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Kalkan Uçar S, Yazıcı H, Canda E, Er E, Bulut FD, Eraslan C, Onay H, Bax BE, Çoker M. Clinical spectrum of early onset "Mediterranean" (homozygous p.P131L mutation) mitochondrial neurogastrointestinal encephalomyopathy. JIMD Rep 2022; 63:484-493. [PMID: 36101829 PMCID: PMC9458607 DOI: 10.1002/jmd2.12315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/17/2022] [Accepted: 06/23/2022] [Indexed: 11/25/2022] Open
Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive mitochondrial disorder characterized by cumulative and progressive gastrointestinal and neurological findings. This retrospective observational study, aimed to explore the time of presentation, diagnosis and clinical follow-up of 13 patients with a confirmed MNGIE disease of Mediterranean origin. The mean age of symptom onset was 7 years (6 months-21 years) and the average diagnosis age was 15.4 years ±8.4. Four of 13 patients (30%) died before 30 years at the mean age of 19.7 years ±6.8. Cachexia and gastrointestinal symptoms were observed in all patients (100%). The mean body mass index standard deviation score at diagnosis was 4.8 ± 2.8. At least three subocclusive episodes were presented in patients who died in last year of their life. The main neurological symptom found in most patients was peripheral neuropathy (92%). Ten patients (77%) had leukoencephalopathy and the remaining three patients without were under 10 years of age. The new homozygous "Mediterranean" TYMP mutation, p.P131L (c.392 C > T) was associated with an early presentation and poor prognosis in nine patients (69%) from five separates families. Based on the observations from this Mediterranean MNGIE cohort, we propose that the unexplained abdominal pain combined with cachexia is an indicator of MNGIE. High-platelet counts and nerve conduction studies may be supportive laboratory findings and the frequent subocclusive episodes could be a negative prognostic factor for mortality. Finally, the homozygous p.P131L (c.392 C > T) mutation could be associated with rapid progressive disease with poor prognosis.
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Affiliation(s)
- Sema Kalkan Uçar
- Department of Pediatrics, Division of Metabolism and NutritionEge University Medical FacultyIzmirTurkey
| | - Havva Yazıcı
- Department of Pediatrics, Division of Metabolism and NutritionEge University Medical FacultyIzmirTurkey
| | - Ebru Canda
- Department of Pediatrics, Division of Metabolism and NutritionEge University Medical FacultyIzmirTurkey
| | - Esra Er
- Department of Pediatrics, Division of Metabolism and NutritionEge University Medical FacultyIzmirTurkey
| | - Fatma Derya Bulut
- Department of Pediatrics, Division of Metabolism and NutritionÇukurova University Medical FacultyAdanaTurkey
| | - Cenk Eraslan
- Department of Radiology, Division of NeuroradiologyEge University Medical FacultyBornovaTurkey
| | - Hüseyin Onay
- Department of GeneticsEge University Medical FacultyIzmirTurkey
| | - Bridget Elizabeth Bax
- Institute of Molecular and Clinical SciencesSt George's University of LondonLondonUK
| | - Mahmut Çoker
- Department of Pediatrics, Division of Metabolism and NutritionEge University Medical FacultyIzmirTurkey
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Gautheron J, Lima L, Akinci B, Zammouri J, Auclair M, Ucar SK, Ozen S, Altay C, Bax BE, Nemazanyy I, Lenoir V, Prip-Buus C, Acquaviva-Bourdain C, Lascols O, Fève B, Vigouroux C, Noel E, Jéru I. Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes. BMC Med 2022; 20:95. [PMID: 35341481 PMCID: PMC8958798 DOI: 10.1186/s12916-022-02296-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 02/10/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2'-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored. METHODS Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model. RESULTS All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients' phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue. CONCLUSIONS The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology.
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Affiliation(s)
- Jérémie Gautheron
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France.
