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Genome editing to treat mitochondrial DNA disorders
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Abstracts / Journal of the Neurological Sciences 357 (2015) e457–e512
1733 WFN15-1945 Neurosurgery for Neurologists T 24.1 Strategies on the treatment of intracranial arteriovenous malformations Y. Tu. Neurosurgery, World Federation of Neurosurgical Societies, Taipei, Taiwan Surgical treatment of intracranial arteriovenous malformation (AVM) is one of the most difficult tasks for neurosurgeons, especially, for patients with large size AVM or AVM at the eloquent and deep location. Recent advent of endovascular treatment and radiosurgery may replace the role of surgery and decrease the difficulty of treatment of AVM to some extend but not all. Surgical excision with or without preoperative embolization remains the main modality of treatment of intracranial AVMs. However, the procedure of embolization itself also carries certain percentage of risk. Selection of this treatment modality needs to be carefully evluated. For small deep seated AVM and small AVM at the eloquent area, radiosurgery is another therapeutic option. However, the efficacy to achieve obliteration of the AVM by radiosurgery is only 60%-70% in general. Combined embolization and radiosurgery has been advocated as an option for treating large complex AVM. However, current treatment results failed to demonstrate any superiority of the result from this combined treatment. Palliative treatment with partial obliteration of the AVM nidus to reduce arteriovenous shunting is considered to be useful for the decrease of the occurrence of steal phenomenon, however, it may also increase shear stress of the abnormal vascular architecture and resulted in increase rate of hemorrhage. From 1989 to 2011, a total of 367 patients with cerebral AVM were treated at the National Taiwan University Hospital and its’ affiliate hospitals. Of these 367 patients, 143 patients underwent microsurgery as the solo treatment and 214 patients received embolization. In the later group, 25 patients had their AVMs cured after one or multiple sessions of endovascular treatment. The other 189 patients in this group, endovascular treatment can only be applied for the reduction of the flow and the size of the AVM. These patients finally underwent microsurgery as the definite treatment. The treatment morbidity was 11% in microsurgical group and 9% in endovascular group. There were 2 mortalities in surgical group (o.6 %) and 2 in endovascular group (0.9 %). Our current selection criteria for different therapeutic modality and surgical strategy for intracranial AVM will be discussed.
prevalence of CTE in modern era sports is unknown. Although, CTE represents a distinct neuropathological entity, the causation has yet to be clearly established. Exposure to repetitive mild TBI has been associated with CTE and is speculated to be an important risk factor for CTE. The genetic risk factors for CTE have yet to be determined but apolipoprotein E ε4 (APOE ε4) may be an effect modifier of the condition. CTE can present with cognitive, behavioral and/or motorical symptomatology. Traditional structural neuroimaging reveals nonspecific findings such as cavum septum pellucidum (CSP), diffuse atrophy, and ventricular dilatation. Reduced fractional anisotropy (FA) on diffusion tensor imaging (DTI) reflective of decreased white matter integrity can be observed in individuals exposed to repetitive head trauma. Although, molecular neuroimaging may provide assistance in establishing the antemortem diagnosis of CTE, currently the diagnosis can only be definitively ascertained at postmortem. doi:10.1016/j.jns.2015.09.308
1735 WFN15-1671 Sports Neurology T 5.1 Peripheral nerve injuries M. Hallett. Human Motor Control Section, NINDS, Bethesda, USA Peripheral nerve can be damaged in sports by direct trauma or entrapment and microtrauma over time. It is the latter that will be the focus of this lecture. The ulnar nerve can be damaged at the medial side of the elbow in the throwing motion. This is due to valgus strain of the elbow and damage to the soft tissues near the ulnar nerve. Common in baseball pitchers, this injury is also seen in football, javelin, volleyball and tennis. The lateral side of the elbow is the site of tennis elbow and is most commonly epicondylitis, but there can be an entrapment of the posterior interosseous nerve. Particularly in volleyball, there can be an entrapment of the infraspinatus branch of the suprascapular nerve at the spinoglenoid notch of the scapula. In bicycling the ulnar nerve may be damaged at the wrist and the pudendal nerve can be compressed by the bicycle seat. In joggers, if there is heel pain other than plantar fasciitis, it can be due to entrapment of the tibial nerve in the tarsal tunnel syndrome, or entrapment of its branches, the medial calcaneal branch or the first branch of the lateral plantar nerve. Pain on the medial side of the foot may be due to entrapment of the medial plantar nerve. doi:10.1016/j.jns.2015.09.309
