- Email: [email protected]
Troponin T in legal medicine
RESEARCH LETTERS
Cystic fibrosis, Young’s syndrome, and normal sweat chloride
Troponin T in legal medicine
Diana Wellesey, Martin Schwarz
The diagnosis of heart contusion during medicolegal necropsies is difficult because attempted reanimation by cardiac massage, defibrillation, or both can cause subepicardial, endocardial, and transmural haemorrhage. Macroscopically it is not possible to say whether noninvasive trauma of the chest took place during life, at death, or after death. Troponin T is a myofibrillary protein and, as a subunit of the troponin complex, a constituent of the contractile apparatus of skeletal and cardiac muscle.1,2 In the cardiac cell, 6% of troponin T is dissolved in the cytosol and 94% structurally bound. Cardiac troponin T differs from that of skeletal muscle, and specific analysis is possible by means of appropriate monoclonal antibodies.1,3,4 Between 1995 and 1997, qualitative troponin T analysis in whose blood and serum by a quick test (Boehringer, Mannheim) and quantitative serum analysis by ELISA were measured in 13 cases whose hearts were known to be contused and 10 cases of death after unsuccessful resuscitation by heart massage, defibrillation, or both without evidence of heart trauma whilst alive. The results are shown in the figure. Mean serum troponin T concentration for the heart contusion cases was 97·75 ng/mL (SD 48·39 ng/mL) compared with 0·07 ng/mL (SD 0·03 ng/mL) for the resuscitation group. The difference between concentrations was significant (p<0·001). The quick test for troponin T in whole blood and serum had been done earlier. All blood and serum samples from those with heart contusion were positive, whereas those from controls were negative. Troponin T can be used as a marker to meet forensic requirements when diagnosing heart contusion.5 A positive troponin T quick test confirms the presence of myocardial lesions.
1
2
3 4
Handelsman DJ, Conway AJ, Boylan LM, Turtle JR. Young’s syndrome: obstructive azoospermia in chronic sinopulmonary infections. N Engl J Med 1984; 310: 3–9. Jones CT, McIntosh I, Keston M, Ferguson A, Brock DJH. Three novel mutations in the cystic fibrosis gene detected by chemical cleavage: analysis of variant splicing and a nonsense mutation. Hum Mol Genet 1992; 1: 11–17. Hirsh A, Williams C, Williamson B. Young’s syndrome and cystic fibrosis mutation Delta F508. N Engl J Med 1993; 342: 118. Le Lannou D, Jezequel P, Blayau M, et al. Obstructive azoospermia with agenesis of the vas deferens or with bronchiectasia (Young’s syndrome): a genetic approach. Hum Reprod 1995; 10: 338–41.
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK (D Wellesey); and Molecular Genetics Laboratory, Royal Manchester Children’s Hospital, Manchester
38
1
2
3
4 5
Katus HA, Remppis A, Neumann FJ, et al. Diagnostic efficiency of Troponin T measurements in acute myocardial infarction. Circulation 1991; 83: 902–12. Lehman W, Craig R, Vibert P. Ca2+-induced tropomyosin movement in Limulus thin filaments revealed by three-dimensional reconstruction. Nature 1994; 368: 65. Lindahl B, Venge P, Wallentin L. Relation between troponin T and the risk of subsequent cardiac events in unstable coronary artery disease. Circulation 1996; 93: 1651–57. Wu AH. Cardiac troponin T: biochemical, analytical and clinical aspects. J Clin Immunoassay 1994; 17: 45–48. Mair P, Mair J, Koller J, et al. Cardiac Troponin T in the diagnosis of heart contusion. Lancet 1991; 338: 693.
