Malate dehydrogenase 2 deficiency is an emerging cause of pediatric epileptic encephalopathy with a recognizable biochemical signature
Malate dehydrogenases (MDH) serve a critical role in maintaining equilibrium of the NAD+/NADH ratio between the mitochondria and cytosol through the catalysis of the oxidation of L-malate to oxaloacetate in a reversible, NADH-dependent manner. MDH2 encodes the mitochondrial isoform, which is integra...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-12-01
|
| Series: | Molecular Genetics and Metabolism Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221442692200091X |
| _version_ | 1811187749923848192 |
|---|---|
| author | Jessica R.C. Priestley Lisa M. Pace Kuntal Sen Anjali Aggarwal Cesar Augusto P.F. Alves Ian M. Campbell Sanmati R. Cuddapah Nicole M. Engelhardt Marina Eskandar Paloma C. Jolín García Andrea Gropman Ingo Helbig Xinying Hong Vykuntaraju K. Gowda Laina Lusk Pamela Trapane Varunvenkat M. Srinivasan Pim Suwannarat Rebecca D. Ganetzky |
| author_facet | Jessica R.C. Priestley Lisa M. Pace Kuntal Sen Anjali Aggarwal Cesar Augusto P.F. Alves Ian M. Campbell Sanmati R. Cuddapah Nicole M. Engelhardt Marina Eskandar Paloma C. Jolín García Andrea Gropman Ingo Helbig Xinying Hong Vykuntaraju K. Gowda Laina Lusk Pamela Trapane Varunvenkat M. Srinivasan Pim Suwannarat Rebecca D. Ganetzky |
| author_sort | Jessica R.C. Priestley |
| collection | DOAJ |
| description | Malate dehydrogenases (MDH) serve a critical role in maintaining equilibrium of the NAD+/NADH ratio between the mitochondria and cytosol through the catalysis of the oxidation of L-malate to oxaloacetate in a reversible, NADH-dependent manner. MDH2 encodes the mitochondrial isoform, which is integral to the tricarboxylic acid cycle and thus energy homeostasis. Recently, five patients harboring compound heterozygous MDH2 variants have been described, three with early-onset epileptic encephalopathy, one with a stroke-like episode, and one with dilated cardiomyopathy. Here, we describe an additional seven patients with biallelic variants in MDH2, the largest and most neurodevelopmentally and ethnically diverse cohort to-date, including homozygous variants, a sibling pair, non-European patients, and an adult. From these patients, we learn that MDH2 deficiency results in a biochemical signature including elevations of plasma lactate and the lactate:pyruvate ratio with urinary excretion of malate. It also results in a recognizable constellation of neuroimaging findings of anterior-predominant cerebral atrophy, subependymal cysts with ventricular septations. We also recognize MDH2 deficiency as a cause of Leigh syndrome. Taken with existing patient reports, we conclude that MDH2 deficiency is an emerging and likely under-recognized cause of infantile epileptic encephalopathy and provide a framework for medical evaluation of patients identified with biallelic MDH2 variants. |
| first_indexed | 2024-04-11T14:07:39Z |
| format | Article |
| id | doaj.art-0c442fea3131425d94111374d304a8a9 |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-04-11T14:07:39Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-0c442fea3131425d94111374d304a8a92022-12-22T04:19:49ZengElsevierMolecular Genetics and Metabolism Reports2214-42692022-12-0133100931Malate dehydrogenase 2 deficiency is an emerging cause of pediatric epileptic encephalopathy with a recognizable biochemical signatureJessica R.C. Priestley0Lisa M. Pace1Kuntal Sen2Anjali Aggarwal3Cesar Augusto P.F. Alves4Ian M. Campbell5Sanmati R. Cuddapah6Nicole M. Engelhardt7Marina Eskandar8Paloma C. Jolín García9Andrea Gropman10Ingo Helbig11Xinying Hong12Vykuntaraju K. Gowda13Laina Lusk14Pamela Trapane15Varunvenkat M. Srinivasan16Pim Suwannarat17Rebecca D. Ganetzky18Section of Biochemical Genetics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USADepartment of Pediatrics, University of Florida College of Medicine, Jacksonville, FL, USADivision of Neurogenetics and Neurodevelopmental Pediatrics, Children's National Hospital, Washington D.C., USADivision of Genetics and Metabolism, University of Minnesota, Minneapolis, MN, USADivision of Neuroradiology, Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, USADivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USASection of Biochemical Genetics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USASection of Biochemical Genetics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Mitochondrial Medicine, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USADivision of Child Neurology, Children's National Hospital, Washington D.C., USASection of Biochemical Genetics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USADivision of Neurogenetics and Neurodevelopmental Pediatrics, Children's National Hospital, Washington D.C., USADivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Epilepsy Neurogenetics Initiative, Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USADepartment of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USADepartment of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, IndiaEpilepsy Neurogenetics Initiative, Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USADivision of Pediatric Genetics, Department of Genetics, University of Florida College of Medicine, Jacksonville, FL, USA; UF Health Precision Medicine