- Email: [email protected]
Mitochondrial disease and lipid storage myopathy due to mutation in CHCHD10 or DNM1L and disordered mitochondrial dynamics
Abstracts of the 10th Neuromuscular Translational Research Conference / Neuromuscular Disorder 27S1 (2017) S5–S44
Methods: Transcripts from semi structured interviews are being analysed using procedures from first-generation grounded theory, analytic induction and constructivist grounded theory. Results: This poster focuses on the key finding of how these women make sense of their diagnosis and how this data has enabled us to create an enhanced model of reproductive decision making (Downing, 2005) individual to this unique genetic defect. This work has led to insight into how women are framing their individualised inheritance risk and the factors contributing to decision making, decisions that have been shown to be both fixed and changeable over time. Conclusions: Exploring how these women navigate this complex and emotive issue has provided important data that will assist with implementation of a patient pathway for the first time in the NHS. M13 Mitochondrial disease and lipid storage myopathy due to mutation in CHCHD10 or DNM1L and disordered mitochondrial dynamics C. Fratter1, E. Dombi2, J. Carver2, K. Sergeant1, I.A. Barbosa3, M. Hofer4, M. Esiri4, D. Hilton-Jones5, S. Jayawant6, S. Olpin7, C. Deshpande8, M.A. Simpson3, J. Poulton2 1 Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 2Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK; 3Division of Genetics and Molecular Medicine, King’s College London School of Medicine, London, UK; 4Neuropathology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 5Clinical Neurosciences, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 6Oxford Children’s Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 7Dept Clinical Chemistry, Sheffield Children’s Hospital, Sheffield, UK; 8Clinical Genetics Unit, Guys and St Thomas’ NHS Foundation Trust, London, UK E-mail: [email protected] Background: Lipid storage myopathy (LSM) is characterized by prominent lipid accumulation in muscle fibres. Some patients with LSM also have mitochondrial respiratory chain dysfunction and vice versa. While the molecular cause is only established in a minority, whole exome sequencing is solving an increasing number of cases. Aim: To identify and characterise the molecular cause in two patients with evidence of mitochondrial disease and LSM. Patients and Methods: Patient 1 presented aged 6 with delayed motor milestones, went on to have a heart transplant for severe dilated cardiomyopathy, and died aged 20. Patient 2 presented with focal status during a febrile illness aged 3, and now, aged 5, has ptosis, right hemiparesis and raised lactate. In both patients, muscle histology and biochemistry showed evidence of LSM and mitochondrial disease. Whole exome sequencing was undertaken, followed by genetic analysis of family members. Secondary mitochondrial DNA (mtDNA) changes were analysed in muscle DNA. Mitochondrial dynamics and mitophagy were assessed in patient fibroblasts. Results: Patient 1 was found to have a pathogenic CHCHD10 mutation, which segregated with LSM and cardiomyopathy in his mother and brother. CHCHD10 is required for the integrity of mitochondrial cristal junctions. Low level multiple mtDNA deletions were detected in muscle DNA. Analysis of fibroblasts showed that mitophagic flux was increased. Patient 2 was found to have a novel mutation in DNM1L, which was shown to have arisen de novo. DNM1L is required for mitochondrial and peroxisomal fission. Analysis of muscle DNA indicated borderline low mtDNA copy number. Fibroblasts from Patient 2 had both increased mitochondrial length and increased mitophagic flux. Conclusions: Whole exome sequencing identified the genetic cause in two patients with mitochondrial disease and LSM (mutation in CHCHD10 or DNM1L). Disordered mitochondrial dynamics was demonstrated in both cases. LSM can be a major feature in disorders of mitochondrial dynamics.