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France.
| | - Lara Lima
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France
| | - Baris Akinci
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Dokuz Eylul University, 35330, Izmir, Turkey
| | - Jamila Zammouri
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France
| | - Martine Auclair
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France
| | - Sema Kalkan Ucar
- Department of Pediatrics, Division of Metabolic Diseases, Ege University, 35100, Izmir, Turkey
| | - Samim Ozen
- Department of Pediatrics, Division of Pediatric Endocrinology, Ege University, 35100, Izmir, Turkey
| | - Canan Altay
- Department of Radiology, Dokuz Eylul University, 35100, Izmir, Turkey
| | - Bridget E Bax
- Institute of Molecular and Clinical Sciences, St George's University of London, London, SW17 0RE, UK
| | - Ivan Nemazanyy
- Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, Inserm, US24/CNRS UMS 3633, 75015, Paris, France
| | - Véronique Lenoir
- Institut Cochin, Université Paris Descartes-CNRS UMR8104, Paris, France
| | - Carina Prip-Buus
- Institut Cochin, Université Paris Descartes-CNRS UMR8104, Paris, France
| | - Cécile Acquaviva-Bourdain
- Service de Biochimie et Biologie Moléculaire Grand Est, Hospices Civils, UM Pathologies Héréditaires du Métabolisme et du Globule Rouge, CHU de Lyon, 69500, Bron, France
| | - Olivier Lascols
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France
- Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, 75012, Paris, France
| | - Bruno Fève
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France
- Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service de Diabétologie et Endocrinologie de la Reproduction, Hôpital Saint-Antoine, AP-HP, 75012, Paris, France
| | - Corinne Vigouroux
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France
- Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, 75012, Paris, France
- Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Service de Diabétologie et Endocrinologie de la Reproduction, Hôpital Saint-Antoine, AP-HP, 75012, Paris, France
| | - Esther Noel
- Département de Médecine Interne, Centre Hospitalier Universitaire, 67000, Strasbourg, France
| | - Isabelle Jéru
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université-Inserm UMRS_938, 27 rue Chaligny 75571, 12, Paris Cedex, France.
- Institute of Cardiometabolism and Nutrition (ICAN), CHU Pitié-Salpêtrière - Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012, Paris, France.
- Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint-Antoine, AP-HP, 75012, Paris, France.
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Gopan A, Sarma MS. Mitochondrial hepatopathy: Respiratory chain disorders- ‘breathing in and out of the liver’. World J Hepatol 2021; 13:1707-1726. [PMID: 34904040 PMCID: PMC8637684 DOI: 10.4254/wjh.v13.i11.1707] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/30/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023] Open
Abstract
Mitochondria, the powerhouse of a cell, are closely linked to the pathophysiology of various common as well as not so uncommon disorders of the liver and beyond. Evolution supports a prokaryotic descent, and, unsurprisingly, the organelle is worthy of being labeled an organism in itself. Since highly metabolically active organs require a continuous feed of energy, any dysfunction in the structure and function of mitochondria can have variable impact, with the worse end of the spectrum producing catastrophic consequences with a multisystem predisposition. Though categorized a hepatopathy, mitochondrial respiratory chain defects are not limited to the liver in time and space. The liver involvement is also variable in clinical presentation as well as in age of onset, from acute liver failure, cholestasis, or chronic liver disease. Other organs like eye, muscle, central and peripheral nervous system, gastrointestinal tract, hematological, endocrine, and renal systems are also variably involved. Diagnosis hinges on recognition of subtle clinical clues, screening metabolic investigations, evaluation of the extra-hepatic involvement, and role of genetics and tissue diagnosis. Treatment is aimed at both circumventing the acute metabolic crisis and long-term management including nutritional rehabilitation. This review lists and discusses the burden of mitochondrial respiratory chain defects, including various settings when to suspect, their evolution with time, including certain specific disorders, their tiered evaluation with diagnostic algorithms, management dilemmas, role of liver transplantation, and the future research tools.
