- Email: [email protected]
IN44-WE-03 Genetic analysis of sporadic neurodegenerative disease
19th World Congress of Neurology, Invited Abstracts / Journal of the Neurological Sciences 285 S1 (2009) S5–S56
isolated optic neuritis occurs in approximatively 20 to 25% of the patients, isolated brainstem dysfunction in 10 to 25%, isolated long tract dysfunction in 40 to 50%. In a small proportion of cases, neurological symptoms may be accompanied by various encephalitic manifestations.4–6 Exacerbating-remitting course is by far the most common form at onset in all published studies with a relapse as the first manifestation of the disease in 85.7 to 97.7% of cases.1,6,8 The estimated median time between onset of MS and the second neurological episode using survival analysis is 2 years, with no difference with adult onset MS (2.2 years).6 By contrast, patients with childhood onset MS convert to secondary progression on average 10 years later than patients with adult onset MS but reach this phase of the disease on average 10 years younger.6 The same observation can be made for the reaching of disability landmarks of DSS 4, DSS 6, and DSS 7, which refutes the notion of a more favourable prognosis in this age group.6 Once a certain threshold of irreversible disability has been reached, further accumulation of disability is similar in childhood and adult onset MS patients. However, the time to reach this threshold is significantly longer in childhood than in adult onset MS patients.6 This is true whatever the definition of early onset MS and not only for childhood onset MS, but the earlier the onset of the disease, the more pronounced this phenomenon.9,10 This leads to consider that there is a continuum rather than heterogeneity between early onset MS and late onset MS, at least from the clinical and statistical standpoint. IN43-WE-02 Multiple sclerosis in pregnancy T. Kilpatrick. Centre for Neuroscience, University of Melbourne, Australia IN43-WE-03 Managing disabilities in multiple sclerosis A. Siva. Turkey
IN44 – Pharmacogenomics IN44-WE-01 The role of APOE polymorphism in drug responses in alzheimer & parkinson A. Korczyn. Chair of Neurology, Tel-Aviv University Medical School, Tel Aviv, Israel IN44-WE-02 The pharmacogenetics of antiepileptic drug hypersensitivity C. Locharernkul. Neurology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand Strong association between HLA-B*1502 and Stevens-Johnson syndrome (SJS) /toxic epidermal necrolysis (TEN) from carbamazepine (CBZ) has recently been discovered. The association has an ethnical preponderance in Asian populations including Han Chinese, Thai, Malay and a few Caucasian subjects with Asian ancestry, but was not found in a group of studied Caucasians (French, German) and in Japanese. HLA-B*1502 association with SJS/TEN was also demonstrated in patients exposed to phenytoin (PHT) and in single case using lamotrigine or oxcarbazepine. Maculopapular rash or hypersensitivity syndrome was not shown to be associated with this genetic marker. High frequency of HLA-B*1502 allele (10–15%) among populations in Southeast Asia may explain the ethnical preponderance of this association and the higher incidence of SJS/TEN observed in Asians than in Europeans. Screening of HLA-B*1502 positivity can prevent genetically susceptible individual from the life threatening idiosyncratic reactions. U.S. Food and Drug Administration alerts [12/12/2007
S33
and 11/24/2008] have suggested screening for HLA-B*1502 allele prior to starting CBZ in patients with Asian ancestry. Patients who tested positive for HLA-B*1502 should not be treated with CBZ and should not receive PHT or fosphenytoin as alternatives. In a recent retrospective cohort in Thailand, cost effectiveness of HLAB*1502 screening was shown outweighing the expense and harm from SJS/TEN. Based on the current available information, screening of HLA-B*1502 seems prudent in ethnic subgroups having high frequency of HLA-B*1502 allele. However, in regions where HLAB*1502 is rare or the SJS/TEN pharmacogenetics is not yet known, HLA-B*1502 screening may be controversial and can raise ethical and financial issues. To date, the genetic testing is costly and can delay starting the drug. Currently needed is the development of rapid and low-cost screening test as well as more replicated studies on wide range of ethnicity. IN44-WE-03 Genetic analysis of sporadic neurodegenerative disease J. Hardy. Institute of Neurology, University College London, London, United Kingdom Genetic analysis of mendelian neurodegenerative diseases has identified the causes of nearly all cases of autosomal dominant neurodegenerative diseases: