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Copper-histidine therapy for Menkes disease
828
Sarkar, Lingertat- Walsh, and Clarke
The Journal of Pediatrics November 1993
Copper-histidine therapy for Menkes disease B i b u d h e n d r a Sarkar, PhD, Karen L i n g e r t a t - W a l s h , BScPhm, a n d J o e TI R, C l a r k e , MD, Phb From the Departments of Biochemistry, Pharmacy, Pediatrics, and Genetics, Hospital for Sick Children, Toronto, and the Departments of Biochemistry and Pediatrics, University of Toronto, Toronto, Ontario, Canada
Menkes disease is an X-linked genetic disorder of copper transport that results in death from severe progressive neurodegeneration by the a g e of 3 years. We report here our 17 years' experience with the treatment of Menkes disease with subcutaneous administrationof copper-histidine. Two patients (16 and 6 years of a g e ) whose therapy was begun within I month of birth have done well neurologically. The other five patients have done poorly despite treatment initiated at 2 to 7 months of age. Copper-histidine therapy may be an effective treatment if started early. (J PEDIATR1993;123:828-30)
Menkes disease is an X-linked genetic disorder associated with a widespread defect of copper transport.1 The disease is characterized by rapidly progressive cerebral degeneration, bone lesions resembling those seen in scurvy, and elongation and tortuosity of the cerebral arteries. Death caused by severe, progressive neurodegeneration almost invariably occurs by the age of 3 years. Recently the candidate gene for Menkes disease has been reported independently by three groups. 24 The gene product is very similar to a bacterial copper-transporting adenosinetriphosphatase; additionally, it contains six putative copper-binding motifs at the N-terminal. Copper-histidine was found in normal human serum, and detailed studies revealed the physiologic importance of copper-histidine.5, 6 Recently, histidine has been shown to enhance the uptake of copper in human trophoblast cells in the presence of serum, a phenomenon considered to be due to the release of copper that is bound to albumin. 7 Parenteral therapy for Menkes disease with various copper salts, commenced either before or after neurologic impairment, has never convincingly shown a significant effect on the devastating neurodegenerative progression of the disease. 8 The results of our studies with copperhistidine led us to test copper-histidine in the treatment of Menkes disease. 911 We report here our experience with this treatment during the past 17 years.
Supported by grants from the Medical Research Council of Canada and the Lunenfeld Foundation. Submitted for publication March 22, 1993; accepted June 17, 1993. Reprint requests: B. Sarkar, PhD, Head, Department of Biochemistry Research, Hospital for Sick Children, Toronto, Ontario M5G IXS, Canada. Copyright 9 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00 + .10 9/26/49490
METHODS Between 1976 and 1993, Menkes disease has been diagnosed in seven patients at the Hospital for Sick Children, Toronto, and all have been treated with daily injections of copper-histidine in an effort to ameliorate the disease. Clinical information on these patients is summarized in the Table. In every case but one, the diagnosis was suspected on the basis of the presence of characteristic clinical findings and confirmed by demonstration of markedly depressed plasma copper and ceruloplasmin levels. Patient 1 was born 31/2 years after the death of a sibling who had died with severe neurodegeneration associated with confirmed classic Menkes disease. Patient 1 is the first patient to be treated with injections of copper-histidine. Copper-histidine solution is prepared for injection with full aseptic technique in a laminar airflow hood under conditions that minimize damage from light. Anhydrous copper chloride, 0.1060 gm, and L-histidine, 0.2444 gm, are dissolved together in approximately 90 ml sterile 0.9% sodium chloride for injection (U.S.P.). A solution of 0.2N sodium hydroxide in sterile sodium chloride 0.9% for injection is used to adjust the pH of the solution to pH 7.38 to 7.40. After adjustment of the pH of the copper-histidine solution, the final volume is made up to 100 ml with sodium chloride 0.9% for injection (U.S.P.). The copper-histidine solution is drawn up into a sterile, disposable, plastic 20 ml syringe and the desired aliquot (5 or 10 ml) filtered through a 0.22 #m filter into sterile glass vials. Sterility, copper analysis, and pyrogen testing are performed on each batch. Samples are refrigerated for storage in brown bags resistant to ultraviolet light. An expiry of 56 days is assigned on the basis of our stability studies. The solution form of copper-histidine is sensitive to light, temperature, and oxygen. Recent resuits show that copper-histidine produced in freeze-dried
The Journal of Pediatrics Volume 123, Number 5
Sarkar, Lingertat- Walsh, and Clarke
829
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Age (yrsl Figure. Plasma copper and ceruloplasmin levels during the first 15 years of life (patient 1). Clear symbols show ceruloplasmin levels (normal, 180 to 450 mg/L); dark symbols indicate copper levels (normal, 10.5 to 23.0/~mol/L). Arrows at top of illustration show the dosage of copper-histidine. Left to right: 675/~g/day; 200/*g/day; 250 #g/day; 500/zg/day; 600/~g/day; and 800/tg/day.