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Affiliation(s)
- Amrit Gopan
- Department of Gastroenterology, Seth G.S Medical College and K.E.M Hospital, Mumbai 400012, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Hirano M, Carelli V, De Giorgio R, Pironi L, Accarino A, Cenacchi G, D’Alessandro R, Filosto M, Martí R, Nonino F, Pinna AD, Baldin E, Bax BE, Bolletta A, Bolletta R, Boschetti E, Cescon M, D’Angelo R, Dotti MT, Giordano C, Gramegna LL, Levene M, Lodi R, Mandel H, Morelli MC, Musumeci O, Pugliese A, Scarpelli M, Siniscalchi A, Spinazzola A, Tal G, Torres-Torronteras J, Vignatelli L, Zaidman I, Zoller H, Rinaldi R, Zeviani M. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network. J Inherit Metab Dis 2021; 44:376-387. [PMID: 32898308 PMCID: PMC8399867 DOI: 10.1002/jimd.12300] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 08/03/2020] [Accepted: 08/05/2020] [Indexed: 02/05/2023]
Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory diagnostic tests are not routinely performed by most laboratories, accounting for common misdiagnosis. Factors predictive of progression and appropriate tests for monitoring are still undefined. Several treatment options showed promising results in restoring the biochemical imbalance of MNGIE. The lack of controlled studies with appropriate follow-up accounts for the limited evidence informing diagnostic and therapeutic choices. The International Consensus Conference (ICC) on MNGIE, held in Bologna, Italy, on 30 March to 31 March 2019, aimed at an evidence-based consensus on diagnosis, prognosis, and treatment of MNGIE among experts, patients, caregivers and other stakeholders involved in caring the condition. The conference was conducted according to the National Institute of Health Consensus Conference methodology. A consensus development panel formulated a set of statements and proposed a research agenda. Specifically, the ICC produced recommendations on: (a) diagnostic pathway; (b) prognosis and the main predictors of disease progression; (c) efficacy and safety of treatments; and (f) research priorities on diagnosis, prognosis, and treatment. The Bologna ICC on diagnosis, management and treatment of MNGIE provided evidence-based guidance for clinicians incorporating patients' values and preferences.
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Affiliation(s)
- Michio Hirano
- Department of Neurology, Columbia University Irving Medical Center, New York, New York
| | - Valerio Carelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Roberto De Giorgio
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Loris Pironi
- Clinical Nutrition and Metabolism Unit and Center for Chronic Intestinal Failure, Department of Digestive System, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Anna Accarino
- Digestive System Research Unit, University Hospital Vall d’Hebron / Centro de Investigación Biomédica en Red de Enfermeda des Hepáticas y Digestivas (CIBEREHD); Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Giovanna Cenacchi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
| | | | - Massimiliano Filosto
- Center for Neuromuscular Diseases, Unit of Neurology, Azienda Socio Sanitaria Territoriale degli Spedali Civili and University of Brescia, Brescia, Italy
| | - Ramon Martí
- Vall d’Hebron Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Autonomous University of Barcelona, Barcelona, Spain
| | - Francesco Nonino
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | | | - Elisa Baldin
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Bridget Elizabeth Bax
- Institute of Molecular and Clinical Sciences, St George’s University of London, London, UK
| | | | | | - Elisa Boschetti
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Matteo Cescon
- General Surgery and Transplant Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Roberto D’Angelo
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Interaziendale Metropolitana (NeuroMet), - Neurologia AOU S.Orsola-Malpighi, Bologna, Italy
| | - Maria Teresa Dotti
- Neurological and Metabolic Diseases Clinic, Siena Hospital, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Carla Giordano
- Department of Radiological, Oncological and Pathological Sciences, Sapienza, University of Rome, Umberto I Policlinic, Rome, Italy
| | - Laura Ludovica Gramegna
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Michelle Levene
- Institute of Molecular and Clinical Sciences, St George’s University of London, London, UK
| | - Raffaele Lodi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Hanna Mandel
- Institute of Human Genetics and Inherited Metabolic Disorders, Galilee Medical Center, Nahariya, Israel
| | - Maria Cristina Morelli
- Department for Care of Organ Failures and Transplants, Internal Medicine for the Treatment of Severe Organ Failures, St. Orsola-Malpighi Hospital, Bologna, Italy
| | - Olimpia Musumeci
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Alessia Pugliese
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Mauro Scarpelli
- Neurology Unit, Department of Neuroscience, Azienda Ospedaliero Universitaria Integrata Verona, Verona, Italy
