Case Reports

Indian Pediatrics 2002; 39:183-185  

Treatment of Menkes Disease with Parenteral Copper Histidine

From the Department of Clinical Pharmacology, Seth G.S. Medical College and KEM Hospital, Parel, Mumbai 400 012, India and *P.D Hinduja Hospital and Research Center, Veer Savarkar Marg, Mahim, Mumbai 400 016, India.

Correspondence to: Dr. N.A. Kshirsagar, Dean, Professor and Head of Clinical Pharmacology, Department of Clinical Pharmacology, M.S. Building, 1st Floor, Seth G.S. Medical College and K.E.M. Hospital, Parel, Mumbai 400 012, India.

E-mail: [email protected]

Manuscript received: March 14, 2001;
Initial review completed: May 3, 2001;
Revision accepted: July 16, 2001.

Menkes disease, also called as Menkes steely hair disease, or Kinky hair syndrome or Menkes syndrome is a rare X-linked neuro-degenerative disorder of copper metabolism with an estimated prevalence rate of 1 in 100,000-250,000 births. This syndrome of copper deficiency results due to accumulation of copper in the intestine, due to defect in intestinal copper absorption. The clinical features of Menkes disease include skeletal abnormalities, severe mental retardation, thrombosis, hypothermia, arterial abnormali-ties and characteristic facial features. All of these result from decreased activity of cupro-enzymes such as dopamine B hydroxylase, cytochrome c oxidase, lysyl oxidase, tyrosin-ase, ceruloplasmin, sulfhydryl oxidase, and copper-zinc superoxide dismutase(1).

Parenteral copper in the form of copper-histidine, copper-acetate or copper-EDTA injected intravenously or subcutaneously has been gaining acceptance as a treatment modality for the last decade. We present in this paper, two cases of Menkes disease treated by us with parenteral copper-histidine manufactured at our department and the results of the treatment.

Case 1: A 13-months child from Goa, born of a consanguineous marriage was referred to us for treatment of mild Menkes disease. The patient had light colored hair, wrinkled skin, pili torti and had repeated episodes of focal seizures. A diagnosis of Menkes disease was confirmed by a reduced basal serum copper and ceruloplasmin levels of 63 µg/dl and 17.9 mg/dl respectively. MR angiography confirmed tortuous, ecstatic intracranial vessels. After informed consent from his guardians, the patient was started on copper-histidine injections as follows - 50 µg/d on Day 1, 100 µg/d on Day 2 and 150 µg/d from Day 3 onwards. The drug was administered subcutaneously in the anterolateral thigh region. Biochemical parameters were repeated at 2 weeks and 1 month. Within 2 weeks of initiation of therapy, serum Cu++ and ceruloplasmin values had normalized (Table I). The texture and color of the hair began to change and there was a reduction in the number of seizures. The patient’s mother was then trained to administer the drug and the patient was discharged.

The patient was lost to follow up three months later when the mother cited financial constraints in procuring copper histidine every two months and making repeated trips to Mumbai. Telephonic follow up confirmed that the patient was alive without further deterioration in his condition.

Case 2: An 18-month-old child born of a non-consanguineous marriage from Lucknow was referred to us for copper-histidine therapy. This patient had similar clinical features and MR angiography but greater mental retarda-tion. Copper histidine in him was started in a similar manner, but the patient died on day 10, before his first follow up. The relatives did not permit an autopsy.

Discussion

Among the different parenteral forms of copper therapy, copper-histidine has been reported to be taken up by the brain most efficiently(2). The dosage of copper-histidine used by various authors ranges from 200-1000 µg once a day or 2-3 times/week(3). Response to therapy is based on monitoring of serum copper, ceruloplasmin, urinary copper excre-tion and liver copper content.

In Menkes disease, with early initiation of therapy (within 2 months of birth), neuro-logical deterioration can be prevented. Copper-histidine after 2 months cannot halt either the neurological deterioration nor can it improve connective tissue laxity or bone deformities, although the hair and bio-chemical abnormalities do normalize. The formulation used by us is identical to the one used earlier in 7 cases of Menkes disease. Of 2 patients where the therapy was begun within 1 month of birth did well neurologically, while the other 5 patients did poorly despite intiation of treatment at 2-7 months of age(4). We saw this in Case 1 with normalization of bio-chemical parameters and beginning of hair normalization. Case 2 had far too advanced disease for the treatment to have any effects.

The copper-histidine formulation used in two cases mentioned was sterile, pyrogen free and manufactured using locally available chemicals. Copper-histidine solution was prepared under aseptic condition using a laminar air flow hood. Anhydrous copper chloride (0.106g) and L(+) Histidine (0.244g) are dissolved in 90 ml of saline. The pH of the solution was adjusted to 7.38-7.4 with 0.2N Sodium hydroxide solution using a pH meter. The final volume was made to 100 ml with 0.9% sodium chloride injection USP. It was aqua blue in color, had to be protected from light, was refrigerated and had a shelf life of 56 days. Given the rarity of the disease, there was wastage of the formulation.

To date, parenteral copper replacement remains the mainstay of therapy for Menkes disease. To our knowledge, these are the first two cases in India to have received copper-histidine which may form the mainstay of treatment till such time that other modalities such as lipid chelators and gene therapy are tried for this disease. Tanaka et al(5) have reported that intra peritoneal administration of diethyl dithio carbamate and dimethyl dithio carbamate resulted in normal survival without any copper treatment in macular mutant mice. These findings suggest that lipid soluble chelators can enhance copper transport across cellular membranes. Both patients treated by us belonged to the lower socio economic strata. The cost per 150 µg dose worked out to be Rs. 40/- and included cost of chemicals, consumables, quality control and personnel. In a developing country like ours, the economics of giving life long copper histidine will remain an important issue in determining patient compliance and follow up.

We are grateful to Dr. B. Sarkar, Head Structural Biology and Biochemistry, The Hospital for Sick Children, University of Toronto and Karen Walsh, Manufacturing Pharmacist, University of Toronto for help and assistance in preparation of sterile copper histidine solution.

Contributors: BGK was responsible for manufacture of copper-histidine solution and data collection. NJG co-ordinated the study, supervised drug administra-tion, patient follow up and drafted the paper. VPU was responsible for patient care and follow up and drafting of paper. NAK was responsible for super-vision of drug manufacture, drug administration, study design and manuscript preparation, and will act as the guarantor for the paper.

Funding: None.

Competing interests: None stated.

 

1. Kodama H, Murata Y, Kobayashi M. Clinical manifestations and treatment of Menkes disease and its variants. Pediatr Int 1999; 41: 423-429.

2. Barnea A, Katz BM. Uptake of 67Copper complexed to 3 H-histidine by brain hypo-thalamic slices: Evidence that dissociation of the complex is not the only factor determining 67Copper uptake. J Inorg Biochem 1990; 40: 81-93.

3. Kaler SG. Menkes disease. Adv Pediatr 1994; 41: 263-304.

4. Sarkar B, Walsh K, Clark TR. Copper histidine therapy for Menkes disease. J Pediatr 1993; 123: 828-830.

5. Tanaka K, Kobayashi K, Fujita Y, Fukuhara C, Onosaka S, Min K. Effects of chelators on copper therapy of macular mouse: A model animal of Menkes’ kinky disease. Res Commun Chem Pathol Pharmacol 1990; 69: 217-227.