Clinical outcome of patients with Menkes disease treated with copper-histidine at the Hospital for Sick Children, Toronto, during 1976 to 1993 Table.
Case No.
Date of birth
A g e at diagnosis
Outcome
1 2 3 4 5 6 7
Nov. 12, 1976 Oct. 4, 1982 May 16, 1984 Sept. 29, 1986 March 17, 1988 March 9, 1990 Aug. 27, 1991
2 wk* 7 mo 4 mo 1 mot 6 mo 4 mo 2 mo
Nearly normal IQ Lost to follow-up Died at 14 mo Nearly normal IQ Died at 2V2 yr of age Died at 22 mo of age Profound mental retardation
*Born at 37 weeks of gestation, corrected age 39 weeks. 1"Born at 35 weeks of gestation, corrected age 39 weeks.
form without any additives has better stability for a long period. 12 RESULTS Patient 1. Patient 1, a 16-year-old boy with Menkes diseas e , has been receiving daily subcutaneous injections of copper-histidine for treatment of his disease. This case was
reported when he was 12 years of age. I1 His copper and ceruloplasmin levels are depicted in the Figure. Clinically, at age 16 years, the patient is intellectually within the normal range (Wechsler Intelligence Scale for C h i l d r e n - - R e vised: Full-Scale IQ, 87) but requires a wheelchair as a result of skeletal deformities, extensive hyperextensibility of joints, and generalized muscle weakness. However, he has
830
Sarkar, Lingertat- Walsh, and Clarke
never had a seizure and enjoys relatively good general health. Patients 2 to 7. On the basis of the initial experience with patient l, all subsequent patients (Table) with Menkes disease were treated from the time of diagnosis with once-daily subcutaneous injections of copper-histidine at a dosage of 50 to 150 t~g elemental copper per kilogram per day. Biochemical outcome. In every case, copper and ceruloplasmin levels returned to the normal range within 2 to 3 weeks of the commencement of copper-histidine injections. Except in patient 1, the levels have remained in the normal range, with the same dosage of copper~hisfidine, throughout the course of the disease. Regular measurements of bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase have consistently been within normal limits. Periodic measurements of blood urea nitrogen and plasma creatinine and the results of urinalysis have consistently been normal. However, urinary excretion of copper in patient 1 is increased. Clinical outcome. Two patients (Nos. 1 and 4) have done wel ! neurologically, though both have had major nonneurologic problems attributable to Menkes disease. Both are intellectually normal, and neither has ever had seizures. In both cases the diagnosis of Menkes disease was made and copper-histidine therapy begun early. The other five patients have done poorly despite treatment that was initiated at 2 to 7 months of age. All five failed to thrive and had progressive neurologic deterioration that did not appear to be influenced significantly by the copper-histidine therapy. DISCUSSION Copper-histidine therapy appears to be effective in preventing the severe neurodegenerative problems in at least some patients with Menkes disease when the treatment is initiated very early in life. The two patients who have done well were born before 40 weeks of gestation, and the diagnosis was made and treatment initiated before 1 month of age. Similar treatment has been reported by others when copper-histidine therapy was started early in life), 13 Because very early treatment with copper-histidine has been associated with improved clinical outcome in patients with Menkes disease, Copper-histidine has recently been administered in utero by Kaler et al. 14 The efficacy of early treatment of copper-histidine may be the result of making copper available during the critical period of myelination and development of the central nervous system. The reason that copper-histidine does not improve some of the nonneuro-
The Journal of Pediatrics November 1993
logic problems associated with the disease is not clear, however. In our experience, copper-histidine therapy by subcutaneous administration, if started early, appears to prevent some of the serious complications of Menkes disease. This article is dedicated to the memory of the late Andrew SassKortsak, MD. REFERENCES
