eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Menkes Kinky Hair Disease: Treatment & Medication

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
Contributor Information and Disclosures

Updated: May 28, 2009

Treatment

Medical Care

Three fundamental issues must be addressed in configuring therapeutic strategies for individuals with Menkes kinky hair disease (MKHD): (1) the block in intestinal absorption of copper must be bypassed, (2) copper must be made available to the enzymes within cells that require it as a cofactor, and (3) infants with Menkes kinky hair disease must be identified and treatment commenced very early in life before irreparable neurodegeneration occurs.

• Published experience on this topic indicates that parenteral administration of copper in any form restores circulating copper and ceruloplasmin to reference range levels and that oral copper does not (except copper nitriloacetate, in some patients).
  • Although low hepatic copper stores are replenished quickly by parenteral therapy, brain copper during treatment increases only gradually, if at all, consistent with trapping of copper within cells comprising the blood-brain barrier.
  • Cerebrospinal fluid (CSF) copper levels increased quickly in one reported patient with Menkes kinky hair disease when fresh frozen plasma was transfused just prior to intravenous (IV) copper histidine; however, no apparent clinical benefit was discerned.
  • More recently, biochemical and molecular investigations of rodent neuroglial cells have confirmed the role of the Menkes kinky hair disease homolog in delivery of copper to the brain.
• The activities of copper enzymes, which are more difficult to study in a detailed fashion in humans than in the mouse, remain subnormal. Responsiveness to copper therapy has been evaluated in various tissues for cytochrome c oxidase (CCO), serum amine oxidase, dopamine beta-hydroxylase (DBH), and superoxide dismutase (SOD).
  • The lack of pretreatment data for brain or muscle CCO activity precludes knowing whether copper replacement has a partial positive effect on this enzyme, the deficiency of which seems primarily responsible for neurologic damage in patients with Menkes kinky hair disease and whose activity is increased in mouse mutants following copper treatment.
  • Serial skin biopsies are required to formally assess the effect of copper treatment on lysyl oxidase (LO) activity. Clinical evidence (ie, darkened hair) reflects that tyrosinase activity is increased by copper replacement in some patients.
  • Ceruloplasmin is the one copper enzyme whose activity always normalizes in response to copper therapy because this enzyme is synthesized in the liver, where the Menkes gene is not expressed at a high level.
• In patients with Menkes kinky hair disease who are treated very early with copper injections, clinical outcomes have varied. In the author's experience, approximately 30% of patients with classic Menkes kinky hair disease who are identified and treated within the first 10 days of life show normal neurodevelopmental outcomes. Characterization of the specific mutations in such individuals has been helpful in suggesting that partial activity of certain mutant copper ATPases may underlie the disparate clinical outcomes observed.
• Because neurodevelopmental status in the 5-day-old brindled mice that are cured by copper injection is considered the equivalent of third-trimester human fetuses, the author attempted in utero treatment in a fetus with Menkes kinky hair disease at 32 weeks' gestation whose parents found termination unacceptable and who understood the associated risks.
  • Several ultrasonographically guided intramuscular injections of copper histidine raised fetal plasma copper and ceruloplasmin levels, but the distinctively abnormal plasma catechol pattern persisted.
  • After pulmonary maturity was documented, the infant was delivered at 35.5 weeks' gestation, and daily copper injections were prescribed.
  • The treatment ultimately proved unsuccessful; failure to thrive, EEG abnormalities, and characteristic bone lesions developed. The infant died when aged 6 months because of pneumonitis.
  • This patient's mutation was later demonstrated to be a severe one, with no functional copper transport activity predicted, and quantitation of postmortem brain copper confirmed abnormally low levels in comparison to an age-matched infant control.
  • Therefore, despite normalization of circulating copper levels, delivery to the brain was impaired in the context of a severe Menkes gene mutation. The outcome in this case, and the significant fetal and maternal risks involved suggests that such intervention be viewed with considerable caution in future Menkes kinky hair disease cases.
• In another patient with Menkes kinky hair disease who was treated from a very early age (aged 8 d), normal neurodevelopment was achieved with very early copper treatment.
  • The family mutation in this instance was a small duplication within a splice junction that was associated with 2 mutant transcripts, 1 of which contained a small in-frame deletion that potentially encodes a functional Menkes copper ATPase.
  • Evidence for partial activity can be drawn from the patient's older brother, a neurologically impaired patient with Menkes kinky hair disease who did not have the benefit of early therapy but in whom copper injections produced noticeable darkening of the hair, indicating activation of the copper enzyme tyrosinase (the Menkes gene product recently was demonstrated in vitro as necessary for this process).
  • The infant with Menkes kinky hair disease who began treatment when aged 8 days exhibited healthy neurodevelopment, including independent walking, by age 14 months. Treatment was discontinued when the child was aged 4 years, with no adverse effects.
  • Currently aged nearly 13 years, the child attends public school with age-appropriate peers and reportedly exhibits no significant neurologic abnormalities.
• Although copper replacement does not provide substantive neurologic improvement in all patients with Menkes kinky hair disease who are treated very early or in older individuals with Menkes kinky hair disease, its use has been associated with modest clinical benefit, including decreased seizure frequency and reduced irritability. No evidence suggests that copper treatment influences life span in patients with Menkes kinky hair disease in a consistent fashion. In light of the possibility of small clinical benefits or improved patient comfort in a hopeless disease, decisions concerning copper replacement treatment in symptomatic patients perhaps best are made by the parents, following frank discussion of the very limited benefits that can be expected. In instances where the diagnosis is made prior to the onset of neurologic damage, copper replacement is clearly indicated because the prevention of the neurodegenerative features is possible, at least for some such individuals.
