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A molecular mechanism for thrombotic thrombocytopenic purpura
SCIENCE AND MEDICINE
A molecular mechanism for thrombotic thrombocytopenic purpura gene in hand should also lead to improved diagnostic tools for the more commonly acquired form of the disease, and for monitoring therapy in all patients”, he adds. Currently, during an “acute episode”, patients are given plasma exchange therapy to replenish active enzyme and deplete circulating inhibitor. This saves many lives, but carries significant risks. “It should now be possible to manufacture recombinant ADAMTS13”, comments Amanda Fosang (University of Melbourne, Australia), co-author of an accompanying commentary (Nature 2001; 413: 475–76). “Potentially, this would be safer for patients than plasma exchange, as it would eliminate all risk of disease transfer through natural blood products”, she says. Ginsburg agrees and concludes that “understanding the biological function of ADAMTS13 and the pathophysiology of TTP may lead to other novel approaches to therapy, not only for TTP but potentially for other bleeding and clotting disorders”.
esearchers in the USA have shown that mutations in the ADAMTS13 gene are responsible for the familial form of thrombotic thrombocytopenic purpura (TTP). Missense mutations in the gene reduce the amount of active protease available to cleave the blood protein von Willebrand factor (VWF); large multimeric forms of VWF have been observed in the plasma of patients with TTP and are proposed to have a pathogenic role in the disease. Gallia Levy (Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI, USA) and colleagues started their search for the gene responsible for TTP by doing a genome-wide linkage scan on DNA from seven individuals with familial TTP. The chosen individuals, and several of their close family members, came from families identified and characterised by the paper’s senior author Han-Mou Tsai (Montefiore Medical Center, Bronx, NY, USA). The location of about 20 candidate genes was mapped to a region on chromosome 9q34, and further
analysis revealed several missense mutations in the predicted exons of a gene later identified as ADAMTS13 (Nature 2001; 413: 488–94). “Han-Mou Tsai has been a pioneer in critical work that has defined the VWF-cleaving protease and its role in TTP; he quite rightly predicted that the gene responsible for familial TTP would be a protease”, comments senior co-author David Ginsburg (also of the Howard Hughes Medical Institute, MI, USA). The ADAMTS13 gene spans 29 exons, is expressed primarily in the liver and encodes a potentially catalytically active ADAMTS protease composed of 1427 aminoacids. Mutations in ADAMTS13 accounted for all but one of the 15 disease alleles studied; patients had a spectrum of mutations that included frameshifts, a single splice mutation, and some aminoacid substitutions. No null alleles were found, suggesting that complete deficiency of ADAMTS13 may be lethal. Ginsburg predicts that specific DNA diagnosis for patients with the relatively rare hereditary form of TTP could now be developed. “Having the
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Ramipril lowers risk of left ventricular hypertrophy
Ketogenic diet reduces seizures A high-fat, low-carbohydrate diet can reduce the number and frequency of seizures in children with severe seizure disorders. 150 children (aged 1–16 years) were put on a ketogenic diet. After 3–6 years, 13% of children were seizure free, and seizures had decreased by at least 90% in an additional 14%. The researchers conclude that the diet is more effective and better tolerated than many new anticonvulsants (Pediatrics 2001; 108: 898–905). US stroke statistics The number of US admissions to hospital for stroke in the USA increased during 1988–97 whereas death from stroke decreased, according to a new study. Epidemiologists analysed data from the National Hospital Discharge Survey and found that the number of admissions to hospital increased by 38·6% while the number of people who died from strokes decreased by 13·4%. The researchers suggest that the reduced death rate may be due to better treatment rather than prevention. The findings are published in the October issue of Stroke. 1162
Kathryn Senior
T
he angiotensin-converting were in regression compared with enzyme inhibitor ramipril 38·6% in the placebo group. Of reverses and prevents left ventricthose patients who did not have ular hypertrophy (LVH) according LVH at the start of treatment, fewer to a Heart Outcome Prevention went on to develop the condition in Evaluation (HOPE) substudy. the ramipril group (4·3%) than “This is the first in the placebo group time an intervention (5·0%). Patients with Rights were not [has been] shown regression/prevention granted to include to cause regression of LVH had a lower of LVH independent risk of cardiovascular this image in of blood pressure death, myocardial electronic media. reduction”, says lead infarction, or stroke. Please refer to the investigator James The authors suggest printed journal. Mathew (University that, among other of Iowa, IA and mechanisms, ramipril Galesburg Cottage may reduce/prevent Hospital, IL, USA). LVH by a direct antiThe researchers hypertrophic effect on Enlarged left ventricle randomly assigned the myocardium. The patients with or without LVH to high level of regression/prevention treatment with ramipril or with in the placebo group, however, is placebo. After a baseline ECG more difficult to explain. “We are recording, follow-up ECGs were intrigued by the finding that regresdone at 2 years and at study end (4·5 sion of LVH occurred in 38·6% of years). ECGs were used to identify patients in the placebo group”, says new development, persistence, or Mathew. “This may be related to regression of LVH (Circulation multiple risk factor interventions 2001; 104: 1615–21). and lifestyle modifications in parAt the end of the study, 46·1% of ticipants in clinical trials.” patients in the ramipril group who Rebecca Love had LVH at the start of treatment Science Photo Library
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THE LANCET • Vol 358 • October 6, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
A molecular mechanism for thrombotic thrombocytopenic purpura gene in hand should also lead to improved diagnostic tools for the more commonly acquired form of the disease, and for monitoring therapy in all patients”, he adds. Currently, during an “acute episode”, patients are given plasma exchange therapy to replenish active enzyme and deplete circulating inhibitor. This saves many lives, but carries significant risks. “It should now be possible to manufacture recombinant ADAMTS13”, comments Amanda Fosang (University of Melbourne, Australia), co-author of an accompanying commentary (Nature 2001; 413: 475–76). “Potentially, this would be safer for patients than plasma exchange, as it would eliminate all risk of disease transfer through natural blood products”, she says. Ginsburg agrees and concludes that “understanding the biological function of ADAMTS13 and the pathophysiology of TTP may lead to other novel approaches to therapy, not only for TTP but potentially for other bleeding and clotting disorders”.