doi:10.1016/j.jns.2015.09.307
1734 WFN15-1943 Sports Neurology T 5.1 Chronic traumatic encephalopathy B. Jordan. Neurology, Burke Rehabilitation Hospital, White Plains, USA Chronic traumatic brain injury (CTBI) represents a spectrum of disorders associated with long term consequences single or repetitive traumatic brain injury (TBI). Although, the prototypic CTBI is chronic traumatic encephalopathy (CTE), other chronic brain injuries can be encountered. These include chronic neurocognitive impairment (CNI), chronic postconcussion syndrome (CPCS) and posttraumatic dementia (PTD). CTE represents the long term neurological consequences of repetitive concussive and/or subconcussive blows, presumably secondary to a progressive tauopathy. Dementia pugilistica represents a subtype of CTE and is typically reserved for cases of severe end-stage dementia secondary to a long boxing career. The exact incidence and
1736 WFN15-1878 Mitochondrial Diseases T 28.1 Nutrition and nutritional signaling as therapy targets for mitochondrial disorders D. Munoz, M. Troncoso, P. Santander. Department of Pediatric Neurology, Hospital Clinico San Borja Arriarán, Santiago, Chile Mitochondrial disorders are degenerative diseases known to be responsible for a number of heterogenous clinical presentations with multi-systemic dysfunctions that often involves the nervous, endocrine, renal and cardiac system. Impaired oxidative phosphorylation leading to a decrease in cellular energy (ATP) production is the most important cause underlying these conditions. Despite significant progress made in the field of mitochondrial medicine during the last two decades, defining the specific biochemical defects and underlying molecular mechanisms, the avaliable information about effective treatment approaches is limited.
Abstracts / Journal of the Neurological Sciences 357 (2015) e457–e512
The goal of nutritional treatment of mitochondrial dysfunction in various neurological syndromes are based primarily in improving the efficiency of the processes of oxidative phosphorylation at the system level. Accumulation of toxic metabolites and reduction of electron transfer activity have prompted the use of new therapeutic agents, such as antioxidants, radical scavangers and cofactors. A literature review of the use of these supplements in mitochondrial disorders is presented. doi:10.1016/j.jns.2015.09.310
1737 WFN15-1901 Mitochondrial Diseases T 28.1 Genome editing to treat mitochondrial DNA disorders M.A. Avaria, K. Kleinsteuber. Pediatric Department Pediatric Neurology Unit, Universidad de Chile Facultad de Medicina Campus Norte, Santiago, Chile It is estimated that mtDNA mutations resulting in diseases affect 1 in 5,000 children, representing the most common neurometabolic disorder of childhood, and that 1 in 200 women could be a mitochondrial disease carrier. Currently, there is no cure for mitochondrial diseases, so great effort has been directed to find genetic treatments that can at least ameliorate symptoms and prevent trans generational transmission. Pre-implantation genetic diagnosis and mitochondrial replacement techniques are currently therapeutic resources, but issues of safety and ethics have been raised. mtDNA is present in multiple copies per cell. Cells with mtDNA mutations are heteroplasmic, containing different proportions of wild and mutant mtDNA. There is a threshold level of percentage of mutated mtDNA that is important for the clinical expression of disease. Threshold levels for biochemical and clinical defects are generally in the range of 60%–95% mutated mtDNA depending on the severity of the mutation. Several strategies for genetic manipulation of mtDNA have been developed based in these characteristics. mtDNA editing to inhibit the replication of mutated mtDNA, expecting cells to replace it with normal mtDNA is the most promising. Experiments in somatic cells containing the mutation for NARP /MILS syndromes, have established restoration of normal mitochondrial function. Recently it has been reported that human mutated mtDNA can be reduced in oocytes by mitochondria-targeted nucleases. A review of key reports on research in this area in scientific literature will be presented. doi:10.1016/j.jns.2015.09.311
1738 WFN15-1719 World Health Organization Neurology Initaitives T 25.1 Latin America's strategic plan for prevention and care of epilepsy C. Acevedo. Chilean League Against Epilepsy, Director Collaborating Center PAHO/WHO Chile, Santiago, Chile • Strategic and plan of action on epilepsy in Latin America is an initiative between International League against Epilepsy (ILAE), International Bureau for Epilepsy (IBE) and Pan American Health Organization (PAHO). • Approved by PAHO Board in September of 2011, for a period between 2012-2021, and signed by Ministries of Health of Americas countries.