• Proximal renal tubular damage is a known adverse effect of copper overload. These effects presumably relate to exacerbation of the natural tendency of the Menkes kidney to sequester copper. However, the clinical significance of this adverse effect is minor in most treated patients because renal losses rarely reach the point where replacement (eg, oral bicarbonate) is needed. Concomitant treatment with penicillamine, a copper-chelating agent, has been used in some patients with Menkes kinky hair disease with the rationale of preventing copper overload.
• Another therapeutic agent that has received attention is vitamin C, which may limit interaction between copper and metallothionein (MT); its capacity as a reducing agent may enhance copper uptake by cells. Although experience with such treatment is scant, apparently vitamin C does not significantly improve the biochemical or clinical problems in patients with Menkes kinky hair disease.
• Vitamin E has also been suggested as therapy for individuals with Menkes kinky hair disease, presumably for its antioxidant property, which may reduce the effects of Cu/Zn SOD deficiency.
• The carbamic acid derivative, diethyldithiocarbamate (DEDTC), is a chelating agent that forms lipophilic complexes with copper.
  • When fed to rats, DEDTC increases copper levels in the brain.
  • In macular mice that die by age 2 weeks without copper treatment, intraperitoneal administration of DEDTC or dimethyldithiocarbamate (DMDTC) resulted in normal survival in the absence of any copper treatment. Furthermore, survival was correlated with increases in macular brain copper levels.
  • In mice that received no exogenous copper and 200 mg/kg DMDTC, the brain copper level was the same as in healthy controls.
  • These experiments suggest that the lipophilic complex was able to bypass the block in macular brain copper uptake. Although toxicity considerations may prohibit long-term use of such agents in humans, the principle that lipid-soluble complexes can enhance copper transport across cellular membranes deserves further attention with respect to treatment of individuals with Menkes kinky hair disease.
• Gene therapy for persons with Menkes kinky hair disease is a theoretical possibility, although a number of potential problems would be faced.
  • Because gene therapy requires targeting of specific organs, a disease similar to Menkes kinky hair disease, which effects nearly every cell in the body, is not amenable to full correction. Assuming the brain is the target organ, concern regarding the potential toxicity of gene therapy viral vectors is heightened.
  • The gene needs to be delivered to many cells, and expression needs to be sustained. The gene product, when produced, has to be targeted to the appropriate membrane.
  • Coproduction of native mutant forms of the copper ATPase could inhibit proper function of the normal molecule expressed by the introduced gene. Parenteral copper replacement would likely remain necessary in order to circumvent the defect in intestinal absorption.
  • Despite these significant caveats, functional characterization of the Menkes copper ATPase, progress in developing systems of gene delivery to the brain, and the severe nature of the untreated condition may render Menkes kinky hair disease a candidate for gene therapy in the future.
• A more recent treatment consideration, intrathecal copper administration, relies on several lines of evidence for support, including (1) NIH treatment experience to date, (2) human and animal data indicating that the Menkes gene (and homolog) mediates copper delivery to the brain in mammals, and (3) the discovery of a class of intracellular copper transporters named copper chaperones that are not dependent on the Menkes transporter.
  • The copper chaperones were identified in the low eukaryote yeast Saccharomyces cerevisiae, and their human counterparts were cloned subsequently.
  • The human protein HAH1 delivers copper to the Menkes ATPase within the secretory pathway of cells; CCS1 delivers copper to Cu/Zn SOD, which is synthesized in the cytosol on free ribosomes; COX17 delivers copper to CCO, located in the mitochondria of cells.
  • If copper is injected directly into the CSF, normal uptake into neuronal cells as well as intracellular delivery to Cu/Zn SOD and CCO (via CCS1 and COX17) should occur in patients with Menkes kinky hair disease. This treatment is not expected to correct deficiency of the secreted glycoprotein enzyme DBH in the brain because a normal Menkes gene product is needed to incorporate copper into DBH. However, indirect evidence reflects that normal DBH activity is not critical for normal neurologic functioning from individuals with congenital absence of DBH, from patients with Menkes kinky hair disease with good neurologic outcomes following very early treatment, and from individuals with occipital horn syndrome (OHS).
  • Obviously, safety considerations must be addressed and clarified before intrathecal copper is actually used in infants with Menkes kinky hair disease; these safety considerations are being addressed and clarified via animal studies.
  • Whatever mode of treatment for Menkes kinky hair disease is used, intervention at the earliest possible moment is of paramount importance because the window of opportunity before neurologic injury is no longer than several months.
  • L-threo-dihydroxyphenylserine (L-DOPS) is used for amelioration of DBH deficiency.
    • L-DOPS is a synthetic amino acid converted to norepinephrine (NE) by the enzyme aromatic-L-amino acid decarboxylase. Provision of this compound to patients with Menkes kinky hair disease should increase their levels of NE and dihydroxyphenylglycol (DHPG), which is the deaminated metabolite of NE, because the block in DBH activity is bypassed. L-DOPS should correct the typical neurochemical abnormalities in plasma and theoretically in CSF if L-DOPS crosses the blood-brain barrier, which is not known.
    • The precise contribution of DBH deficiency to the Menkes kinky hair disease phenotype is unclear. The autosomal recessive trait, congenital absence of DBH, is evidently not lethal in humans, as per reports of adults with Menkes kinky hair disease in whom dysautonomic symptoms (ie, orthostatic hypotension, eyelid ptosis, chronic diarrhea) were the predominant neurologic abnormalities. However, in mice with targeted disruption of the murine DBH gene, fetal and perinatal lethality, failure to thrive, and abnormal cold acclimatization occur. Given this murine phenotype, correcting the neurochemical abnormalities in patients with Menkes kinky hair disease may contribute to improved neurodevelopmental outcomes.
    • Similarly, in patients with OHS, treatment with L-DOPS should correct neurochemical abnormalities and resolve dysautonomic symptoms, which include orthostatic hypotension and chronic diarrhea.
    • A clinical trial at the NIH to evaluate this agent is planned.

