1491
Mutations were detected in only 2 families (table), in both of which codon 248 was affected. The mutation in family 2 causes the arginine residue to be substituted by glutamine. The mutant allele in family 5 codes for tryptophan instead of an arginine residue. Thus far, codon 248 is affected in 4 of the 8 known families (ie, families 2 and 5 in this report and 6 families previously published) in which constitutional p53 alterations have been described. These four mutations involve a CpG moiety. It is therefore possible that deamination of 5-methylcytosine to thymine has a role in the generation of these mutations. Furthermore, codon 248 has been identified as a mutational "hot spot" in human tumour tissue.1o In the original reports of germline mutations in the p53 gene/,3 the implication is that such mutations are the genetic basis of LFS. Perhaps our most striking finding is that 6 of 8 families do not have these mutations, even though all 8 conform to the criteria defined by Li et al,3 It is noteworthy that 1 of the known families with p53 mutations (family 4 of Malkin et al2) does not fulfil the above criteria. It seems therefore that some families with typical LFS do not have the germline mutations in p53 whereas other cancer families not conforming to LFS may do so. To examine the pattern of cancers associated with known germline mutations of the p53 gene in LFS families compared with that in general LFS families (ie, those described by others but in whom p53 mutations have not been sought), we assessed the frequency of syndrome and multiple primary cancers. To standardise the comparison as much as possible, only families that we have described, conforming to the criteria of Li et al5 (13 families, 8 included in the present study), together with the 24 kindreds described by Li et al, were included and the analysis was restricted to probands and their first-degree and second-degree relatives. Among families with p53 mutations the ratio of osteosarcoma to soft-tissue sarcoma is 1/1-25. In the general families this ratio is 1/0-6. Brain tumours accounted for 22% (10/46) of tumours in the p53 families but only 11 % (22/192) among general families. The most pronounced difference was the greater proportion of individuals with multiple cancers among p53 families (41% [14/34] vs 18% [30/171]). There is some indication that there may be a subset of LFS families with a distinct pattern of cancers associated with specific germline p53 mutations. In our study, only the conserved region in exon 7 of the p53 gene was sequenced, but other regions of the gene may be affected. Studies to examine this possibility are in progress. However, in family 8 we excluded the involvement of p53 by restriction fragment length polymorphism analysis. In this family, 2 sisters with breast cancer diagnosed at ages 31 and 36 years did not share any p53 allele (details are available from J. M. B.). According to these results, there seem to be several uncertainties about whether to counsel and screen families that carry a germline p53 mutation. There are no data on the age, site, and sex specific cancer risks conferred by such mutations, and assigning risks in these families on the basis of presence of p53 mutations should be done with caution. Furthermore, because of the broad spectrum of cancers involved, an effective screening programme will be difficult to plan. The clinical, ethical, and social issues of screening and counselling in affected families need to be resolved. We thank Dr C. M. Steel for provision of material from family 6 and Mr G. R. M. White and Mr B. Woodhouse for technical assistance. J. M. B. is a CRC senior research fellow. This work was supported by the Cancer Research Campaign.
REFERENCES 1. Birch JM, Hartley AL, Blair V, et al. Cancer in the families of children with soft tissue sarcoma. Cancer 1990; 66: 2239-48. 2. Malkin D, Li FP, Strong LC, et al. Germline p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science
1990; 250: 1233-38. 3. Srivastava S, Zou Z, Pirollo K, et al. Germ line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 1990; 348: 747-49. 4. Nigro JM, Baker SJ, Preisinger AC, et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 1989; 342: 705-08. 5. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988; 48: 5358-62. 6. Sambrook J, Fritsch EF, Maniatis T. Molecular cloning, a laboratory manual. Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 1989. 7. Wnght DK, Manos M. In: Innis MA, Gelfand DH, Snisky JJ, White TJ, eds. PCR protocols. San Diego: Academic Press, 1990: 153-58. 8. Deane MD, Norton J. Immunoglobin heavy chain variable region family usage in independent of tumour cell phenotype in human B lineage leukaemias. Eur J Immunol 1990; 20: 2209-17. 9. Harris N, Brill E, Shohat O, et al. Molecular basis for heterogeneity of the human p53. Mol Cell Biol 1986; 6: 4650-56. 10. Levine AJ, Momand J, Finlay CA. The p53 tumour suppressor gene.
Nature 1991; 351: 453-56.