S21
M14 A national cohort study of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) – implications to clinical practice and therapeutic study Y.S. Ng1, A.M. Schaefer1, J. Hall2, M.E. Farrugia3, M.E. Roberts4, T. Baird3, C. Hirst5, R.W. Taylor1, D.M. Turnbull1, R. McFarland1, G.S. Gorman1 1 Wellcome Trust Centre for Mitochondrial Research, Newcastle upon Tyne, UK; 2Department of Neuroradiology, Royal Victoria Infirmary, Newcastle upon Tyne, UK; 3Institute of Neurological Sciences Queen Elizabeth University Hospital, Glasgow, UK; 4The Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford, UK; 5Department of Neurology, Abertawe Bro Morgannwg University Health Board, Wales, UK E-mail: [email protected] Background: Mitochondrial diseases are a group of genetic disorders that give rise to a wide spectrum of clinical symptoms. They are typically characterised by multi-system involvement, often affecting organs with high energy demand and frequently relentlessly progressive with high morbidity and mortality. A discrete group of individuals experience repeated stroke-like episodes and progressive encephalopathy (MELAS – Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), that are associated with significant patient and societal health burdens. Currently, longitudinal study of a large cohort of patients with different genotypes presenting with MELAS is lacking. Aims: To study the natural history of patients with mitochondrial disease presenting with stroke-like episodes. Methods: Patients were identified from the MRC Mitochondrial Disease Patient Cohort and the NHS Highly Specialised Service for Rare Mitochondrial Disorders in Newcastle (2000–2016). Clinical, radiological, electrophysiological, laboratory, molecular and histological data were evaluated. Results: Seventy three patients (36 men) presenting with stroke-like episodes were identified. The most common genetic mutation was the m.3243A>G mutation (68%), followed by recessive POLG mutations (19%) and other mtDNA point mutations (13%). The median age of first stroke-like episode was significantly lower in recessive POLG mutations, compared to the primary mitochondrial DNA point mutations (19 vs 33 years, p=0.006). The interval between stroke-like episodes was variable. Visual phenomena including occipital seizure and visual field deficit, and/or focal motor seizure were frequently observed. Occipital, parietal and temporal lobes had a predisposition to the formation of acute stroke-like lesions. However, global cerebral and cerebellar atrophy were evident on serial imaging. Conclusions: Our findings from a large cohort of genetically defined patients with MELAS provided an unrivalled framework to further interrogate the pathophysiology of stroke-like episodes and neurodegeneration. ‡M15 A two part, multi-centre, multiple dose study of Erythrocyte Encapsulated Thymidine Phosphorylase (EETP) in patients with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) N. Nirmalananthan1, M. Levene2, M. Filosto3,*, T. Klopstock4,*, C. Kornblum5,*, H. Mandel6,*, S. Rahman7,*, A. Roubertie8,*, M. Scarpelli3,*, Orphan Technologies Ltd9, B.E. Bax2 1 St Georges University Hospitals NHS Foundation Trust, London, UK; 2St George’s University of London, UK; 3University Hospital “Spedali Civili”, Brescia, Italy; 4University of Munich, Munich Germany; 5University of Bonn, Bonn, Germany; 6Galilee Medical Center, Nahariya, Israel; 7University College London, London, UK; 8Centre Hospitalier Universitaire de Montpellier, Montpellier, France; 9Rapperswil, Switzerland *Equal contributors E-mail: [email protected] Background: MNGIE is a fatal inherited disease caused by mutations in the gene encoding thymidine phosphorylase, leading to reduced enzyme activity, systemic toxic accumulation of nucleosides and secondary mitochondrial DNA damage. Enzyme replacement with EETP has demonstrated metabolic and clinical improvements in MNGIE in our compassionate treatment programme. Aims: To determine the long-term safety, tolerability, pharmacodynamics and clinical efficacy of repeated doses of EETP in patients with MNGIE.
Methods: Transcripts from semi structured interviews are being analysed using procedures from first-generation grounded theory, analytic induction and constructivist grounded theory. Results: This poster focuses on the key finding of how these women make sense of their diagnosis and how this data has enabled us to create an enhanced model of reproductive decision making (Downing, 2005) individual to this unique genetic defect. This work has led to insight into how women are framing their individualised inheritance risk and the factors contributing to decision making, decisions that have been shown to be both fixed and changeable over time. Conclusions: Exploring how these women navigate this complex and emotive issue has provided important data that will assist with implementation of a patient pathway for the first time in the NHS. M13 Mitochondrial disease and lipid storage myopathy due to mutation in CHCHD10 or DNM1L and disordered mitochondrial dynamics C. Fratter1, E. Dombi2, J. Carver2, K. Sergeant1, I.A. Barbosa3, M. Hofer4, M. Esiri4, D. Hilton-Jones5, S. Jayawant6, S. Olpin7, C. Deshpande8, M.A. Simpson3, J. Poulton2 1 Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 2Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK; 3Division of Genetics and Molecular Medicine, King’s College London School of Medicine, London, UK; 4Neuropathology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 5Clinical Neurosciences, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 6Oxford Children’s Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 7Dept Clinical Chemistry, Sheffield Children’s Hospital, Sheffield, UK; 8Clinical Genetics Unit, Guys and St Thomas’ NHS Foundation Trust, London, UK E-mail: [email protected] Background: Lipid storage myopathy (LSM) is characterized by prominent lipid accumulation in muscle fibres. Some patients with LSM also have mitochondrial respiratory chain dysfunction and vice versa. While the molecular cause is only established in a minority, whole exome sequencing is solving an increasing number of cases. Aim: To identify and characterise the molecular cause in two patients with evidence of mitochondrial disease and LSM. Patients and Methods: Patient 1 presented aged 6 with delayed motor milestones, went on to have a heart transplant for severe dilated cardiomyopathy, and died aged 20. Patient 2 presented with focal status during a febrile illness aged 3, and now, aged 5, has ptosis, right hemiparesis and raised lactate. In both patients, muscle histology and biochemistry showed evidence of LSM and mitochondrial disease. Whole exome sequencing was undertaken, followed by genetic analysis of family members. Secondary mitochondrial DNA (mtDNA) changes were analysed in muscle DNA. Mitochondrial dynamics and mitophagy were assessed in patient fibroblasts. Results: Patient 1 was found to have a pathogenic CHCHD10 mutation, which segregated with LSM and cardiomyopathy in his mother and brother. CHCHD10 is required for the integrity of mitochondrial cristal junctions. Low level multiple mtDNA deletions were detected in muscle DNA. Analysis of fibroblasts showed that mitophagic flux was increased. Patient 2 was found to have a novel mutation in DNM1L, which was shown to have arisen de novo. DNM1L is required for mitochondrial and peroxisomal fission. Analysis of muscle DNA indicated borderline low mtDNA copy number. Fibroblasts from Patient 2 had both increased mitochondrial length and increased mitophagic flux. Conclusions: Whole exome sequencing identified the genetic cause in two patients with mitochondrial disease and LSM (mutation in CHCHD10 or DNM1L). Disordered mitochondrial dynamics was demonstrated in both cases. LSM can be a major feature in disorders of mitochondrial dynamics.
