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Predictive testing for Huntington's disease: a universal model?
Reflection & Reaction Predictive testing for Huntington’s disease: a universal model?
THE LANCET Neurology Vol 2 March 2003
HD requires significant effort: clinical genetic centres, which are already overstretched, have voiced concern that if these guidelines were extended to include predictive testing in all adultonset genetic disorders there would be insufficient resources to provide such services.
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Philippe Plailly/Science Photo Library
It is 20 years since the first polymorphic DNA marker linked to Huntington’s disease (HD) was reported, a discovery that heralded the first predictive test for any adult-onset genetic disease.1 After substantial debate and detailed consultation between scientists, families, and the lay groups that represent patients with HD worldwide, the first predictive test for the disease was offered in 1986. Initially, DNA testing for HD was fraught with ambiguity; individuals were given a modification of risk with significant residual uncertainty about the result. Test results generally identified a 2–10% likelihood of inheriting the HD mutation. The cloning of the huntingtin gene 10 years ago, and the subsequent delineation of a universal mutation underlying HD, eliminated the risk of uncertainty. However, this was superseded by a new ambiguity: when would the disease manifest? Today, predictive testing for HD is accepted worldwide and its practice is based on guidelines that have been approved by patients, families, lay organisations, governments, and health-insurance providers.2 Thousands of people who are neurologically normal have been told that they will develop HD in the absence of any treatment to delay the onset of this illness.3,4 The term adopted to describe this group of people is “presymptomatic individuals”. Predictive testing for HD might be a useful model for similar testing in many other disorders, both genetic and nongenetic, where a blood test could determine the likelihood of infection. In both cases, new technology has given us the ability to define a future risk. Fundamental principles that have emerged from presymptomatic testing for HD have already been incorporated into testing for other genetic illnesses such as breast cancer, polycystic kidney disease, Alzheimer’s disease, and nongenetic illnesses such as AIDS. These include the importance of counselling to explain the risks and benefits of testing and the time necessary between a test request being made and provision of the test results. Predictive testing for
Cloning of the huntingtin gene has eliminated uncertainty in predictive testing for Huntington’s disease
Although predictive testing for HD has been heralded as a model for this type of testing, until now there have been no direct comparisons in single geographic areas with predictive testing for any other disease. However, in a recent study,5 the experience of predictive testing for HD in France was compared with that of the autosomal dominant cerebellar ataxias. The investigators noted similarities between predictive testing for these late-onset neurological disorders. The observation that most individuals that requested testing were women suggests that the main reason for testing was concern regarding child bearing. However, numerous factors indicate that this is not the case. Most people that request testing are in their mid-30s and about half of them have already had children by the time they seek testing.5 Finally, the main reason given for testing is to relieve
http://neurology.thelancet.com
uncertainty about the risk of illness. It is notable that about 40% of individuals abandon testing after their first visit. This highlights the importance of a time lag between the first visit and the provision of test results, and clearly indicates the importance of providing pretest counselling to at-risk individuals so that they can make an informed choice. The absence of pretest counselling could significantly increase the likelihood that individuals are given their test results before they have fully understood the risks and benefits of testing and, in many cases, before they have had the opportunity to opt out. This high drop-out rate reinforces the importance of pretest counselling and the provision of test results face-to-face. Predictive testing for HD, as well as for other disorders, is not just a test but represents an important process that has an effect far beyond the individual being tested. Counselling is an essential requirement for the safe and effective integration of predictive testing into the health-care system. According to the recent study,5 a third (12 of 35) of individuals with subtle neurological signs and symptoms were not carrying the HD mutation. This observation reinforces the importance of a detailed clinical examination and the danger of categorising those with minimal signs and symptoms as affected, particularly when a positive family history is present. On the one hand, the DNA test merely provides information as to whether someone has or has not inherited the mutation; it provides no information as to whether the individual is affected at the present time. On the other hand, for those individuals that have some early signs and symptoms, a negative test result indicates that they do not have HD, although the cause and reason for their neurological signs and symptoms is unknown. The usefulness of a detailed neurological assessment in determining whether someone is affected cannot be underestimated or surpassed by any technology at present.