these include the prion gene in Creuzfeld-Jakob disease and Gerstmann Straussler syndrome, the APP and presenilin genes in Alzheimer’s disease, the MAPT gene in hereditary tangle diseases and the asynuclein and LRRK2 gene in Parkinson’s disease. In all these cases however, the autosomal dominant forms of the disease account for a small percentage (typically 1%–10%) of all cases. The genetic predisposition for the more common sporadic cases of these diseases (beyond the strong association of apoe with Alzheimer’s disease) has not been clear. I will discuss two approaches to this problem. First, we and others have been analysing the loci involved in mendelian disease for genetic association with sporadic disease. These analyses have shown that, in most cases, genetic variability at these loci contribute to the risk of sporadic disease, with the risk allele being associated with high expressing haplotypes. This is particularly clear in the case of MAPT, where the risk haplotype for progressive supranuclear palsy, H1c, is associated with marginally increased expression of the 4 repeat isoform of tau. Second, whole genome association studies test genetic variability across the genome for association with disease. These studies are now identifying risk loci for common neurological disease, which I will discuss. I will also discuss how high throughput sequencing strategies will impact on the dissection of the genetic aetiologies of these diseases Hardy and Singleton, N Engl J Med 2009, 360: 1759).
IN45 – Epilepsy 3 IN45-WE-01 The value of “new” versus standard drugs in epilepsy A.G. Marson. Neurological Science, University of Liverpool, Liverpool, United Kingdom Epilepsy is a chronic condition, often requiring years of antiepileptic drug (AED). Evidence regarding the value of new and standard AEDs will come from long term randomized controlled trials (RCTs) where new and standard AEDs are compared head to head. The outcomes measured to assess value should includes measures of effectiveness (efficacy, adverse effects and trade-offs between the two), quality of life, heath economic outcomes. New AEDs are most commonly used as add-on treatments and have been licensed for this use based on short term placebo controlled trials. There is some evidence that the new AEDs, when used as add-on treatments, have brought about long term improvement in seizure control and fewer adverse effects for people with epilepsy.
isolated optic neuritis occurs in approximatively 20 to 25% of the patients, isolated brainstem dysfunction in 10 to 25%, isolated long tract dysfunction in 40 to 50%. In a small proportion of cases, neurological symptoms may be accompanied by various encephalitic manifestations.4–6 Exacerbating-remitting course is by far the most common form at onset in all published studies with a relapse as the first manifestation of the disease in 85.7 to 97.7% of cases.1,6,8 The estimated median time between onset of MS and the second neurological episode using survival analysis is 2 years, with no difference with adult onset MS (2.2 years).6 By contrast, patients with childhood onset MS convert to secondary progression on average 10 years later than patients with adult onset MS but reach this phase of the disease on average 10 years younger.6 The same observation can be made for the reaching of disability landmarks of DSS 4, DSS 6, and DSS 7, which refutes the notion of a more favourable prognosis in this age group.6 Once a certain threshold of irreversible disability has been reached, further accumulation of disability is similar in childhood and adult onset MS patients. However, the time to reach this threshold is significantly longer in childhood than in adult onset MS patients.6 This is true whatever the definition of early onset MS and not only for childhood onset MS, but the earlier the onset of the disease, the more pronounced this phenomenon.9,10 This leads to consider that there is a continuum rather than heterogeneity between early onset MS and late onset MS, at least from the clinical and statistical standpoint. IN43-WE-02 Multiple sclerosis in pregnancy T. Kilpatrick. Centre for Neuroscience, University of Melbourne, Australia IN43-WE-03 Managing disabilities in multiple sclerosis A. Siva. Turkey