Departments of Legal Medicine (J Dressler) and Computer Science and Biometry, Technical University Medical School, D-01307 Dresden, Germany (e-mail: [email protected])
3 Log10 of troponin T (ng/mL)
Two brothers presented in early childhood with chronic lung disorders. They had no pancreatic problems and sweat tests were normal; they were, therefore, treated as asthmatics for many years. Their lung function decreased and both had substantial lung impairment as adults (brother A aged 27 years forced expiratory volume in 1s 2·37 [predicted 4·15], forced vital capacity 4·12 [predicted 4·88], maximum expiratory flow in 50 s 1·3 [predicted 5·37]). A chest radiograph in each showed bronchiectatic changes consistent with cystic fibrosis. Previous infertility investigations had shown that both brothers had azoospermia. Brother A moved and was reinvestigated, once again his sweat test was normal but because of his azoospermia was diagnosed as having Young’s syndrome (chronic sinopulmonary disease with azoospermia, said by Handelsman1 in 1984 to be more common than cystic fibrosis). His treatment was changed and his lung function and well-being improved substantially. His brother continued to be managed as having asthma. Brother A therefore sought genetic advice. Molecular analysis of the CFTR gene showed that both men were heterozygous for the ⌬F508 mutation. Cystic fibrosis was suspected and a more detailed search was started that showed the two brothers as having the Q1291H mutation. Their diagnosis changed, therefore, to cystic fibrosis. The Q1291H mutation is the substitution of a histidine aminoacid residue by a glutamine residue at position 1291, because of the substitution of a guanine base by a cytosine at the last nucleotide of exon 20. Investigators have shown that this nucleotide change leads to abberant splicing of the mRNA.2 The patient in that report had mild lung disease and no pancreatic malfunction, although his sweat chloride was slightly raised. Although the presence of ⌬F508 and Q1291H suggests a diagnosis of cystic fibrosis, the number of CFTR mutations is increasing. Related disorders have become known as CFTR gene diseases, which include the milder regions of the disease spectrum (such as congenital bilateral absence of the vas deferens), which must cast doubt on the simple delineation of these disorders. We suggest that Young’s syndrome may in some cases be a mild form of cystic fibrosis. CFTR mutations have been considered previously as an aetiology for Young’s syndrome,3,4 but with inconsistent results. Few mutations were, however, sought in each study and did not include the Q1291H mutation. Suspicion of Young’s syndrome in chronic lung disease, even without raised sweat chloride, will ensure that children are not mistakenly treated as asthmatics. A comprehensive mutation analysis of the CFTR gene in Young’s syndrome will help to further elucidate the aetiology of this disorder.
J Dressler, D Felscher, R Koch, E Müller
2 1 0 –1 –2
*
Heart contusion Controls (n = 13) (n = 10) Serum troponin T in heart contusion cases and controls
THE LANCET • Vol 352 • July 4, 1998
Cystic fibrosis, Young’s syndrome, and normal sweat chloride
Troponin T in legal medicine
Diana Wellesey, Martin Schwarz
The diagnosis of heart contusion during medicolegal necropsies is difficult because attempted reanimation by cardiac massage, defibrillation, or both can cause subepicardial, endocardial, and transmural haemorrhage. Macroscopically it is not possible to say whether noninvasive trauma of the chest took place during life, at death, or after death. Troponin T is a myofibrillary protein and, as a subunit of the troponin complex, a constituent of the contractile apparatus of skeletal and cardiac muscle.1,2 In the cardiac cell, 6% of troponin T is dissolved in the cytosol and 94% structurally bound. Cardiac troponin T differs from that of skeletal muscle, and specific analysis is possible by means of appropriate monoclonal antibodies.1,3,4 Between 1995 and 1997, qualitative troponin T analysis in whose blood and serum by a quick test (Boehringer, Mannheim) and quantitative serum analysis by ELISA were measured in 13 cases whose hearts were known to be contused and 10 cases of death after unsuccessful resuscitation by heart massage, defibrillation, or both without evidence of heart trauma whilst alive. The results are shown in the figure. Mean serum troponin T concentration for the heart contusion cases was 97·75 ng/mL (SD 48·39 ng/mL) compared with 0·07 ng/mL (SD 0·03 ng/mL) for the resuscitation group. The difference between concentrations was significant (p<0·001). The quick test for troponin T in whole blood and serum had been done earlier. All blood and serum samples from those with heart contusion were positive, whereas those from controls were negative. Troponin T can be used as a marker to meet forensic requirements when diagnosing heart contusion.5 A positive troponin T quick test confirms the presence of myocardial lesions.