141
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Reflection & Reaction The investigators also report a significant adverse-event rate in presymptomatic individuals. Even for people at risk of cerebellar ataxia— which was thought to carry a lesser psychological burden—30–40% of individuals who were told they were likely to develop the disease had significant adverse events, such as psychological distress that required treatment and psychiatric hospitalisation. In families with HD, about 10% of individuals who were informed that they did not carry the HD mutation also had significant psychological problems that required treatment. Presymptomatic individuals require continued support and counselling to cope with the genetic diagnosis. However, people who will not develop the disease may also exhibit psychological distress. The demand for predictive testing for HD in France is generally similar to that in the USA—about 5%—but it is significantly lower than that in Canada and the UK.3,4 Although there may be many reasons for these geographic
differences—eg, the availability of a universal health-care system and a long-standing relationship between the research community and the families at risk—the overwhelming finding with regard to all predictive testing programmes for HD is that demand and uptake is much lower than previously thought. Despite this, services are already overstretched and the pressure to limit services and support is intense. Clearly, any potential treatments for HD will further exacerbate this demand on resources. Now is the time to begin planning for such a situation; one possible solution may be for predictive testing, both of HD and other disorders, to be done not only by physicians in genetic counselling centres but also by family physicians and practitioners in primary care. Training of other professionals, including nurses and family physicians, must be initiated so that they can participate in the provision of services. The results of the
present study clearly indicate that predictive-testing guidelines for HD are applicable to other disorders. The lessons learned can inform practice not only in genetic centres that provide such presymptomatic testing protocols, but also for individuals in primary care where much of genetic medicine will be practised. Michael R Hayden Centre for Molecular Medicine & Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada. Email [email protected] References 1 2 3 4
5
Hayden, MR Predictive testing for Huntington’s disease: the calm after the storm. Lancet 2000; 356: 1944–45. Went L. Guidelines for the molecular genetics predictive test Huntington’s disease. J Med Genet 1994; 31: 555–59. Harper PS, Lim C, Crauford D, on behalf of the UK Huntington’s Disease Prediction Consortium. J Med Genet 2000; 37: 567–71. Creighton S, Almqvist EW, Hayden MR. Predictive, prenatal and diagnostic genetic testing for Huntington’s disease: the experience in Canada from 1987–2000. Clin Genet (in press). Goizet C, Lesca G, Durr A. Presymptomatic testing in Huntington’s disease and autosomal dominant cerebellar ataxias. Neurology 2002; 59: 1330–36.
Monoamine oxidase inhibitors—is it time to up the TEMPO? Selegiline—a selective monoamine oxidase-B (MAO-B) inhibitor—is not widely used at present as an antiparkinsonian drug for several reasons: it produces modest improvements in symptoms as a monotherapy;1 there is little evidence to support its longterm usefulness; beneficial effects for motor fluctuations are poorly documented;2 and safety concerns have been raised.3 The popularity of selegiline has varied greatly over the years. In the early 1990s, on the basis of preclinical and preliminary clinical findings, selegiline was proposed to have a neuroprotective effect. As a result many patients were treated with selegiline in the hope that it would reduce disease progression. Although it soon became apparent that premature conclusions had been made,1 prescription habits persisted. In a trial of selegiline in combination with levodopa, a high mortality ratio raised safety concerns.3 Although further studies did not reproduce this finding, selegiline was seen as a potentially
142
dangerous drug, old and out of patent, with little commercial value and an indeterminate benefit-to-risk ratio. Sales of selegiline have decreased substantially, whereas rasagiline— another selective, irreversible MAO-B inhibitor—has reached phase III trials. Does rasagiline represent a therapeutic innovation? It is still too early to tell, but several issues—such as efficacy, safety, convenience, and cost—can be discussed. In the recent TEMPO study,4 rasagiline monotherapy (1 mg or 2 mg per day) was better than placebo in patients with early Parkinson’s disease (PD). However, the magnitude of this effect was small (a decrease of 4 points on the total Unified Parkinson’s Disease Rating Scale [UPDRS] score) and the clinical relevance of this is not known. In comparison, dopamine agonists and levodopa have shown greater effects in similar trials, but a UPDRS minimum clinically relevant difference has never been defined. It seems unlikely, however, that rasagiline will be any more efficacious
than other MAO-B inhibitors, such as selegiline and lazabemide.1,5 Is rasagiline effective in the treatment of motor fluctuations? Can rasagiline improve symptoms that are resistant to current dopaminergic treatments—eg, falls, dementia, depression, and sleep problems? Does rasagiline modify disease progression? Unfortunately the TEMPO study did not address these issues. The duration of the study was 6 months, which although sufficient for regulatory approval, is too short to assess accurately the outcome with regard to disease duration. Furthermore, whether rasagiline is effective and useful for long-term management, particularly after the introduction of levodopa, is unknown. Although the TEMPO study was not designed to assess disease progression, rasagiline did not delay the need for levodopa (an endpoint that has been proposed as a measure of neuroprotection1). An unpublished active-extension follow-up to the TEMPO study—in which patients in the rasagiline groups
THE LANCET Neurology Vol 2 March 2003
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
THE LANCET Neurology Vol 2 March 2003
HD requires significant effort: clinical genetic centres, which are already overstretched, have voiced concern that if these guidelines were extended to include predictive testing in all adultonset genetic disorders there would be insufficient resources to provide such services.