ADDRESSES CRC Department of Cancer Genetics, Paterson Institute (M. F Santibáñez-Koref, MD), CRC Paediatric and Familial Cancer Research Group (J. M. Birch, PhD, A. L. Hartley, PhD), CRC Department of Medical Oncology (D. Crowther, PhD), and Department of Pathology (M. Harris, MD), Christie Hospital, Manchester M20 9BX; Royal Manchester Children’s Hospital,
Manchester(P. H. Morris Jones, FRCP, A. M. Kelsey, MRCPath); Royal Infirmary, Newcastle upon Tyne (A. W. Craft, MD); and Royal Hospital for Sick Children, Edinburgh (T. Eden, FRCPE), UK. Correspondence to Dr J. M Birch.
Victoria
Evidence for related myopathies in exertional heat stroke and
malignant hyperthermia
Malignant hyperthermia may be a human stress syndrome, of which heat stroke is one manifestation. Two men in military service who had episodes of exertional heat stroke, and their immediate family members, were tested for susceptibility to malignant hyperthermia by in-vitro contracture tests on skeletal muscle samples. Muscle from both patients had a normal response to caffeine but an abnormal response to halothane. Muscle from the father of one patient had an abnormal response to halothane, and that from the father of the second patient had an abnormal response to ryanodine. The results indicate that clinical heat stroke may be associated with an underlying inherited abnormality of skeletal muscle that is similar, but not identical, to that of malignant
hyperthermia.
Exertional heat stroke is a life-threatening syndrome of raised body core temperature with rhabdomyolysis, hyperkalaemia, and metabolic acidosis, leading to acute renal, cardiac, and haemostatic failure.1 Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that is triggered when a susceptible
1492
individual receives suxamethonium or a volatile anaesthetic agent (eg, halothane, enflurane, isoflurane).2 These drugs cause a rise in skeletal muscle myoplasmic calcium ion concentration3 that leads to muscle rigidity, hypermetabolism (pyrexia, hypoxia, and metabolic acidosis), and sarcolemmal disruption (hyperkalaemia, myoglobinaemia). MH is diagnosed by testing for abnormal in-vitro muscle-contracture responses to halothane and to caffeine.4 MH resembles the porcine stress syndrome in, for example, response to anaesthetic agents, but the pig condition is notable for episodes that occur when the animal is awake and physically stressed. It has been postulated (but never proved) that MH is a human stress syndrome, of which heat stroke is one manifestation.5 We have investigated two men in military service who had episodes of heat stroke for their susceptibility to MH. The first patient-a19-year-old soldier--collapsed after 75 miles (12-1km) of alternate marching and running. At the time, he was carrying 15 kg of equipment and a rifle, and was wearing boots, lightweight trousers, combat jacket, and a steel helmet. His rectal temperature was 41°C and he was treated with sponging and intravenous fluids. 90 min after collapsing, his serum potassium and blood gases and pH were normal, but creatine kinase was raised at 2329 IU/1 (normal 28-205 IU/1). On the next day, creatine kinase was 35 000 IU/1 and urine was negative for myoglobin. The ambient temperature at the time of the incident was 22-5°C with a relative humidity of73%. The patient had not taken alcohol, had no intercurrent infection, was not taking drugs, and was not obese. Eleven months after the incident, we took muscle specimens from the patient’s vastus medialis under regional anaesthesia. In-vitro contracture testing of the muscle specimens with halothane (normal response =< 0-2 g contracture at 2% halothane) and caffeine (normal response < 0-2 g contracture at 2 mmoljl caffeine) was done according to the protocol of the European Malignant Hyperthermia Croup,4 and a ryanodine contracture test was also done.6 The response to caffeine was normal (02 g contracture at 4 mmol/1 caffeine). However, there was an abnormal response to halothane (0-2 g contracture at 2% halothane), which, according to the protocol, is classified as MH equivocal, but which is invariably interpreted as indicating clinical susceptibility to MH. The ryanodine contracture test did not support the diagnosis of MH. Subsequently, both of the patient’s parents had identical diagnostic procedures. The mother’s muscle samples gave a normal response to all tests, but the father’s samples had an abnormal response to halothane (MH equivocal) with normal caffeine and ryanodine results. The second patient-a 23-year-old soldier-had two documented episodes of heat intolerance. The first, when the patient was 18 years old, occurred on a hot day after he had run 6 miles (9-7 km) while wearing a singlet, trousers, and boots and carrying a rifle. He collapsed but remained conscious and responded to intravenous fluid therapy. The second incident was 5 years later and followed 8 miles (12-9 km) of running in full battle dress while carrying 15 kg of equipment. On this occasion, consciousness was lost for about 45 min and an axillary temperature of 39*C was recorded. The patient’s maternal grandfather had died in his sixties with a late-onset myopathy. No other member of the family was thought to have been similarly affected. Eight months after the second episode of heat stroke, the patient had muscle-biopsy samples taken for in-vitro contracture testing. The testing procedure was the same as that described for patient 1. The response to caffeine was normal (0-2 g at 3 mmol/1 caffeine), but the response to halothane was abnormal (0-3 g at 2% halothane). The response to ryanodine was abnormal, but not typical for MH muscle. The patient was classified as MH equivocal. As with patient 1, we have done in-vitro contracture testing on muscle samples from both parents of the second soldier. The mother’s muscle samples responded normally to the tests, whereas the father’s muscle had a normal response to caffeine and halothane but an abnormal response to ryanodine. The brother of patient 2 has =
also been tested, and shown to have in-vitro contracture-test results identical to his father.
