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Mitochondrial encephalopathies in epilepsy: A case series
904
Abstracts
18 FGF-21 secretion and ketogenic enzyme expression are hallmarks of chronic energy deficiency in human skeletal muscles depleted of iron sulfur clusters Presenter: Daniel R. Crooks Daniel R. Crooksa,b, Thanemozhi G. Natarajana, Chuming Chenc, Hongzhan Huangc, Manik C. Ghoshb, Wing-Hang Tongb, Ronald G. Hallerd, Cathy Wua,c, Tracey A. Rouaultb a Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, United States b Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, United States c Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE 19711, United States d Department of Neurology, University of Texas Southwestern Medical Center and VA North Texas Medical Center, and Neuromuscular Center, Institute for Exercise and Environmental Medicine, Dallas, TX 75231, United States Abstract: Iron-sulfur (Fe-S) clusters are ancient enzyme cofactors found in all forms of life. We evaluated the physiological effects of chronic Fe-S cluster deficiency in human skeletal muscle, a tissue that relies heavily on Fe-S cluster-mediated aerobic energy metabolism. Despite their greatly-decreased oxygen consumption, muscle biopsies from mitochondrial myopathy patients deficient in the Fe-S scaffold protein ISCU showed a greater proportion of type I oxidative muscle fibers and increased capillary abundance, accompanied by gene expression indicative of enhanced fatty acid uptake and oxidation. These Fe-S cluster-deficient tissues showed a dramatic up-regulation of the ketogenic enzyme HMGCS2 and the starvation response hormone FGF-21, which were associated with activation of the transcriptional coactivator PGC-1α. Enhanced muscle FGF-21 expression was mirrored by elevated circulating FGF-21 levels in the patients, and FGF-21 secretion could be recapitulated by respiratory chain inhibition in normal cultured myotubes. Our findings reveal a coordinated mitochondrial energy starvation response in Fe-S-deficient skeletal muscle that can be observed systemically by measuring plasma FGF-21 levels. Our data also suggest that measurement of changes in plasma FGF-21 levels may constitute a new and non-invasive method of evaluating the efficacy of new experimental therapies for ISCU myopathy as well as other mitochondrial myopathies. doi:10.1016/j.mito.2013.07.018
21 Mitochondrial encephalopathies in epilepsy: A case series Presenter: Amy C. Goldstein Amy C. Goldsteina, Miya Asatoa,b, Lalit Bansala, Jodie Ventoa, Giulio Zuccolic a Department of Pediatrics, Division of Child Neurology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, Unites States b Department of Psychiatry, UPMC, Pittsburgh, PA, Unites States c Department of Radiology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, Unites States Mitochondrial disorders are a group of genetically and clinically heterogeneous multi-systemic disorders. The unifying feature of mitochondrial disorders is a failure of energy production in the form of adenosine triphosphate (ATP) through defects in the electron transport chain involving oxidative phosphorylation. Epilepsy is a common feature of mitochondrial disease, especially when it presents with epilepsia partialis continua, myoclonic epilepsy, or explosive in onset. Important forms of mitochondrial disease relevant in epilepsy include mutations in the polymerase gamma gene (POLG), respiratory chain deficiencies such
as NADH dehydrogenase (NADH-CoQ reductase) deficiency, and mitochondrial DNA point mutations. This case series presents 4 patients with epilepsy presenting in childhood and early adulthood with clinical correlation using electroencephalogram (EEG) and neuroradiological studies who were later found to have underlying mitochondrial disease. The various clinical findings illustrate the heterogenous presentation of mitochondrial disease and review the appropriate workup and multidisciplinary approach to these patients. Patient 1: 16 year old girl with initial symptoms of irritability, memory deficits and insomnia; within 4 months developed epilepsy correlated to stroke-like lesions on MRI (MELAS-like); subsequently found to have secondary cerebral folate deficiency; doing well on folinic acid and Lamictal; evaluation found POLG mutations W748S + p. A467T. Patient 2: 10 year old girl with history of developmental delays, learning disability, attention-deficit disorder; EEG revealed atypical absence epilepsy; intractable to all medications including celontin, clobazam, rufinimide, VNS, and ketogenic diet; muscle