IN44 – Pharmacogenomics IN44-WE-01 The role of APOE polymorphism in drug responses in alzheimer & parkinson A. Korczyn. Chair of Neurology, Tel-Aviv University Medical School, Tel Aviv, Israel IN44-WE-02 The pharmacogenetics of antiepileptic drug hypersensitivity C. Locharernkul. Neurology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand Strong association between HLA-B*1502 and Stevens-Johnson syndrome (SJS) /toxic epidermal necrolysis (TEN) from carbamazepine (CBZ) has recently been discovered. The association has an ethnical preponderance in Asian populations including Han Chinese, Thai, Malay and a few Caucasian subjects with Asian ancestry, but was not found in a group of studied Caucasians (French, German) and in Japanese. HLA-B*1502 association with SJS/TEN was also demonstrated in patients exposed to phenytoin (PHT) and in single case using lamotrigine or oxcarbazepine. Maculopapular rash or hypersensitivity syndrome was not shown to be associated with this genetic marker. High frequency of HLA-B*1502 allele (10–15%) among populations in Southeast Asia may explain the ethnical preponderance of this association and the higher incidence of SJS/TEN observed in Asians than in Europeans. Screening of HLA-B*1502 positivity can prevent genetically susceptible individual from the life threatening idiosyncratic reactions. U.S. Food and Drug Administration alerts [12/12/2007
S33
and 11/24/2008] have suggested screening for HLA-B*1502 allele prior to starting CBZ in patients with Asian ancestry. Patients who tested positive for HLA-B*1502 should not be treated with CBZ and should not receive PHT or fosphenytoin as alternatives. In a recent retrospective cohort in Thailand, cost effectiveness of HLAB*1502 screening was shown outweighing the expense and harm from SJS/TEN. Based on the current available information, screening of HLA-B*1502 seems prudent in ethnic subgroups having high frequency of HLA-B*1502 allele. However, in regions where HLAB*1502 is rare or the SJS/TEN pharmacogenetics is not yet known, HLA-B*1502 screening may be controversial and can raise ethical and financial issues. To date, the genetic testing is costly and can delay starting the drug. Currently needed is the development of rapid and low-cost screening test as well as more replicated studies on wide range of ethnicity. IN44-WE-03 Genetic analysis of sporadic neurodegenerative disease J. Hardy. Institute of Neurology, University College London, London, United Kingdom Genetic analysis of mendelian neurodegenerative diseases has identified the causes of nearly all cases of autosomal dominant neurodegenerative diseases: these include the prion gene in Creuzfeld-Jakob disease and Gerstmann Straussler syndrome, the APP and presenilin genes in Alzheimer’s disease, the MAPT gene in hereditary tangle diseases and the asynuclein and LRRK2 gene in Parkinson’s disease. In all these cases however, the autosomal dominant forms of the disease account for a small percentage (typically 1%–10%) of all cases. The genetic predisposition for the more common sporadic cases of these diseases (beyond the strong association of apoe with Alzheimer’s disease) has not been clear. I will discuss two approaches to this problem. First, we and others have been analysing the loci involved in mendelian disease for genetic association with sporadic disease. These analyses have shown that, in most cases, genetic variability at these loci contribute to the risk of sporadic disease, with the risk allele being associated with high expressing haplotypes. This is particularly clear in the case of MAPT, where the risk haplotype for progressive supranuclear palsy, H1c, is associated with marginally increased expression of the 4 repeat isoform of tau. Second, whole genome association studies test genetic variability across the genome for association with disease. These studies are now identifying risk loci for common neurological disease, which I will discuss. I will also discuss how high throughput sequencing strategies will impact on the dissection of the genetic aetiologies of these diseases Hardy and Singleton, N Engl J Med 2009, 360: 1759).
IN45 – Epilepsy 3 IN45-WE-01 The value of “new” versus standard drugs in epilepsy A.G. Marson. Neurological Science, University of Liverpool, Liverpool, United Kingdom Epilepsy is a chronic condition, often requiring years of antiepileptic drug (AED). Evidence regarding the value of new and standard AEDs will come from long term randomized controlled trials (RCTs) where new and standard AEDs are compared head to head. The outcomes measured to assess value should includes measures of effectiveness (efficacy, adverse effects and trade-offs between the two), quality of life, heath economic outcomes. New AEDs are most commonly used as add-on treatments and have been licensed for this use based on short term placebo controlled trials. There is some evidence that the new AEDs, when used as add-on treatments, have brought about long term improvement in seizure control and fewer adverse effects for people with epilepsy.