Muscle-biopsy specimens from both patients had a normal response to caffeine but an abnormal contracture on exposure to halothane. This type of in-vitro response is seen with muscle of MH-susceptible individuals, but has also been found with the muscle of patients with other muscle diseases? However, the heat-stroke patients’ muscle differed from MH-susceptible muscle in its response to ryanodine.6 Our study indicates that both heat-stroke patients have an underlying skeletal muscle abnormality that is probably distinct from MH but involves a similar deregulation of control of myoplasmic calcium ion concentration, which in turn leads to in-vitro contracture in response to drugs and to clinical heat stroke after extreme exertion. The family investigations suggest there is an inherited component to this muscle abnormality. This is most evident in patient 1, where the father had abnormal pharmacological responses identical to those of the patient. That the evidence in patient 2 is less compelling could be due to a dominantly inherited abnormality being expressed to a greater degree in the heat-stroke patient than in his father and brother. This would be analogous to MH, where susceptible members of the same family may display considerable heterogeneity of in-vitro responses. It is unlikely that all patients with heat stroke will have a demonstrable skeletal muscle abnormality, just as not all patients who display an apparent hypermetabolic response to triggering anaesthetics have MH. Nevertheless, we suggest that individuals who have this syndrome undergo in-vitro muscle-contracture studies to exclude such an abnormality. By studying the muscle of heat-stroke patients and that of their families we may improve understanding of the pathophysiology and inheritance of at least some forms of heat stroke, of the relation between heat stroke and MH, and of the problems of anaesthesia in heat-stroke patients and their families. It is important to point out that correct interpretation of in-vitro contracture studies requires carefully controlled biopsy and laboratory conditions.4 REFERENCES 1. Knochel JP. Heat stroke and related heart stress disorders. Dis Mon 1989; 35: 301-77. 2. Ellis FR, Heffron JJA. Clinical and biochemical aspects of malignant hyperpyrexia. In: Atkinson RS, Adams AP, eds. Recent advances in anaesthesia and analgesia, vol 15. Edinburgh: Churchill Livingstone, 1985: 173-207. 3. Iaizzo PA, Klein W, Lehmann-Horn F. Fura-2 detected myoplasmic calcium and its correlation with contracture force in skeletal muscle from normal and malignant hyperthermia susceptible pigs. Pflugers Arch 1988; 411: 648-53. 4. European MH Group. A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility. Br J Anaesth 1984; 56:1267-69. 5. Wingard DW, Gatz EE. Some observations on stress susceptible patients. In: Aldrete JA, Britt FA, eds. The second international symposium on malignant hyperthermia. New York: Grune and Stratton, 1978: 363-72. 6. Hopkins PM, Ellis FR, Halsall PJ. Ryanodine contracture: a potentially specific in vitro diagnostic test for malignant hyperthermia. Br J Anaesth 1991; 66: 611-13. 7. Lehmann-Hom F, Iaizzo PA. Are myotonias and periodic paralyses associated with susceptibility to malignant hyperthermia? Br J Anaesth 1990; 65: 692-97.
ADDRESS
Malignant Hyperthermia Investigation Unit, University Department of Clinical Medicine, St James’s University Hospital, Leeds LS9 7TF, UK (P M. Hopkins, FCAnaes, F R. Ellis, FCAnaes, P J Halsall, MD) Correspondence to Dr P. M Hopkins.
