Genetics of Menkes Kinky Hair Disease Treatment & Management

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.

• A more recent treatment consideration, brain-directed viral gene therapy, ^[15] 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.

  • Obviously, safety considerations must be clarified before brain-directed viral gene therapy is 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.

Patients with Menkes kinky hair disease tolerate surgery well and do not appear to have a heightened anesthetic risk. ^{[16, 17]} 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.

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) ^[18]

• 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)

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.