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Philippe Plailly/Science Photo Library
It is 20 years since the first polymorphic DNA marker linked to Huntington’s disease (HD) was reported, a discovery that heralded the first predictive test for any adult-onset genetic disease.1 After substantial debate and detailed consultation between scientists, families, and the lay groups that represent patients with HD worldwide, the first predictive test for the disease was offered in 1986. Initially, DNA testing for HD was fraught with ambiguity; individuals were given a modification of risk with significant residual uncertainty about the result. Test results generally identified a 2–10% likelihood of inheriting the HD mutation. The cloning of the huntingtin gene 10 years ago, and the subsequent delineation of a universal mutation underlying HD, eliminated the risk of uncertainty. However, this was superseded by a new ambiguity: when would the disease manifest? Today, predictive testing for HD is accepted worldwide and its practice is based on guidelines that have been approved by patients, families, lay organisations, governments, and health-insurance providers.2 Thousands of people who are neurologically normal have been told that they will develop HD in the absence of any treatment to delay the onset of this illness.3,4 The term adopted to describe this group of people is “presymptomatic individuals”. Predictive testing for HD might be a useful model for similar testing in many other disorders, both genetic and nongenetic, where a blood test could determine the likelihood of infection. In both cases, new technology has given us the ability to define a future risk. Fundamental principles that have emerged from presymptomatic testing for HD have already been incorporated into testing for other genetic illnesses such as breast cancer, polycystic kidney disease, Alzheimer’s disease, and nongenetic illnesses such as AIDS. These include the importance of counselling to explain the risks and benefits of testing and the time necessary between a test request being made and provision of the test results. Predictive testing for
Cloning of the huntingtin gene has eliminated uncertainty in predictive testing for Huntington’s disease
Although predictive testing for HD has been heralded as a model for this type of testing, until now there have been no direct comparisons in single geographic areas with predictive testing for any other disease. However, in a recent study,5 the experience of predictive testing for HD in France was compared with that of the autosomal dominant cerebellar ataxias. The investigators noted similarities between predictive testing for these late-onset neurological disorders. The observation that most individuals that requested testing were women suggests that the main reason for testing was concern regarding child bearing. However, numerous factors indicate that this is not the case. Most people that request testing are in their mid-30s and about half of them have already had children by the time they seek testing.5 Finally, the main reason given for testing is to relieve
http://neurology.thelancet.com
uncertainty about the risk of illness. It is notable that about 40% of individuals abandon testing after their first visit. This highlights the importance of a time lag between the first visit and the provision of test results, and clearly indicates the importance of providing pretest counselling to at-risk individuals so that they can make an informed choice. The absence of pretest counselling could significantly increase the likelihood that individuals are given their test results before they have fully understood the risks and benefits of testing and, in many cases, before they have had the opportunity to opt out. This high drop-out rate reinforces the importance of pretest counselling and the provision of test results face-to-face. Predictive testing for HD, as well as for other disorders, is not just a test but represents an important process that has an effect far beyond the individual being tested. Counselling is an essential requirement for the safe and effective integration of predictive testing into the health-care system. According to the recent study,5 a third (12 of 35) of individuals with subtle neurological signs and symptoms were not carrying the HD mutation. This observation reinforces the importance of a detailed clinical examination and the danger of categorising those with minimal signs and symptoms as affected, particularly when a positive family history is present. On the one hand, the DNA test merely provides information as to whether someone has or has not inherited the mutation; it provides no information as to whether the individual is affected at the present time. On the other hand, for those individuals that have some early signs and symptoms, a negative test result indicates that they do not have HD, although the cause and reason for their neurological signs and symptoms is unknown. The usefulness of a detailed neurological assessment in determining whether someone is affected cannot be underestimated or surpassed by any technology at present.