1
2
3 4
Handelsman DJ, Conway AJ, Boylan LM, Turtle JR. Young’s syndrome: obstructive azoospermia in chronic sinopulmonary infections. N Engl J Med 1984; 310: 3–9. Jones CT, McIntosh I, Keston M, Ferguson A, Brock DJH. Three novel mutations in the cystic fibrosis gene detected by chemical cleavage: analysis of variant splicing and a nonsense mutation. Hum Mol Genet 1992; 1: 11–17. Hirsh A, Williams C, Williamson B. Young’s syndrome and cystic fibrosis mutation Delta F508. N Engl J Med 1993; 342: 118. Le Lannou D, Jezequel P, Blayau M, et al. Obstructive azoospermia with agenesis of the vas deferens or with bronchiectasia (Young’s syndrome): a genetic approach. Hum Reprod 1995; 10: 338–41.
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton SO16 5YA, UK (D Wellesey); and Molecular Genetics Laboratory, Royal Manchester Children’s Hospital, Manchester
38
1
2
3
4 5
Katus HA, Remppis A, Neumann FJ, et al. Diagnostic efficiency of Troponin T measurements in acute myocardial infarction. Circulation 1991; 83: 902–12. Lehman W, Craig R, Vibert P. Ca2+-induced tropomyosin movement in Limulus thin filaments revealed by three-dimensional reconstruction. Nature 1994; 368: 65. Lindahl B, Venge P, Wallentin L. Relation between troponin T and the risk of subsequent cardiac events in unstable coronary artery disease. Circulation 1996; 93: 1651–57. Wu AH. Cardiac troponin T: biochemical, analytical and clinical aspects. J Clin Immunoassay 1994; 17: 45–48. Mair P, Mair J, Koller J, et al. Cardiac Troponin T in the diagnosis of heart contusion. Lancet 1991; 338: 693.
Departments of Legal Medicine (J Dressler) and Computer Science and Biometry, Technical University Medical School, D-01307 Dresden, Germany (e-mail: [email protected])
3 Log10 of troponin T (ng/mL)
Two brothers presented in early childhood with chronic lung disorders. They had no pancreatic problems and sweat tests were normal; they were, therefore, treated as asthmatics for many years. Their lung function decreased and both had substantial lung impairment as adults (brother A aged 27 years forced expiratory volume in 1s 2·37 [predicted 4·15], forced vital capacity 4·12 [predicted 4·88], maximum expiratory flow in 50 s 1·3 [predicted 5·37]). A chest radiograph in each showed bronchiectatic changes consistent with cystic fibrosis. Previous infertility investigations had shown that both brothers had azoospermia. Brother A moved and was reinvestigated, once again his sweat test was normal but because of his azoospermia was diagnosed as having Young’s syndrome (chronic sinopulmonary disease with azoospermia, said by Handelsman1 in 1984 to be more common than cystic fibrosis). His treatment was changed and his lung function and well-being improved substantially. His brother continued to be managed as having asthma. Brother A therefore sought genetic advice. Molecular analysis of the CFTR gene showed that both men were heterozygous for the ⌬F508 mutation. Cystic fibrosis was suspected and a more detailed search was started that showed the two brothers as having the Q1291H mutation. Their diagnosis changed, therefore, to cystic fibrosis. The Q1291H mutation is the substitution of a histidine aminoacid residue by a glutamine residue at position 1291, because of the substitution of a guanine base by a cytosine at the last nucleotide of exon 20. Investigators have shown that this nucleotide change leads to abberant splicing of the mRNA.2 The patient in that report had mild lung disease and no pancreatic malfunction, although his sweat chloride was slightly raised. Although the presence of ⌬F508 and Q1291H suggests a diagnosis of cystic fibrosis, the number of CFTR mutations is increasing. Related disorders have become known as CFTR gene diseases, which include the milder regions of the disease spectrum (such as congenital bilateral absence of the vas deferens), which must cast doubt on the simple delineation of these disorders. We suggest that Young’s syndrome may in some cases be a mild form of cystic fibrosis. CFTR mutations have been considered previously as an aetiology for Young’s syndrome,3,4 but with inconsistent results. Few mutations were, however, sought in each study and did not include the Q1291H mutation. Suspicion of Young’s syndrome in chronic lung disease, even without raised sweat chloride, will ensure that children are not mistakenly treated as asthmatics. A comprehensive mutation analysis of the CFTR gene in Young’s syndrome will help to further elucidate the aetiology of this disorder.
J Dressler, D Felscher, R Koch, E Müller
2 1 0 –1 –2
*
Heart contusion Controls (n = 13) (n = 10) Serum troponin T in heart contusion cases and controls
THE LANCET • Vol 352 • July 4, 1998