S21
M14 A national cohort study of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) – implications to clinical practice and therapeutic study Y.S. Ng1, A.M. Schaefer1, J. Hall2, M.E. Farrugia3, M.E. Roberts4, T. Baird3, C. Hirst5, R.W. Taylor1, D.M. Turnbull1, R. McFarland1, G.S. Gorman1 1 Wellcome Trust Centre for Mitochondrial Research, Newcastle upon Tyne, UK; 2Department of Neuroradiology, Royal Victoria Infirmary, Newcastle upon Tyne, UK; 3Institute of Neurological Sciences Queen Elizabeth University Hospital, Glasgow, UK; 4The Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford, UK; 5Department of Neurology, Abertawe Bro Morgannwg University Health Board, Wales, UK E-mail: [email protected] Background: Mitochondrial diseases are a group of genetic disorders that give rise to a wide spectrum of clinical symptoms. They are typically characterised by multi-system involvement, often affecting organs with high energy demand and frequently relentlessly progressive with high morbidity and mortality. A discrete group of individuals experience repeated stroke-like episodes and progressive encephalopathy (MELAS – Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), that are associated with significant patient and societal health burdens. Currently, longitudinal study of a large cohort of patients with different genotypes presenting with MELAS is lacking. Aims: To study the natural history of patients with mitochondrial disease presenting with stroke-like episodes. Methods: Patients were identified from the MRC Mitochondrial Disease Patient Cohort and the NHS Highly Specialised Service for Rare Mitochondrial Disorders in Newcastle (2000–2016). Clinical, radiological, electrophysiological, laboratory, molecular and histological data were evaluated. Results: Seventy three patients (36 men) presenting with stroke-like episodes were identified. The most common genetic mutation was the m.3243A>G mutation (68%), followed by recessive POLG mutations (19%) and other mtDNA point mutations (13%). The median age of first stroke-like episode was significantly lower in recessive POLG mutations, compared to the primary mitochondrial DNA point mutations (19 vs 33 years, p=0.006). The interval between stroke-like episodes was variable. Visual phenomena including occipital seizure and visual field deficit, and/or focal motor seizure were frequently observed. Occipital, parietal and temporal lobes had a predisposition to the formation of acute stroke-like lesions. However, global cerebral and cerebellar atrophy were evident on serial imaging. Conclusions: Our findings from a large cohort of genetically defined patients with MELAS provided an unrivalled framework to further interrogate the pathophysiology of stroke-like episodes and neurodegeneration. ‡M15 A two part, multi-centre, multiple dose study of Erythrocyte Encapsulated Thymidine Phosphorylase (EETP) in patients with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) N. Nirmalananthan1, M. Levene2, M. Filosto3,*, T. Klopstock4,*, C. Kornblum5,*, H. Mandel6,*, S. Rahman7,*, A. Roubertie8,*, M. Scarpelli3,*, Orphan Technologies Ltd9, B.E. Bax2 1 St Georges University Hospitals NHS Foundation Trust, London, UK; 2St George’s University of London, UK; 3University Hospital “Spedali Civili”, Brescia, Italy; 4University of Munich, Munich Germany; 5University of Bonn, Bonn, Germany; 6Galilee Medical Center, Nahariya, Israel; 7University College London, London, UK; 8Centre Hospitalier Universitaire de Montpellier, Montpellier, France; 9Rapperswil, Switzerland *Equal contributors E-mail: [email protected] Background: MNGIE is a fatal inherited disease caused by mutations in the gene encoding thymidine phosphorylase, leading to reduced enzyme activity, systemic toxic accumulation of nucleosides and secondary mitochondrial DNA damage. Enzyme replacement with EETP has demonstrated metabolic and clinical improvements in MNGIE in our compassionate treatment programme. Aims: To determine the long-term safety, tolerability, pharmacodynamics and clinical efficacy of repeated doses of EETP in patients with MNGIE.