1. Danks DM. Disorder of copper transport. In: Scriver C, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. New York: McGraw-Hill, 1989;1411-31. 2. Vulpe C, Levinson B, Whitney S, Packman S, Gitschier J. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nature Genetics 1993;3:7-13. 3. Chelly J, Tfimer Z, Tonnesen T, et al. Isolation of a candidate gene for Menkes disease that encodes potential heavy metal binding protein. Nature Genetics 1993;3:14-9. 4. Mercer JFB, Livingstone J, Hall B, et al. Isolation of a partial candidate gene for Menkes disease by positional cloning. Nature Genetics 1993;3:20-5. 5. Sarkar B, Kruck T. Copper amino acid complexes in human serum. In: Peisach J, Aisen P, and Blumberg W, eds. Biochemistry of copper. New York: Academic Press, 1966;183-96. 6. Sarkar B. Transport of copper. In: Sigel H, ed. Metal ions in biological systems; vol 12. New York: Marcel Dekker, 1981:233-81. 7. Mas A, Sarkar B. Uptake of 67Cu by isolated human trophoblast cells. Biochim Biophys Acta 1992;1135:123-8. 8. Garnica AD. The failure of parenteral copper therapy in Menkes kinky hair syndrome. Eur J Pediatr 1984; 142:98-102. 9. Sarkar B. Recent trends in the application of coordination chemistry in biology and medicine. In: Banerjea D, ed. IUPAC ]International Union of Pure and Applied Chemistry] Coordination chemistry; vol 20. New York: Pergamon Press, 1980:191-200. 10. Sarkar B. Specificity of metal-binding in normal physiology and biochemical alterations in disease conditions: Wilson's and Menkes' diseases. In: Arora RB, Vohora SB, Khan MSY, eds. Proceedings of the First International Conference on Elements in Health and Disease. New Delhi: Institute of History of Medicine and Medical Research, 1984:27-41. 11. Sherwood G~ Sarkar B, Sass-Kortsak A. Copper histidinate therapy in Menkes' disease: prevention of progressive neurodegeneration. J Inherit Metab Dis 1989;2:393-6. 12. Gantam-Basak M, Gallelli JF, Sarkar B. Formulation of copper-histidine for the treatment of Menkes disease: a genetic disorder of copper transport [Abstract]. J Inorg Biochem 1993;51:415. 13. Kaler SG, Gahl WA. Biochemical response to copper-histidine therapy in Menkes disease [Abstract]. Am J Hum Genet 1992;5 l(snppl. I):A170. 14. Kaler SG, Miller RC, Wolf E J, et al. In utero treatment of Menkes disease [Abstract]. Pediatr Res 1993;33(pt 2):192A.
Sarkar, Lingertat- Walsh, and Clarke
The Journal of Pediatrics November 1993
Copper-histidine therapy for Menkes disease B i b u d h e n d r a Sarkar, PhD, Karen L i n g e r t a t - W a l s h , BScPhm, a n d J o e TI R, C l a r k e , MD, Phb From the Departments of Biochemistry, Pharmacy, Pediatrics, and Genetics, Hospital for Sick Children, Toronto, and the Departments of Biochemistry and Pediatrics, University of Toronto, Toronto, Ontario, Canada
Menkes disease is an X-linked genetic disorder of copper transport that results in death from severe progressive neurodegeneration by the a g e of 3 years. We report here our 17 years' experience with the treatment of Menkes disease with subcutaneous administrationof copper-histidine. Two patients (16 and 6 years of a g e ) whose therapy was begun within I month of birth have done well neurologically. The other five patients have done poorly despite treatment initiated at 2 to 7 months of age. Copper-histidine therapy may be an effective treatment if started early. (J PEDIATR1993;123:828-30)
Menkes disease is an X-linked genetic disorder associated with a widespread defect of copper transport.1 The disease is characterized by rapidly progressive cerebral degeneration, bone lesions resembling those seen in scurvy, and elongation and tortuosity of the cerebral arteries. Death caused by severe, progressive neurodegeneration almost invariably occurs by the age of 3 years. Recently the candidate gene for Menkes disease has been reported independently by three groups. 24 The gene product is very similar to a bacterial copper-transporting adenosinetriphosphatase; additionally, it contains six putative copper-binding motifs at the N-terminal. Copper-histidine was found in normal human serum, and detailed studies revealed the physiologic importance of copper-histidine.5, 6 Recently, histidine has been shown to enhance the uptake of copper in human trophoblast cells in the presence of serum, a phenomenon considered to be due to the release of copper that is bound to albumin. 7 Parenteral therapy for Menkes disease with various copper salts, commenced either before or after neurologic impairment, has never convincingly shown a significant effect on the devastating neurodegenerative progression of the disease. 8 The results of our studies with copperhistidine led us to test copper-histidine in the treatment of Menkes disease. 911 We report here our experience with this treatment during the past 17 years.