Mutations were detected in only 2 families (table), in both of which codon 248 was affected. The mutation in family 2 causes the arginine residue to be substituted by glutamine. The mutant allele in family 5 codes for tryptophan instead of an arginine residue. Thus far, codon 248 is affected in 4 of the 8 known families (ie, families 2 and 5 in this report and 6 families previously published) in which constitutional p53 alterations have been described. These four mutations involve a CpG moiety. It is therefore possible that deamination of 5-methylcytosine to thymine has a role in the generation of these mutations. Furthermore, codon 248 has been identified as a mutational "hot spot" in human tumour tissue.1o In the original reports of germline mutations in the p53 gene/,3 the implication is that such mutations are the genetic basis of LFS. Perhaps our most striking finding is that 6 of 8 families do not have these mutations, even though all 8 conform to the criteria defined by Li et al,3 It is noteworthy that 1 of the known families with p53 mutations (family 4 of Malkin et al2) does not fulfil the above criteria. It seems therefore that some families with typical LFS do not have the germline mutations in p53 whereas other cancer families not conforming to LFS may do so. To examine the pattern of cancers associated with known germline mutations of the p53 gene in LFS families compared with that in general LFS families (ie, those described by others but in whom p53 mutations have not been sought), we assessed the frequency of syndrome and multiple primary cancers. To standardise the comparison as much as possible, only families that we have described, conforming to the criteria of Li et al5 (13 families, 8 included in the present study), together with the 24 kindreds described by Li et al, were included and the analysis was restricted to probands and their first-degree and second-degree relatives. Among families with p53 mutations the ratio of osteosarcoma to soft-tissue sarcoma is 1/1-25. In the general families this ratio is 1/0-6. Brain tumours accounted for 22% (10/46) of tumours in the p53 families but only 11 % (22/192) among general families. The most pronounced difference was the greater proportion of individuals with multiple cancers among p53 families (41% [14/34] vs 18% [30/171]). There is some indication that there may be a subset of LFS families with a distinct pattern of cancers associated with specific germline p53 mutations. In our study, only the conserved region in exon 7 of the p53 gene was sequenced, but other regions of the gene may be affected. Studies to examine this possibility are in progress. However, in family 8 we excluded the involvement of p53 by restriction fragment length polymorphism analysis. In this family, 2 sisters with breast cancer diagnosed at ages 31 and 36 years did not share any p53 allele (details are available from J. M. B.). According to these results, there seem to be several uncertainties about whether to counsel and screen families that carry a germline p53 mutation. There are no data on the age, site, and sex specific cancer risks conferred by such mutations, and assigning risks in these families on the basis of presence of p53 mutations should be done with caution. Furthermore, because of the broad spectrum of cancers involved, an effective screening programme will be difficult to plan. The clinical, ethical, and social issues of screening and counselling in affected families need to be resolved. We thank Dr C. M. Steel for provision of material from family 6 and Mr G. R. M. White and Mr B. Woodhouse for technical assistance. J. M. B. is a CRC senior research fellow. This work was supported by the Cancer Research Campaign.
REFERENCES 1. Birch JM, Hartley AL, Blair V, et al. Cancer in the families of children with soft tissue sarcoma. Cancer 1990; 66: 2239-48. 2. Malkin D, Li FP, Strong LC, et al. Germline p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science
1990; 250: 1233-38. 3. Srivastava S, Zou Z, Pirollo K, et al. Germ line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 1990; 348: 747-49. 4. Nigro JM, Baker SJ, Preisinger AC, et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 1989; 342: 705-08. 5. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988; 48: 5358-62. 6. Sambrook J, Fritsch EF, Maniatis T. Molecular cloning, a laboratory manual. Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 1989. 7. Wnght DK, Manos M. In: Innis MA, Gelfand DH, Snisky JJ, White TJ, eds. PCR protocols. San Diego: Academic Press, 1990: 153-58. 8. Deane MD, Norton J. Immunoglobin heavy chain variable region family usage in independent of tumour cell phenotype in human B lineage leukaemias. Eur J Immunol 1990; 20: 2209-17. 9. Harris N, Brill E, Shohat O, et al. Molecular basis for heterogeneity of the human p53. Mol Cell Biol 1986; 6: 4650-56. 10. Levine AJ, Momand J, Finlay CA. The p53 tumour suppressor gene.
Nature 1991; 351: 453-56.