biopsy revealed complex I deficiency; MRI shows mild global cerebral atrophy. Patient 3: 17 year old male presented with life-long history of severe learning disability and behavioral issues, sensorineural hearing loss, short stature; developed acute onset epilepsia partialis continua related to stroke-like episodes seen on MRI; his mother has diabetes, deafness, and migraines; found to have MELAS A3243G. Patient 4: 9 month old girl presented in status epilepticus; has severe hypotonia and global developmental delay; MRI consistent with Leigh syndrome; mtDNA revelaed T8993C mutation. Conclusions: In this small series of patients with mitochondrial disease and epilepsy, epilepsy was not the first symptom, but led to an investigation for the underlying diagnosis. Pattern recognition of multisystemic features such as growth failure, global developmental delay, hypotonia, and sensorineural hearing loss, in a patient with newonset epilepsy, begs for a mitochondrial evaluation. In addition, all of our patients have neuropsychiatric and neurobehavioral manifestations that worsened with the onset of seizure activity due to an epileptic encephalopathy in addition to their mitochondrial encephalopathy. doi:10.1016/j.mito.2013.07.019
22 Mitochondrial etiologies of chronic pseudo-obstruction and dysmotility in children: A 10 year follow-up study Presenter: Amy C. Goldstein Amy Goldsteina, Carolyn Bayb, Ellen Sowryc, Lee-Ann McDonaldc, Maria DelVecchioc, Jodie Ventoa, Sara Shansked, Michio Hiranoe, Carlo DiLorenzof a Division of Child Neurology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States b Department of Genetics, University of Louisville, Louisville, KY, United States c Department of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States d Department of Pathology, Columbia University, New York, NY, United States e Department of Neurology, Columbia University, New York, NY, United States f Department of Gastroenterology, Nationwide Children's Hospital, Columbus, OH, United States Abstract: Intestinal pseudo-obstruction and GI dysmotility are symptoms seen in primary mitochondrial disease, although the etiology remains idiopathic in many children. We hypothesize that genetic analysis of children with pseudo-obstruction and/or GI dysmotility may aid in the determination of the underlying mechanisms of pathogenesis
Abstracts
18 FGF-21 secretion and ketogenic enzyme expression are hallmarks of chronic energy deficiency in human skeletal muscles depleted of iron sulfur clusters Presenter: Daniel R. Crooks Daniel R. Crooksa,b, Thanemozhi G. Natarajana, Chuming Chenc, Hongzhan Huangc, Manik C. Ghoshb, Wing-Hang Tongb, Ronald G. Hallerd, Cathy Wua,c, Tracey A. Rouaultb a Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, United States b Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, United States c Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE 19711, United States d Department of Neurology, University of Texas Southwestern Medical Center and VA North Texas Medical Center, and Neuromuscular Center, Institute for Exercise and Environmental Medicine, Dallas, TX 75231, United States Abstract: Iron-sulfur (Fe-S) clusters are ancient enzyme cofactors found in all forms of life. We evaluated the physiological effects of chronic Fe-S cluster deficiency in human skeletal muscle, a tissue that relies heavily on Fe-S cluster-mediated aerobic energy metabolism. Despite their greatly-decreased oxygen consumption, muscle biopsies from mitochondrial myopathy patients deficient in the Fe-S scaffold protein ISCU showed a greater proportion of type I oxidative muscle fibers and increased capillary abundance, accompanied by gene expression indicative of enhanced fatty acid uptake and oxidation. These Fe-S cluster-deficient tissues showed a dramatic up-regulation of the ketogenic enzyme HMGCS2 and the starvation response hormone FGF-21, which were associated with activation of the transcriptional coactivator PGC-1α. Enhanced muscle FGF-21 expression was mirrored by elevated circulating FGF-21 levels in the patients, and FGF-21 secretion could be recapitulated by respiratory chain inhibition in normal cultured myotubes. Our findings reveal a coordinated mitochondrial energy starvation response in Fe-S-deficient skeletal muscle that can be observed systemically by measuring plasma FGF-21 levels. Our data also suggest that measurement of changes in plasma FGF-21 levels may constitute a new and non-invasive method of evaluating the efficacy of new experimental therapies for ISCU myopathy as well as other mitochondrial myopathies. doi:10.1016/j.mito.2013.07.018