Supported by grants from the Medical Research Council of Canada and the Lunenfeld Foundation. Submitted for publication March 22, 1993; accepted June 17, 1993. Reprint requests: B. Sarkar, PhD, Head, Department of Biochemistry Research, Hospital for Sick Children, Toronto, Ontario M5G IXS, Canada. Copyright 9 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00 + .10 9/26/49490
METHODS Between 1976 and 1993, Menkes disease has been diagnosed in seven patients at the Hospital for Sick Children, Toronto, and all have been treated with daily injections of copper-histidine in an effort to ameliorate the disease. Clinical information on these patients is summarized in the Table. In every case but one, the diagnosis was suspected on the basis of the presence of characteristic clinical findings and confirmed by demonstration of markedly depressed plasma copper and ceruloplasmin levels. Patient 1 was born 31/2 years after the death of a sibling who had died with severe neurodegeneration associated with confirmed classic Menkes disease. Patient 1 is the first patient to be treated with injections of copper-histidine. Copper-histidine solution is prepared for injection with full aseptic technique in a laminar airflow hood under conditions that minimize damage from light. Anhydrous copper chloride, 0.1060 gm, and L-histidine, 0.2444 gm, are dissolved together in approximately 90 ml sterile 0.9% sodium chloride for injection (U.S.P.). A solution of 0.2N sodium hydroxide in sterile sodium chloride 0.9% for injection is used to adjust the pH of the solution to pH 7.38 to 7.40. After adjustment of the pH of the copper-histidine solution, the final volume is made up to 100 ml with sodium chloride 0.9% for injection (U.S.P.). The copper-histidine solution is drawn up into a sterile, disposable, plastic 20 ml syringe and the desired aliquot (5 or 10 ml) filtered through a 0.22 #m filter into sterile glass vials. Sterility, copper analysis, and pyrogen testing are performed on each batch. Samples are refrigerated for storage in brown bags resistant to ultraviolet light. An expiry of 56 days is assigned on the basis of our stability studies. The solution form of copper-histidine is sensitive to light, temperature, and oxygen. Recent resuits show that copper-histidine produced in freeze-dried
The Journal of Pediatrics Volume 123, Number 5
Sarkar, Lingertat- Walsh, and Clarke
829
T'~
600
30 500
25
...I 13)
A
E 400
--I m
O r-
E m m Q. O
20 300
Im
15
L_
G)
(J
I::: ::L
200
Q QO. O O
10
100
0 50
1
2
3
4
S
$
7
8
9
10
11
12
13
14
15
16
Age (yrsl Figure. Plasma copper and ceruloplasmin levels during the first 15 years of life (patient 1). Clear symbols show ceruloplasmin levels (normal, 180 to 450 mg/L); dark symbols indicate copper levels (normal, 10.5 to 23.0/~mol/L). Arrows at top of illustration show the dosage of copper-histidine. Left to right: 675/~g/day; 200/*g/day; 250 #g/day; 500/zg/day; 600/~g/day; and 800/tg/day.
Clinical outcome of patients with Menkes disease treated with copper-histidine at the Hospital for Sick Children, Toronto, during 1976 to 1993 Table.
Case No.
Date of birth
A g e at diagnosis
Outcome
1 2 3 4 5 6 7
Nov. 12, 1976 Oct. 4, 1982 May 16, 1984 Sept. 29, 1986 March 17, 1988 March 9, 1990 Aug. 27, 1991
2 wk* 7 mo 4 mo 1 mot 6 mo 4 mo 2 mo
Nearly normal IQ Lost to follow-up Died at 14 mo Nearly normal IQ Died at 2V2 yr of age Died at 22 mo of age Profound mental retardation
*Born at 37 weeks of gestation, corrected age 39 weeks. 1"Born at 35 weeks of gestation, corrected age 39 weeks.