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• PAHO, ILAE and IBE-and other partners-will collaborated together to support this plan, and specially work on set priorities, mobilize resources, and encourage the cooperation between countries included in this plan. • To accomplished these purposes the plan required: - Universal access - Countries involved solidarity - Respect for the human rights of people with epilepsy - Social participation - Scientific evidence - Protection to vulnerable groups - Respect for the historical and cultural frameworks of communities - Comprehensive care in health units - Responsibility and accountability • Strategic Areas: 1. Programs and legislation for the care of people with epilepsy and protection of their human rights 2. Health services network for the treatment of people with epilepsy, with emphasis on primary health care and the provision of drugs 3. Education and sensitization of the population, including the people with epilepsy and their families 4. Strengthening of the ability to produce, asses, and use information on epilepsy
This regional initiative in the Americas in unique in the world and has opened up a scenario of cooperation between scientific, social, and governmental world, and PAHO to reduce the huge gap surrounding epilepsy and the stigma associated.
doi:10.1016/j.jns.2015.09.312
1739 WFN15-0077 World Health Organization Neurology Initaitives T 25.1 Africa and WHO: fighting non-communicable diseases A.G. Diop. Department of Neurology, University of Dakar, Senegal In the early 60’s, non-communicable disorders such as diabetes, hypertension, obesity and their consequences (stroke, heart infarction, and cancers) were considered as almost nonexistent in Africa. Neurological conditions such as epilepsy, dementia, Parkinson were seldom reported. Nowadays, Africa is in a situation of developmental and sociocultural transition, characterized by a close coexistence of traditions and modernism. Infectious diseases are still occurring, but non-communicable diseases are increasingly the leading cause of morbidity and mortality. Changes in the life style, diet, and rural exodus of poor population to suburban areas of cities, generate comorbid situations from communicable and non-communicable diseases. In African countries, increasing cases of epilepsy, stroke, dementias, cancers are now diagnosed at any age. African nations and WHO are dealing with a new epidemiological situation in the context of high rates of illiteracy, poverty, but also due to rapid disharmonized urbanization. Usually, the management of these issues is difficult due to the scarcity of specialized health staff, financial and/or unavailability of diagnostic means and major drugs. This led to the set up non-communicable units in the ministries of health, programs and initiatives for tackling such new medical situations. This resulted in the Global Campaign against Epilepsy, and other programs dedicated to diabetes and cancer. There is a need for similar programs for the prevention and management of stroke, pain, dementia and neurodegenerative disorders. All of which are also major, and increasing factors to the public health burden in Africa.
Abstracts / Journal of the Neurological Sciences 357 (2015) e457–e512
1733 WFN15-1945 Neurosurgery for Neurologists T 24.1 Strategies on the treatment of intracranial arteriovenous malformations Y. Tu. Neurosurgery, World Federation of Neurosurgical Societies, Taipei, Taiwan Surgical treatment of intracranial arteriovenous malformation (AVM) is one of the most difficult tasks for neurosurgeons, especially, for patients with large size AVM or AVM at the eloquent and deep location. Recent advent of endovascular treatment and radiosurgery may replace the role of surgery and decrease the difficulty of treatment of AVM to some extend but not all. Surgical excision with or without preoperative embolization remains the main modality of treatment of intracranial AVMs. However, the procedure of embolization itself also carries certain percentage of risk. Selection of this treatment modality needs to be carefully evluated. For small deep seated AVM and small AVM at the eloquent area, radiosurgery is another therapeutic option. However, the efficacy to achieve obliteration of the AVM by radiosurgery is only 60%-70% in general. Combined embolization and radiosurgery has been advocated as an option for treating large complex AVM. However, current treatment results failed to demonstrate any superiority of the result from this combined treatment. Palliative treatment with partial obliteration of the AVM nidus to reduce arteriovenous shunting is considered to be useful for the decrease of the occurrence of steal phenomenon, however, it may also increase shear stress of the abnormal vascular architecture and resulted in increase rate of hemorrhage. From 1989 to 2011, a total of 367 patients with cerebral AVM were treated at the National Taiwan University Hospital and its’ affiliate hospitals. Of these 367 patients, 143 patients underwent microsurgery as the solo treatment and 214 patients received embolization. In the later group, 25 patients had their AVMs cured after one or multiple sessions of endovascular treatment. The other 189 patients in this group, endovascular treatment can only be applied for the reduction of the flow and the size of the AVM. These patients finally underwent microsurgery as the definite treatment. The treatment morbidity was 11% in microsurgical group and 9% in endovascular group. There were 2 mortalities in surgical group (o.6 %) and 2 in endovascular group (0.9 %). Our current selection criteria for different therapeutic modality and surgical strategy for intracranial AVM will be discussed.