141
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Reflection & Reaction The investigators also report a significant adverse-event rate in presymptomatic individuals. Even for people at risk of cerebellar ataxia— which was thought to carry a lesser psychological burden—30–40% of individuals who were told they were likely to develop the disease had significant adverse events, such as psychological distress that required treatment and psychiatric hospitalisation. In families with HD, about 10% of individuals who were informed that they did not carry the HD mutation also had significant psychological problems that required treatment. Presymptomatic individuals require continued support and counselling to cope with the genetic diagnosis. However, people who will not develop the disease may also exhibit psychological distress. The demand for predictive testing for HD in France is generally similar to that in the USA—about 5%—but it is significantly lower than that in Canada and the UK.3,4 Although there may be many reasons for these geographic
differences—eg, the availability of a universal health-care system and a long-standing relationship between the research community and the families at risk—the overwhelming finding with regard to all predictive testing programmes for HD is that demand and uptake is much lower than previously thought. Despite this, services are already overstretched and the pressure to limit services and support is intense. Clearly, any potential treatments for HD will further exacerbate this demand on resources. Now is the time to begin planning for such a situation; one possible solution may be for predictive testing, both of HD and other disorders, to be done not only by physicians in genetic counselling centres but also by family physicians and practitioners in primary care. Training of other professionals, including nurses and family physicians, must be initiated so that they can participate in the provision of services. The results of the
present study clearly indicate that predictive-testing guidelines for HD are applicable to other disorders. The lessons learned can inform practice not only in genetic centres that provide such presymptomatic testing protocols, but also for individuals in primary care where much of genetic medicine will be practised. Michael R Hayden Centre for Molecular Medicine & Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada. Email [email protected] References 1 2 3 4
5
Hayden, MR Predictive testing for Huntington’s disease: the calm after the storm. Lancet 2000; 356: 1944–45. Went L. Guidelines for the molecular genetics predictive test Huntington’s disease. J Med Genet 1994; 31: 555–59. Harper PS, Lim C, Crauford D, on behalf of the UK Huntington’s Disease Prediction Consortium. J Med Genet 2000; 37: 567–71. Creighton S, Almqvist EW, Hayden MR. Predictive, prenatal and diagnostic genetic testing for Huntington’s disease: the experience in Canada from 1987–2000. Clin Genet (in press). Goizet C, Lesca G, Durr A. Presymptomatic testing in Huntington’s disease and autosomal dominant cerebellar ataxias. Neurology 2002; 59: 1330–36.
Monoamine oxidase inhibitors—is it time to up the TEMPO? Selegiline—a selective monoamine oxidase-B (MAO-B) inhibitor—is not widely used at present as an antiparkinsonian drug for several reasons: it produces modest improvements in symptoms as a monotherapy;1 there is little evidence to support its longterm usefulness; beneficial effects for motor fluctuations are poorly documented;2 and safety concerns have been raised.3 The popularity of selegiline has varied greatly over the years. In the early 1990s, on the basis of preclinical and preliminary clinical findings, selegiline was proposed to have a neuroprotective effect. As a result many patients were treated with selegiline in the hope that it would reduce disease progression. Although it soon became apparent that premature conclusions had been made,1 prescription habits persisted. In a trial of selegiline in combination with levodopa, a high mortality ratio raised safety concerns.3 Although further studies did not reproduce this finding, selegiline was seen as a potentially
142
dangerous drug, old and out of patent, with little commercial value and an indeterminate benefit-to-risk ratio. Sales of selegiline have decreased substantially, whereas rasagiline— another selective, irreversible MAO-B inhibitor—has reached phase III trials. Does rasagiline represent a therapeutic innovation? It is still too early to tell, but several issues—such as efficacy, safety, convenience, and cost—can be discussed. In the recent TEMPO study,4 rasagiline monotherapy (1 mg or 2 mg per day) was better than placebo in patients with early Parkinson’s disease (PD). However, the magnitude of this effect was small (a decrease of 4 points on the total Unified Parkinson’s Disease Rating Scale [UPDRS] score) and the clinical relevance of this is not known. In comparison, dopamine agonists and levodopa have shown greater effects in similar trials, but a UPDRS minimum clinically relevant difference has never been defined. It seems unlikely, however, that rasagiline will be any more efficacious
than other MAO-B inhibitors, such as selegiline and lazabemide.1,5 Is rasagiline effective in the treatment of motor fluctuations? Can rasagiline improve symptoms that are resistant to current dopaminergic treatments—eg, falls, dementia, depression, and sleep problems? Does rasagiline modify disease progression? Unfortunately the TEMPO study did not address these issues. The duration of the study was 6 months, which although sufficient for regulatory approval, is too short to assess accurately the outcome with regard to disease duration. Furthermore, whether rasagiline is effective and useful for long-term management, particularly after the introduction of levodopa, is unknown. Although the TEMPO study was not designed to assess disease progression, rasagiline did not delay the need for levodopa (an endpoint that has been proposed as a measure of neuroprotection1). An unpublished active-extension follow-up to the TEMPO study—in which patients in the rasagiline groups
THE LANCET Neurology Vol 2 March 2003
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.