esearchers in the USA have shown that mutations in the ADAMTS13 gene are responsible for the familial form of thrombotic thrombocytopenic purpura (TTP). Missense mutations in the gene reduce the amount of active protease available to cleave the blood protein von Willebrand factor (VWF); large multimeric forms of VWF have been observed in the plasma of patients with TTP and are proposed to have a pathogenic role in the disease. Gallia Levy (Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI, USA) and colleagues started their search for the gene responsible for TTP by doing a genome-wide linkage scan on DNA from seven individuals with familial TTP. The chosen individuals, and several of their close family members, came from families identified and characterised by the paper’s senior author Han-Mou Tsai (Montefiore Medical Center, Bronx, NY, USA). The location of about 20 candidate genes was mapped to a region on chromosome 9q34, and further
analysis revealed several missense mutations in the predicted exons of a gene later identified as ADAMTS13 (Nature 2001; 413: 488–94). “Han-Mou Tsai has been a pioneer in critical work that has defined the VWF-cleaving protease and its role in TTP; he quite rightly predicted that the gene responsible for familial TTP would be a protease”, comments senior co-author David Ginsburg (also of the Howard Hughes Medical Institute, MI, USA). The ADAMTS13 gene spans 29 exons, is expressed primarily in the liver and encodes a potentially catalytically active ADAMTS protease composed of 1427 aminoacids. Mutations in ADAMTS13 accounted for all but one of the 15 disease alleles studied; patients had a spectrum of mutations that included frameshifts, a single splice mutation, and some aminoacid substitutions. No null alleles were found, suggesting that complete deficiency of ADAMTS13 may be lethal. Ginsburg predicts that specific DNA diagnosis for patients with the relatively rare hereditary form of TTP could now be developed. “Having the
News in brief
Ramipril lowers risk of left ventricular hypertrophy
Ketogenic diet reduces seizures A high-fat, low-carbohydrate diet can reduce the number and frequency of seizures in children with severe seizure disorders. 150 children (aged 1–16 years) were put on a ketogenic diet. After 3–6 years, 13% of children were seizure free, and seizures had decreased by at least 90% in an additional 14%. The researchers conclude that the diet is more effective and better tolerated than many new anticonvulsants (Pediatrics 2001; 108: 898–905). US stroke statistics The number of US admissions to hospital for stroke in the USA increased during 1988–97 whereas death from stroke decreased, according to a new study. Epidemiologists analysed data from the National Hospital Discharge Survey and found that the number of admissions to hospital increased by 38·6% while the number of people who died from strokes decreased by 13·4%. The researchers suggest that the reduced death rate may be due to better treatment rather than prevention. The findings are published in the October issue of Stroke. 1162
Kathryn Senior
T
he angiotensin-converting were in regression compared with enzyme inhibitor ramipril 38·6% in the placebo group. Of reverses and prevents left ventricthose patients who did not have ular hypertrophy (LVH) according LVH at the start of treatment, fewer to a Heart Outcome Prevention went on to develop the condition in Evaluation (HOPE) substudy. the ramipril group (4·3%) than “This is the first in the placebo group time an intervention (5·0%). Patients with Rights were not [has been] shown regression/prevention granted to include to cause regression of LVH had a lower of LVH independent risk of cardiovascular this image in of blood pressure death, myocardial electronic media. reduction”, says lead infarction, or stroke. Please refer to the investigator James The authors suggest printed journal. Mathew (University that, among other of Iowa, IA and mechanisms, ramipril Galesburg Cottage may reduce/prevent Hospital, IL, USA). LVH by a direct antiThe researchers hypertrophic effect on Enlarged left ventricle randomly assigned the myocardium. The patients with or without LVH to high level of regression/prevention treatment with ramipril or with in the placebo group, however, is placebo. After a baseline ECG more difficult to explain. “We are recording, follow-up ECGs were intrigued by the finding that regresdone at 2 years and at study end (4·5 sion of LVH occurred in 38·6% of years). ECGs were used to identify patients in the placebo group”, says new development, persistence, or Mathew. “This may be related to regression of LVH (Circulation multiple risk factor interventions 2001; 104: 1615–21). and lifestyle modifications in parAt the end of the study, 46·1% of ticipants in clinical trials.” patients in the ramipril group who Rebecca Love had LVH at the start of treatment Science Photo Library
R
THE LANCET • Vol 358 • October 6, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.