prevalence of CTE in modern era sports is unknown. Although, CTE represents a distinct neuropathological entity, the causation has yet to be clearly established. Exposure to repetitive mild TBI has been associated with CTE and is speculated to be an important risk factor for CTE. The genetic risk factors for CTE have yet to be determined but apolipoprotein E ε4 (APOE ε4) may be an effect modifier of the condition. CTE can present with cognitive, behavioral and/or motorical symptomatology. Traditional structural neuroimaging reveals nonspecific findings such as cavum septum pellucidum (CSP), diffuse atrophy, and ventricular dilatation. Reduced fractional anisotropy (FA) on diffusion tensor imaging (DTI) reflective of decreased white matter integrity can be observed in individuals exposed to repetitive head trauma. Although, molecular neuroimaging may provide assistance in establishing the antemortem diagnosis of CTE, currently the diagnosis can only be definitively ascertained at postmortem. doi:10.1016/j.jns.2015.09.308
1735 WFN15-1671 Sports Neurology T 5.1 Peripheral nerve injuries M. Hallett. Human Motor Control Section, NINDS, Bethesda, USA Peripheral nerve can be damaged in sports by direct trauma or entrapment and microtrauma over time. It is the latter that will be the focus of this lecture. The ulnar nerve can be damaged at the medial side of the elbow in the throwing motion. This is due to valgus strain of the elbow and damage to the soft tissues near the ulnar nerve. Common in baseball pitchers, this injury is also seen in football, javelin, volleyball and tennis. The lateral side of the elbow is the site of tennis elbow and is most commonly epicondylitis, but there can be an entrapment of the posterior interosseous nerve. Particularly in volleyball, there can be an entrapment of the infraspinatus branch of the suprascapular nerve at the spinoglenoid notch of the scapula. In bicycling the ulnar nerve may be damaged at the wrist and the pudendal nerve can be compressed by the bicycle seat. In joggers, if there is heel pain other than plantar fasciitis, it can be due to entrapment of the tibial nerve in the tarsal tunnel syndrome, or entrapment of its branches, the medial calcaneal branch or the first branch of the lateral plantar nerve. Pain on the medial side of the foot may be due to entrapment of the medial plantar nerve. doi:10.1016/j.jns.2015.09.309
doi:10.1016/j.jns.2015.09.307
1734 WFN15-1943 Sports Neurology T 5.1 Chronic traumatic encephalopathy B. Jordan. Neurology, Burke Rehabilitation Hospital, White Plains, USA Chronic traumatic brain injury (CTBI) represents a spectrum of disorders associated with long term consequences single or repetitive traumatic brain injury (TBI). Although, the prototypic CTBI is chronic traumatic encephalopathy (CTE), other chronic brain injuries can be encountered. These include chronic neurocognitive impairment (CNI), chronic postconcussion syndrome (CPCS) and posttraumatic dementia (PTD). CTE represents the long term neurological consequences of repetitive concussive and/or subconcussive blows, presumably secondary to a progressive tauopathy. Dementia pugilistica represents a subtype of CTE and is typically reserved for cases of severe end-stage dementia secondary to a long boxing career. The exact incidence and
1736 WFN15-1878 Mitochondrial Diseases T 28.1 Nutrition and nutritional signaling as therapy targets for mitochondrial disorders D. Munoz, M. Troncoso, P. Santander. Department of Pediatric Neurology, Hospital Clinico San Borja Arriarán, Santiago, Chile Mitochondrial disorders are degenerative diseases known to be responsible for a number of heterogenous clinical presentations with multi-systemic dysfunctions that often involves the nervous, endocrine, renal and cardiac system. Impaired oxidative phosphorylation leading to a decrease in cellular energy (ATP) production is the most important cause underlying these conditions. Despite significant progress made in the field of mitochondrial medicine during the last two decades, defining the specific biochemical defects and underlying molecular mechanisms, the avaliable information about effective treatment approaches is limited.