ADDRESSES CRC Department of Cancer Genetics, Paterson Institute (M. F Santibáñez-Koref, MD), CRC Paediatric and Familial Cancer Research Group (J. M. Birch, PhD, A. L. Hartley, PhD), CRC Department of Medical Oncology (D. Crowther, PhD), and Department of Pathology (M. Harris, MD), Christie Hospital, Manchester M20 9BX; Royal Manchester Children’s Hospital,
Manchester(P. H. Morris Jones, FRCP, A. M. Kelsey, MRCPath); Royal Infirmary, Newcastle upon Tyne (A. W. Craft, MD); and Royal Hospital for Sick Children, Edinburgh (T. Eden, FRCPE), UK. Correspondence to Dr J. M Birch.
Victoria
Evidence for related myopathies in exertional heat stroke and
malignant hyperthermia
Malignant hyperthermia may be a human stress syndrome, of which heat stroke is one manifestation. Two men in military service who had episodes of exertional heat stroke, and their immediate family members, were tested for susceptibility to malignant hyperthermia by in-vitro contracture tests on skeletal muscle samples. Muscle from both patients had a normal response to caffeine but an abnormal response to halothane. Muscle from the father of one patient had an abnormal response to halothane, and that from the father of the second patient had an abnormal response to ryanodine. The results indicate that clinical heat stroke may be associated with an underlying inherited abnormality of skeletal muscle that is similar, but not identical, to that of malignant
hyperthermia.
Exertional heat stroke is a life-threatening syndrome of raised body core temperature with rhabdomyolysis, hyperkalaemia, and metabolic acidosis, leading to acute renal, cardiac, and haemostatic failure.1 Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that is triggered when a susceptible
1492
individual receives suxamethonium or a volatile anaesthetic agent (eg, halothane, enflurane, isoflurane).2 These drugs cause a rise in skeletal muscle myoplasmic calcium ion concentration3 that leads to muscle rigidity, hypermetabolism (pyrexia, hypoxia, and metabolic acidosis), and sarcolemmal disruption (hyperkalaemia, myoglobinaemia). MH is diagnosed by testing for abnormal in-vitro muscle-contracture responses to halothane and to caffeine.4 MH resembles the porcine stress syndrome in, for example, response to anaesthetic agents, but the pig condition is notable for episodes that occur when the animal is awake and physically stressed. It has been postulated (but never proved) that MH is a human stress syndrome, of which heat stroke is one manifestation.5 We have investigated two men in military service who had episodes of heat stroke for their susceptibility to MH. The first patient-a19-year-old soldier--collapsed after 75 miles (12-1km) of alternate marching and running. At the time, he was carrying 15 kg of equipment and a rifle, and was wearing boots, lightweight trousers, combat jacket, and a steel helmet. His rectal temperature was 41°C and he was treated with sponging and intravenous fluids. 90 min after collapsing, his serum potassium and blood gases and pH were normal, but creatine kinase was raised at 2329 IU/1 (normal 28-205 IU/1). On the next day, creatine kinase was 35 000 IU/1 and urine was negative for myoglobin. The ambient temperature at the time of the incident was 22-5°C with a relative humidity of73%. The patient had not taken alcohol, had no intercurrent infection, was not taking drugs, and was not obese. Eleven months after the incident, we took muscle specimens from the patient’s vastus medialis under regional anaesthesia. In-vitro contracture testing of the muscle specimens with halothane (normal response =< 0-2 g contracture at 2% halothane) and caffeine (normal response < 0-2 g contracture at 2 mmoljl caffeine) was done according to the protocol of the European Malignant Hyperthermia Croup,4 and a ryanodine contracture test was also done.6 The response to caffeine was normal (02 g contracture at 4 mmol/1 caffeine). However, there was an abnormal response to halothane (0-2 g contracture at 2% halothane), which, according to the protocol, is classified as MH equivocal, but which is invariably interpreted as indicating clinical susceptibility to MH. The ryanodine contracture test did not support the diagnosis of MH. Subsequently, both of the patient’s parents had identical diagnostic procedures. The mother’s muscle samples gave a normal response to all tests, but the father’s samples had an abnormal response to halothane (MH equivocal) with normal caffeine and ryanodine results. The second patient-a 23-year-old soldier-had two documented episodes of heat intolerance. The first, when the patient was 18 years old, occurred on a hot day after he had run 6 miles (9-7 km) while wearing a singlet, trousers, and boots and carrying a rifle. He collapsed but remained conscious and responded to intravenous fluid therapy. The second incident was 5 years later and followed 8 miles (12-9 km) of running in full battle dress while carrying 15 kg of equipment. On this occasion, consciousness was lost for about 45 min and an axillary temperature of 39*C was recorded. The patient’s maternal grandfather had died in his sixties with a late-onset myopathy. No other member of the family was thought to have been similarly affected. Eight months after the second episode of heat stroke, the patient had muscle-biopsy samples taken for in-vitro contracture testing. The testing procedure was the same as that described for patient 1. The response to caffeine was normal (0-2 g at 3 mmol/1 caffeine), but the response to halothane was abnormal (0-3 g at 2% halothane). The response to ryanodine was abnormal, but not typical for MH muscle. The patient was classified as MH equivocal. As with patient 1, we have done in-vitro contracture testing on muscle samples from both parents of the second soldier. The mother’s muscle samples responded normally to the tests, whereas the father’s muscle had a normal response to caffeine and halothane but an abnormal response to ryanodine. The brother of patient 2 has =
also been tested, and shown to have in-vitro contracture-test results identical to his father.
