Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1992-04-13
1995-05-09
Parr, Margaret
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
536 235, 536 2431, C12Q 168, C07H 2104
Patent
active
054139074
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the animal disease malignant hyperthermia (MH) and to the cloning and characterization of a gene associated with (MH), and to the development of methods for detecting individuals susceptible to MH.
BACKGROUND OF THE INVENTION
Although malignant hyperthermia is associated primarily with humans and was first realized as a reaction to inhalation anaesthetics, it is understood that MH is also a very common problem in certain animals, particularly pigs. There is therefore particular commercial interest in developing suitable assays to determine MH in pigs, as well as providing suitable diagnosis to test humans to avoid life threatening circumstances in the operating room.
Malignant hyperthermia (MH) is an inherited predisposition to a hypermetabolic syndrome (adverse reaction) triggered by inhalation anaesthetics such as halothane and some skeletal muscle relaxants such as succinylcholine. The primary defect in MH is related to a sustained increase in myoplasmic calcium which causes muscle contracture and increased glycolysis concomitant with the production of H.sub.2 O, CO.sub.2 and heat and excessive consumption of O.sub.2. Other signs of the disorder (including the hyperthermia for which it was named) may be explained as a direct result of muscle contracture and increased glycolysis [Steward, D. J. and O'Connor, G. A. R, "Malignant Hyperthermia--The Acute Crisis", in Britt B. A. ed. Malignant Hyperthermia, Boston, Martinus Nijhoff, (1987)].
The disease in humans is a serious health problem as the affected individuals are usually unaware of their condition and problem with a potentially lethal reaction to the drugs administered at surgery. The observed frequency of the disease is dependent on the drugs administered. The highest estimate based on the use of succinylcholine in combination with halothane, gives a frequency of 1 in 4200 anaesthetics [Ording, H., Anesth Analg. 64: 700-704, (1985)]. This may be a gross underestimate of the true gene frequency since many individuals who carry the gene are never exposed to the triggering agent and thus remain undiagnosed. Additionally the incidence of masseter muscle spasm following halothane-succinylcholine induction of anaesthesia is 1 in 200; 50% of these individuals have been subsequently shown to have biopsies positive for MH suggesting that the true incidence of the trait may be considerably higher [Rosenberg, H, and Fletcher, J. E., Anesth. Analg. 65: 161-164, (1986)]. In many families the disease segregates as an autosomal dominant condition [Kalow, W., "Inheritance of Malignant Hyperthermia--A review of Published Data", in Britt, B. A. Ed. Malignant Hyperthermia, supra, (1987)] although other modes of inheritance have been reported in some families.
The mortality rate for MH in North America has decreased from 84% in the 1960s to about 7% [Britt, B. A., "Preface: A History of Malignant Hyperthermia", in Britt B. A. ed. Malignant Hyperthermia, Boston, Martinus Nijhoff, pp 1-10, (1987)], following improvements in monitoring systems, increased awareness of MH and the advent of dantrolene treatment in 1975. A marked elevation in end-tidal (exhaled) carbon dioxide levels is an early indicator of an MH reaction and,where monitored and recognized, may allow prompt treatment with sodium dantrolene (dantrium) to avert a full crisis. The fatality rate is still unacceptably high in many countries in the world ( e.g. 24% in the U.K.).
Fatalities may result from one or more of multiple complications in a fulminant MH crisis. Skeletal muscle, smooth (involuntary) muscle and cardiac muscle are all affected in an MH reaction. Contraction of smooth muscle of the blood vessels causes hypertension which further decreases the oxygen supply and results in accelerated deep breathing. Pulmonary edema may occur as the crisis progresses especially at the onset of cardiac failure. Cardiac failure is triggered both by rigidity of the heart muscle and by elevated levels of potassium in the blood. Once the temperature of an affected i
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Britt Beverley A.
MacLennan David H.
Worton Ronald G.
Horlick Kenneth
HSC Research and Development Limited Partnership
Parr Margaret
The Toronto Hospital
The University of Toronto Innovations Foundation
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