Levinson B, Whitney S, et al. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nat Genet. 1993 Jan. 3(1):7-13. [Medline].

 
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Classic Menkes kinky hair disease in an 8-month-old male infant. Note the abnormal hair, eyelid ptosis, and jowly facial appearance.
Adolescent patient with typical occipital horn syndrome. Note elbow dislocations and genu valgum. Radiographs exhibited bilateral occipital exostoses of the skull and club-shaped distal clavicles.
Successfully treated classic Menkes kinky hair disease. Diagnosis at birth enabled copper therapy to begin when the infant was aged 8 days. The child walked independently when aged 14 months. This patient's mutation (IVS8,AS,dup5) was associated with a transcript harboring a small in-frame deletion, potentially encoding a functional copper adenosine triphosphatase (ATPase).
Menkes kinky hair disease copper adenosine triphosphatase (see text for detailed discussion).
 
 
 
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