Genetics of Menkes Kinky Hair Disease Medication

  • Author: Stephen G Kaler, MD, MPH; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 22, 2012
 

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.

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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

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

Disclosure: Nothing to disclose.

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, New York

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

Disclosure: Genzyme Grant/research funds PI

Daniel Rauch, MD, FAAP  Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine

Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine

Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

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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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