Surgical Care

Patients with Menkes kinky hair disease tolerate surgery well and do not appear to have a heightened anesthetic risk.^10,11 Certain surgical situations commonly arise in patients with Menkes kinky hair disease.

• Myringotomy tubes are needed for chronic otitis media.
• Gastrostomy tube placement is required for feeding problems.
• Occasionally, repair of bladder diverticula is necessary.

Consultations

Consultation with multiple specialists, ideally at a central location (eg, academic pediatric medical center), is often very helpful in the care and treatment of individuals with Menkes kinky hair disease. The following specialties are particularly useful for the patients and their families:

• Medical geneticist (eg, for counseling and guidance on recurrence risks, prenatal assessment of subsequent pregnancies, carrier testing of at-risk family members)
• Neurologist (eg, for seizure management, developmental assessment)
• Gastroenterologist and nutritionist (for feeding issues)
• Urologist (for management of urinary tract issues, including obstruction related to bladder diverticula)
• Otolaryngologist (if chronic ear infections develop)
• Dentist (for caries prevention)¹²
• Psychologist/social worker (if needed, to help parents and family members with emotional and practical economic concerns related to the care of an infant or child with Menkes kinky hair disease)
• Physical and occupational therapist (to maximize neurodevelopmental outcome)

Diet

• In general, maximizing caloric intake in children with Menkes kinky hair disease is important because their weight gain and overall nutritional status is often poor. This can be accomplished by the addition of formula supplements (eg, Polycose, MCT oil) or by emphasizing high-calorie foods, such as cheese and yogurt.
• Often, formal evaluation by a gastroenterology/nutrition consultant, as noted above, is warranted with consideration of aggressive caloric supplementation via nasogastric or gastrostomy feeding tubes.

Medication

Trace metals

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 chloride (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.

L-threo-dihydroxyphenylserine (L-DOPS)

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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