21 Mitochondrial encephalopathies in epilepsy: A case series Presenter: Amy C. Goldstein Amy C. Goldsteina, Miya Asatoa,b, Lalit Bansala, Jodie Ventoa, Giulio Zuccolic a Department of Pediatrics, Division of Child Neurology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, Unites States b Department of Psychiatry, UPMC, Pittsburgh, PA, Unites States c Department of Radiology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, Unites States Mitochondrial disorders are a group of genetically and clinically heterogeneous multi-systemic disorders. The unifying feature of mitochondrial disorders is a failure of energy production in the form of adenosine triphosphate (ATP) through defects in the electron transport chain involving oxidative phosphorylation. Epilepsy is a common feature of mitochondrial disease, especially when it presents with epilepsia partialis continua, myoclonic epilepsy, or explosive in onset. Important forms of mitochondrial disease relevant in epilepsy include mutations in the polymerase gamma gene (POLG), respiratory chain deficiencies such
as NADH dehydrogenase (NADH-CoQ reductase) deficiency, and mitochondrial DNA point mutations. This case series presents 4 patients with epilepsy presenting in childhood and early adulthood with clinical correlation using electroencephalogram (EEG) and neuroradiological studies who were later found to have underlying mitochondrial disease. The various clinical findings illustrate the heterogenous presentation of mitochondrial disease and review the appropriate workup and multidisciplinary approach to these patients. Patient 1: 16 year old girl with initial symptoms of irritability, memory deficits and insomnia; within 4 months developed epilepsy correlated to stroke-like lesions on MRI (MELAS-like); subsequently found to have secondary cerebral folate deficiency; doing well on folinic acid and Lamictal; evaluation found POLG mutations W748S + p. A467T. Patient 2: 10 year old girl with history of developmental delays, learning disability, attention-deficit disorder; EEG revealed atypical absence epilepsy; intractable to all medications including celontin, clobazam, rufinimide, VNS, and ketogenic diet; muscle biopsy revealed complex I deficiency; MRI shows mild global cerebral atrophy. Patient 3: 17 year old male presented with life-long history of severe learning disability and behavioral issues, sensorineural hearing loss, short stature; developed acute onset epilepsia partialis continua related to stroke-like episodes seen on MRI; his mother has diabetes, deafness, and migraines; found to have MELAS A3243G. Patient 4: 9 month old girl presented in status epilepticus; has severe hypotonia and global developmental delay; MRI consistent with Leigh syndrome; mtDNA revelaed T8993C mutation. Conclusions: In this small series of patients with mitochondrial disease and epilepsy, epilepsy was not the first symptom, but led to an investigation for the underlying diagnosis. Pattern recognition of multisystemic features such as growth failure, global developmental delay, hypotonia, and sensorineural hearing loss, in a patient with newonset epilepsy, begs for a mitochondrial evaluation. In addition, all of our patients have neuropsychiatric and neurobehavioral manifestations that worsened with the onset of seizure activity due to an epileptic encephalopathy in addition to their mitochondrial encephalopathy. doi:10.1016/j.mito.2013.07.019
22 Mitochondrial etiologies of chronic pseudo-obstruction and dysmotility in children: A 10 year follow-up study Presenter: Amy C. Goldstein Amy Goldsteina, Carolyn Bayb, Ellen Sowryc, Lee-Ann McDonaldc, Maria DelVecchioc, Jodie Ventoa, Sara Shansked, Michio Hiranoe, Carlo DiLorenzof a Division of Child Neurology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States b Department of Genetics, University of Louisville, Louisville, KY, United States c Department of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States d Department of Pathology, Columbia University, New York, NY, United States e Department of Neurology, Columbia University, New York, NY, United States f Department of Gastroenterology, Nationwide Children's Hospital, Columbus, OH, United States Abstract: Intestinal pseudo-obstruction and GI dysmotility are symptoms seen in primary mitochondrial disease, although the etiology remains idiopathic in many children. We hypothesize that genetic analysis of children with pseudo-obstruction and/or GI dysmotility may aid in the determination of the underlying mechanisms of pathogenesis