Abstracts / Journal of the Neurological Sciences 357 (2015) e457–e512
The goal of nutritional treatment of mitochondrial dysfunction in various neurological syndromes are based primarily in improving the efficiency of the processes of oxidative phosphorylation at the system level. Accumulation of toxic metabolites and reduction of electron transfer activity have prompted the use of new therapeutic agents, such as antioxidants, radical scavangers and cofactors. A literature review of the use of these supplements in mitochondrial disorders is presented. doi:10.1016/j.jns.2015.09.310
1737 WFN15-1901 Mitochondrial Diseases T 28.1 Genome editing to treat mitochondrial DNA disorders M.A. Avaria, K. Kleinsteuber. Pediatric Department Pediatric Neurology Unit, Universidad de Chile Facultad de Medicina Campus Norte, Santiago, Chile It is estimated that mtDNA mutations resulting in diseases affect 1 in 5,000 children, representing the most common neurometabolic disorder of childhood, and that 1 in 200 women could be a mitochondrial disease carrier. Currently, there is no cure for mitochondrial diseases, so great effort has been directed to find genetic treatments that can at least ameliorate symptoms and prevent trans generational transmission. Pre-implantation genetic diagnosis and mitochondrial replacement techniques are currently therapeutic resources, but issues of safety and ethics have been raised. mtDNA is present in multiple copies per cell. Cells with mtDNA mutations are heteroplasmic, containing different proportions of wild and mutant mtDNA. There is a threshold level of percentage of mutated mtDNA that is important for the clinical expression of disease. Threshold levels for biochemical and clinical defects are generally in the range of 60%–95% mutated mtDNA depending on the severity of the mutation. Several strategies for genetic manipulation of mtDNA have been developed based in these characteristics. mtDNA editing to inhibit the replication of mutated mtDNA, expecting cells to replace it with normal mtDNA is the most promising. Experiments in somatic cells containing the mutation for NARP /MILS syndromes, have established restoration of normal mitochondrial function. Recently it has been reported that human mutated mtDNA can be reduced in oocytes by mitochondria-targeted nucleases. A review of key reports on research in this area in scientific literature will be presented. doi:10.1016/j.jns.2015.09.311
1738 WFN15-1719 World Health Organization Neurology Initaitives T 25.1 Latin America's strategic plan for prevention and care of epilepsy C. Acevedo. Chilean League Against Epilepsy, Director Collaborating Center PAHO/WHO Chile, Santiago, Chile • Strategic and plan of action on epilepsy in Latin America is an initiative between International League against Epilepsy (ILAE), International Bureau for Epilepsy (IBE) and Pan American Health Organization (PAHO). • Approved by PAHO Board in September of 2011, for a period between 2012-2021, and signed by Ministries of Health of Americas countries.
e503
• PAHO, ILAE and IBE-and other partners-will collaborated together to support this plan, and specially work on set priorities, mobilize resources, and encourage the cooperation between countries included in this plan. • To accomplished these purposes the plan required: - Universal access - Countries involved solidarity - Respect for the human rights of people with epilepsy - Social participation - Scientific evidence - Protection to vulnerable groups - Respect for the historical and cultural frameworks of communities - Comprehensive care in health units - Responsibility and accountability • Strategic Areas: 1. Programs and legislation for the care of people with epilepsy and protection of their human rights 2. Health services network for the treatment of people with epilepsy, with emphasis on primary health care and the provision of drugs 3. Education and sensitization of the population, including the people with epilepsy and their families 4. Strengthening of the ability to produce, asses, and use information on epilepsy
This regional initiative in the Americas in unique in the world and has opened up a scenario of cooperation between scientific, social, and governmental world, and PAHO to reduce the huge gap surrounding epilepsy and the stigma associated.
doi:10.1016/j.jns.2015.09.312
1739 WFN15-0077 World Health Organization Neurology Initaitives T 25.1 Africa and WHO: fighting non-communicable diseases A.G. Diop. Department of Neurology, University of Dakar, Senegal In the early 60’s, non-communicable disorders such as diabetes, hypertension, obesity and their consequences (stroke, heart infarction, and cancers) were considered as almost nonexistent in Africa. Neurological conditions such as epilepsy, dementia, Parkinson were seldom reported. Nowadays, Africa is in a situation of developmental and sociocultural transition, characterized by a close coexistence of traditions and modernism. Infectious diseases are still occurring, but non-communicable diseases are increasingly the leading cause of morbidity and mortality. Changes in the life style, diet, and rural exodus of poor population to suburban areas of cities, generate comorbid situations from communicable and non-communicable diseases. In African countries, increasing cases of epilepsy, stroke, dementias, cancers are now diagnosed at any age. African nations and WHO are dealing with a new epidemiological situation in the context of high rates of illiteracy, poverty, but also due to rapid disharmonized urbanization. Usually, the management of these issues is difficult due to the scarcity of specialized health staff, financial and/or unavailability of diagnostic means and major drugs. This led to the set up non-communicable units in the ministries of health, programs and initiatives for tackling such new medical situations. This resulted in the Global Campaign against Epilepsy, and other programs dedicated to diabetes and cancer. There is a need for similar programs for the prevention and management of stroke, pain, dementia and neurodegenerative disorders. All of which are also major, and increasing factors to the public health burden in Africa.