form without any additives has better stability for a long period. 12 RESULTS Patient 1. Patient 1, a 16-year-old boy with Menkes diseas e , has been receiving daily subcutaneous injections of copper-histidine for treatment of his disease. This case was
reported when he was 12 years of age. I1 His copper and ceruloplasmin levels are depicted in the Figure. Clinically, at age 16 years, the patient is intellectually within the normal range (Wechsler Intelligence Scale for C h i l d r e n - - R e vised: Full-Scale IQ, 87) but requires a wheelchair as a result of skeletal deformities, extensive hyperextensibility of joints, and generalized muscle weakness. However, he has
830
Sarkar, Lingertat- Walsh, and Clarke
never had a seizure and enjoys relatively good general health. Patients 2 to 7. On the basis of the initial experience with patient l, all subsequent patients (Table) with Menkes disease were treated from the time of diagnosis with once-daily subcutaneous injections of copper-histidine at a dosage of 50 to 150 t~g elemental copper per kilogram per day. Biochemical outcome. In every case, copper and ceruloplasmin levels returned to the normal range within 2 to 3 weeks of the commencement of copper-histidine injections. Except in patient 1, the levels have remained in the normal range, with the same dosage of copper~hisfidine, throughout the course of the disease. Regular measurements of bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase have consistently been within normal limits. Periodic measurements of blood urea nitrogen and plasma creatinine and the results of urinalysis have consistently been normal. However, urinary excretion of copper in patient 1 is increased. Clinical outcome. Two patients (Nos. 1 and 4) have done wel ! neurologically, though both have had major nonneurologic problems attributable to Menkes disease. Both are intellectually normal, and neither has ever had seizures. In both cases the diagnosis of Menkes disease was made and copper-histidine therapy begun early. The other five patients have done poorly despite treatment that was initiated at 2 to 7 months of age. All five failed to thrive and had progressive neurologic deterioration that did not appear to be influenced significantly by the copper-histidine therapy. DISCUSSION Copper-histidine therapy appears to be effective in preventing the severe neurodegenerative problems in at least some patients with Menkes disease when the treatment is initiated very early in life. The two patients who have done well were born before 40 weeks of gestation, and the diagnosis was made and treatment initiated before 1 month of age. Similar treatment has been reported by others when copper-histidine therapy was started early in life), 13 Because very early treatment with copper-histidine has been associated with improved clinical outcome in patients with Menkes disease, Copper-histidine has recently been administered in utero by Kaler et al. 14 The efficacy of early treatment of copper-histidine may be the result of making copper available during the critical period of myelination and development of the central nervous system. The reason that copper-histidine does not improve some of the nonneuro-
The Journal of Pediatrics November 1993
logic problems associated with the disease is not clear, however. In our experience, copper-histidine therapy by subcutaneous administration, if started early, appears to prevent some of the serious complications of Menkes disease. This article is dedicated to the memory of the late Andrew SassKortsak, MD. REFERENCES
1. Danks DM. Disorder of copper transport. In: Scriver C, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. New York: McGraw-Hill, 1989;1411-31. 2. Vulpe C, Levinson B, Whitney S, Packman S, Gitschier J. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nature Genetics 1993;3:7-13. 3. Chelly J, Tfimer Z, Tonnesen T, et al. Isolation of a candidate gene for Menkes disease that encodes potential heavy metal binding protein. Nature Genetics 1993;3:14-9. 4. Mercer JFB, Livingstone J, Hall B, et al. Isolation of a partial candidate gene for Menkes disease by positional cloning. Nature Genetics 1993;3:20-5. 5. Sarkar B, Kruck T. Copper amino acid complexes in human serum. In: Peisach J, Aisen P, and Blumberg W, eds. Biochemistry of copper. New York: Academic Press, 1966;183-96. 6. Sarkar B. Transport of copper. In: Sigel H, ed. Metal ions in biological systems; vol 12. New York: Marcel Dekker, 1981:233-81. 7. Mas A, Sarkar B. Uptake of 67Cu by isolated human trophoblast cells. Biochim Biophys Acta 1992;1135:123-8. 8. Garnica AD. The failure of parenteral copper therapy in Menkes kinky hair syndrome. Eur J Pediatr 1984; 142:98-102. 9. Sarkar B. Recent trends in the application of coordination chemistry in biology and medicine. In: Banerjea D, ed. IUPAC ]International Union of Pure and Applied Chemistry] Coordination chemistry; vol 20. New York: Pergamon Press, 1980:191-200. 10. Sarkar B. Specificity of metal-binding in normal physiology and biochemical alterations in disease conditions: Wilson's and Menkes' diseases. In: Arora RB, Vohora SB, Khan MSY, eds. Proceedings of the First International Conference on Elements in Health and Disease. New Delhi: Institute of History of Medicine and Medical Research, 1984:27-41. 11. Sherwood G~ Sarkar B, Sass-Kortsak A. Copper histidinate therapy in Menkes' disease: prevention of progressive neurodegeneration. J Inherit Metab Dis 1989;2:393-6. 12. Gantam-Basak M, Gallelli JF, Sarkar B. Formulation of copper-histidine for the treatment of Menkes disease: a genetic disorder of copper transport [Abstract]. J Inorg Biochem 1993;51:415. 13. Kaler SG, Gahl WA. Biochemical response to copper-histidine therapy in Menkes disease [Abstract]. Am J Hum Genet 1992;5 l(snppl. I):A170. 14. Kaler SG, Miller RC, Wolf E J, et al. In utero treatment of Menkes disease [Abstract]. Pediatr Res 1993;33(pt 2):192A.