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Early copper histidine therapy in classic menkes disease.

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Early Copper Histidine Therapy in Classic
Menkes Disease
Bibudhendra Sarkar. MD
The study by Kaler and associates [I] concluded that early
copper histidine treatment did not normalize neurological
outcome in Menkes disease (MD) with the Q724H splice
mutation. I am r-esponditig now in view of another report by
the same group concluding that a patient with an in-frame
deletion showed successful neurological outcome [ 2 ] .Suggestions have been made that the preservation of residual Menkes ATPase activity may be necessary for clinical efficacy
from such treatment.
While the nature of the mutation could determine the
benefit from such treatment, an iniportant issue in these
studies that has not been addressed concerns the formulations of copper histidine used to treat these patients. At our
institution, where the treatment originated, patients received
copper histidine in 0.9% sodium chloride solution throughout the treatment 131, whereas Kaler and group [l] patients
V-2 (born at 37 weeks’ gestation) and V-4 (treated in utero)
received two different formulations of copper histidine. The
first formulation of copper histidine contained 5% mannitol,
which was later switched to a nonmannitol preparation [l, 2,
Mannitol binds copper strongly 151. Furthermore, 5%
mannitol represents a 100-fold excess of mannitol compared
with copper in their copper histidine preparation. The combined effect of the strong affinity of mannitol for copper,
coupled with the mass action phenomenon of‘ mannitol
caused by its large excess, is expected to produce mostly copper mannitol and very little, if any, copper histidine (12).
Copper mannitol is nonphysiological and the bioavailability
of copper in this form is in question [6].A patient, treated
by the same group with a nonmannitol preparation of copper histidine from the start, is currently doing well neurologically (21. Once the differences in the copper histidine formulation are taken in account, there is, to date, no treatment
failure reported in the literature in patients treated with
properly formulated copper histidine, provided that trearment was initiated sufficiently early.
Although my name was acknowledged in the article [I], I
was neither aware of the work prior to its publication nor
did I endorse the mutation analysis on patients treated with
the 5% maiinitol-containing preparation.
The bioavailahility of copper histidine is a potentially critical determinant of successful clinical outcome [GI. A case in
Annals of Neurology
Vol 41
N o 1 January 1997
point is the result with our 2 patients at ages 19 (M.F.) and
9 (R.H.), who are functionally well neurologically, by early
treatment with copper histidine [3]with no additives such as
mannitol [ I ] . Mutation in R.H. lies within the third metal
binding domain, which would predict the lack of the entire
ATPase “core,” and that in M.F. would cause the lack of an
ATPase core except for the first 4 transmembrane domains
[7].Speculation has been made of reinitiation of translation
downstream of a premature stop codon in our patient R.H.
[8]. Although theoretically possible, there is currently no evidence to substantiate the claim. M.F., however, had an older
brother who did not receive early copper histidine treatment
and died at age 3 with severe M D . When the results of the
mutation analysis are considered in conjunction with this
significant family history, it is exceedingly unlikely that M.F.
has anything but the severe form of MD. However, he is
alive and well neurologically at age 19, which is a strong
argument in favor of treatment efficacy for neurological improvement. Researchers in the field should not be discouraged with the assessment of the treatment based on the
mutation analysis performed on patients treated with mannitol-containing copper histidine preparation [ I].
The Hospital f o r Sick Children and
Department of Biochemistry
University of Toronto
Toronto, Ontario, Canadu
CS, et al. Early copper therapy
in classic Menkes disease patients with a novel splicing mutation.
Ann Neurol 1995;38:921-928
2. Kaler SG, Das S, Levinson B, et al. Successful early copper therapy in Menkes disease associated with a mutant transcript containing a small in-frame deletion. Biochem Mol Med 1996;57:
3. Sarkar B, Lingertat-Walsh K, Clarke, J l R . Copper-histidine
therapy for Menkes disease. J Pediatr 1993;123:828 -830
4. Gautam-Basak M , Gallelli JF, Sarkar B. Formulation of copper
histidine for the treatment of Menkes disease, a genetic disorder
of copper transport. J Inorg Biochem 1993;51:415 (Abstract)
5. Rriggs J, Finch P, Matulewicz MC, et al. Complexes of copper
(II), calcium and other metal ions with carbohydrates: thin-layer
ligand-exchange chromatography and determination of relative
stabilities of complexes. Carbohydr Res 1381;97:181-188
6. Sarkar B. Copper-histidine therapy for Menkes disease: a reply.
J Pediatr 1994;125:337-338
7. Turner 2, Horn N , Tonnesen T, et al. Efficacy of early copperhistidine treatment for Menkcs disease. Nature Genet 1996; 12:
8. Kaler SG. Menkes disease mutation response to early copper histidine treatment. Nature Genet 1996;13:21-22
1. Kaler SG, Buist NRM, Holmes
Stephen G. Kaler, MD
Thank you for the invitation to respond to Dr Sarkar. Several years ago, we modified our original, FDA-approved copper histidine formulation that included 5% mannitol, based
on the slightly improved stability of a non-mannitol-containing preparation at various storage temperatures, as stated
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menken, classic, disease, coppel, histidine, therapy, early
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