Program, University of Florida Health System, Jacksonville, FL, USADepartment of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, IndiaGenetics, Kaiser Permanente MidAtlantic, Rockville, MD, USASection of Biochemical Genetics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Mitochondrial Medicine, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Corresponding author at: Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.Malate dehydrogenases (MDH) serve a critical role in maintaining equilibrium of the NAD+/NADH ratio between the mitochondria and cytosol through the catalysis of the oxidation of L-malate to oxaloacetate in a reversible, NADH-dependent manner. MDH2 encodes the mitochondrial isoform, which is integral to the tricarboxylic acid cycle and thus energy homeostasis. Recently, five patients harboring compound heterozygous MDH2 variants have been described, three with early-onset epileptic encephalopathy, one with a stroke-like episode, and one with dilated cardiomyopathy. Here, we describe an additional seven patients with biallelic variants in MDH2, the largest and most neurodevelopmentally and ethnically diverse cohort to-date, including homozygous variants, a sibling pair, non-European patients, and an adult. From these patients, we learn that MDH2 deficiency results in a biochemical signature including elevations of plasma lactate and the lactate:pyruvate ratio with urinary excretion of malate. It also results in a recognizable constellation of neuroimaging findings of anterior-predominant cerebral atrophy, subependymal cysts with ventricular septations. We also recognize MDH2 deficiency as a cause of Leigh syndrome. Taken with existing patient reports, we conclude that MDH2 deficiency is an emerging and likely under-recognized cause of infantile epileptic encephalopathy and provide a framework for medical evaluation of patients identified with biallelic MDH2 variants.http://www.sciencedirect.com/science/article/pii/S221442692200091XMalate dehydrogenaseMDH2Mitochondrial malate dehydrogenaseTCA cycleEpileptic encephalopathyLeigh syndrome |
| spellingShingle | Jessica R.C. Priestley Lisa M. Pace Kuntal Sen Anjali Aggarwal Cesar Augusto P.F. Alves Ian M. Campbell Sanmati R. Cuddapah Nicole M. Engelhardt Marina Eskandar Paloma C. Jolín García Andrea Gropman Ingo Helbig Xinying Hong Vykuntaraju K. Gowda Laina Lusk Pamela Trapane Varunvenkat M. Srinivasan Pim Suwannarat Rebecca D. Ganetzky Malate dehydrogenase 2 deficiency is an emerging cause of pediatric epileptic encephalopathy with a recognizable biochemical signature Molecular Genetics and Metabolism Reports Malate dehydrogenase MDH2 Mitochondrial malate dehydrogenase TCA cycle Epileptic encephalopathy Leigh syndrome |
| title | Malate dehydrogenase 2 deficiency is an emerging cause of pediatric epileptic encephalopathy with a recognizable biochemical signature |
| title_full | Malate dehydrogenase 2 deficiency is an emerging cause of pediatric epileptic encephalopathy with a recognizable biochemical signature |
| title_fullStr | Malate dehydrogenase 2 deficiency is an emerging cause of pediatric epileptic encephalopathy with a recognizable biochemical signature |
| title_full_unstemmed | Malate dehydrogenase 2 deficiency is an emerging cause of pediatric epileptic encephalopathy with a recognizable biochemical signature |
| title_short | Malate dehydrogenase 2 deficiency is an emerging cause of pediatric epileptic encephalopathy with a recognizable biochemical signature |
| title_sort | malate dehydrogenase 2 deficiency is an emerging cause of pediatric epileptic encephalopathy with a recognizable biochemical signature |
| topic | Malate dehydrogenase MDH2 Mitochondrial malate dehydrogenase TCA cycle Epileptic encephalopathy Leigh syndrome |
| url | http://www.sciencedirect.com/science/article/pii/S221442692200091X |
| work_keys_str_mv | AT jessicarcpriestley malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT lisampace malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT kuntalsen malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT anjaliaggarwal malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT cesaraugustopfalves malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT ianmcampbell malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT sanmatircuddapah malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT nicolemengelhardt malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT marinaeskandar malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT palomacjolingarcia malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT andreagropman malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT ingohelbig malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT xinyinghong malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT vykuntarajukgowda malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT lainalusk malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT pamelatrapane malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT varunvenkatmsrinivasan malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT pimsuwannarat malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature AT rebeccadganetzky malatedehydrogenase2deficiencyisanemergingcauseofpediatricepilepticencephalopathywitharecognizablebiochemicalsignature |