Muscle-biopsy specimens from both patients had a normal response to caffeine but an abnormal contracture on exposure to halothane. This type of in-vitro response is seen with muscle of MH-susceptible individuals, but has also been found with the muscle of patients with other muscle diseases? However, the heat-stroke patients’ muscle differed from MH-susceptible muscle in its response to ryanodine.6 Our study indicates that both heat-stroke patients have an underlying skeletal muscle abnormality that is probably distinct from MH but involves a similar deregulation of control of myoplasmic calcium ion concentration, which in turn leads to in-vitro contracture in response to drugs and to clinical heat stroke after extreme exertion. The family investigations suggest there is an inherited component to this muscle abnormality. This is most evident in patient 1, where the father had abnormal pharmacological responses identical to those of the patient. That the evidence in patient 2 is less compelling could be due to a dominantly inherited abnormality being expressed to a greater degree in the heat-stroke patient than in his father and brother. This would be analogous to MH, where susceptible members of the same family may display considerable heterogeneity of in-vitro responses. It is unlikely that all patients with heat stroke will have a demonstrable skeletal muscle abnormality, just as not all patients who display an apparent hypermetabolic response to triggering anaesthetics have MH. Nevertheless, we suggest that individuals who have this syndrome undergo in-vitro muscle-contracture studies to exclude such an abnormality. By studying the muscle of heat-stroke patients and that of their families we may improve understanding of the pathophysiology and inheritance of at least some forms of heat stroke, of the relation between heat stroke and MH, and of the problems of anaesthesia in heat-stroke patients and their families. It is important to point out that correct interpretation of in-vitro contracture studies requires carefully controlled biopsy and laboratory conditions.4 REFERENCES 1. Knochel JP. Heat stroke and related heart stress disorders. Dis Mon 1989; 35: 301-77. 2. Ellis FR, Heffron JJA. Clinical and biochemical aspects of malignant hyperpyrexia. In: Atkinson RS, Adams AP, eds. Recent advances in anaesthesia and analgesia, vol 15. Edinburgh: Churchill Livingstone, 1985: 173-207. 3. Iaizzo PA, Klein W, Lehmann-Horn F. Fura-2 detected myoplasmic calcium and its correlation with contracture force in skeletal muscle from normal and malignant hyperthermia susceptible pigs. Pflugers Arch 1988; 411: 648-53. 4. European MH Group. A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility. Br J Anaesth 1984; 56:1267-69. 5. Wingard DW, Gatz EE. Some observations on stress susceptible patients. In: Aldrete JA, Britt FA, eds. The second international symposium on malignant hyperthermia. New York: Grune and Stratton, 1978: 363-72. 6. Hopkins PM, Ellis FR, Halsall PJ. Ryanodine contracture: a potentially specific in vitro diagnostic test for malignant hyperthermia. Br J Anaesth 1991; 66: 611-13. 7. Lehmann-Hom F, Iaizzo PA. Are myotonias and periodic paralyses associated with susceptibility to malignant hyperthermia? Br J Anaesth 1990; 65: 692-97.
ADDRESS
Malignant Hyperthermia Investigation Unit, University Department of Clinical Medicine, St James’s University Hospital, Leeds LS9 7TF, UK (P M. Hopkins, FCAnaes, F R. Ellis, FCAnaes, P J Halsall, MD) Correspondence to Dr P. M Hopkins.