| | - Antonio Siniscalchi
- Anaesthesiology Intensive Care and Transplantation Unit, St. Orsola-Malpighi Hospital, Bologna, Italy
| | - Antonella Spinazzola
- Department of Clinical Movement Neurosciences, Royal Free Campus, University College of London, Queen Square Institute of Neurology, London, UK
| | - Galit Tal
- Metabolic Unit, Ruth Rappaport Children’s Hospital, Rambam Health Care Campus, Haifa, Israel
| | - Javier Torres-Torronteras
- Vall d’Hebron Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Autonomous University of Barcelona, Barcelona, Spain
| | - Luca Vignatelli
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Irina Zaidman
- Department of Bone Marrow Transplantation, Hadassah University Medical Center, Jerusalem, Israel
| | - Heinz Zoller
- Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
| | - Rita Rinaldi
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Interaziendale Metropolitana (NeuroMet), - Neurologia AOU S.Orsola-Malpighi, Bologna, Italy
| | - Massimo Zeviani
- Department of Neurosciences, Veneto Institute of Molecular Medicine, University of Padova, Padova, Italy
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Ronchi D, Caporali L, Manenti GF, Meneri M, Mohamed S, Bordoni A, Tagliavini F, Contin M, Piga D, Sciacco M, Saetti C, Carelli V, Comi GP. TYMP Variants Result in Late-Onset Mitochondrial Myopathy With Altered Muscle Mitochondrial DNA Homeostasis. Front Genet 2020; 11:860. [PMID: 32849836 PMCID: PMC7419576 DOI: 10.3389/fgene.2020.00860] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 07/14/2020] [Indexed: 12/02/2022] Open
Abstract
Biallelic TYMP variants result in the mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a juvenile-onset disorder with progressive course and fatal outcome. Milder late-onset (>40 years) form has been rarely described. Gene panel sequencing in a cohort of 60 patients featuring muscle accumulation of mitochondrial DNA (mtDNA) deletions detected TYMP defects in three subjects (5%), two of them with symptom onset in the fifth decade. One of the patients only displayed ptosis and ophthalmoparesis. Biochemical and molecular studies supported the diagnosis. Screening of TYMP is recommended in adult patients with muscle mtDNA instability, even in the absence of cardinal MNGIE features.
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Affiliation(s)
- Dario Ronchi
- IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy.,Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Leonardo Caporali
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Giulia Francesca Manenti
- Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Megi Meneri
- IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy
| | - Susan Mohamed
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Andreina Bordoni
- IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy
| | | | - Manuela Contin
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.,Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), Università di Bologna, Bologna, Italy
| | - Daniela Piga
- IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy
| | - Monica Sciacco
- IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Disease Unit, Milan, Italy
| | - Cristina Saetti
- IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy.,Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Valerio Carelli
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.,Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), Università di Bologna, Bologna, Italy
| | - Giacomo Pietro Comi
- Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.,IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Disease Unit, Milan, Italy
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6
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D'Angelo R, Boschetti E, Amore G, Costa R, Pugliese A, Caporali L, Gramegna LL, Papa V, Vizioli L, Capristo M, Contin M, Mohamed S, Cenacchi G, Lodi R, Morelli MC, Fasano L, Pisani L, Cescon M, Tonon C, Pinna AD, Dotti MT, Sicurelli F, Scarpelli M, Filosto M, Casali C, Pironi L, Carelli V, De Giorgio R, Rinaldi R. Liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical long-term follow-up and pathogenic implications. J Neurol 2020; 267:3702-3710. [PMID: 32683607 DOI: 10.1007/s00415-020-10051-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/30/2020] [Accepted: 07/02/2020] [Indexed: 01/21/2023]
Abstract
We report the longest follow-up of clinical and biochemical features of two previously reported adult mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients treated with liver transplantation (LT), adding information on a third, recently transplanted, patient. All three patients overcame the early post-operative period and tolerated immunosuppressive therapy. Plasma nucleoside levels dramatically decreased, with evidence of clinical improvement of ambulation and neuropathy. Conversely, other features of MNGIE, as gastrointestinal dysmotility, low weight, ophthalmoparesis, and leukoencephalopathy were essentially unchanged. A similar picture characterized two patients treated with allogenic hematopoietic stem cell transplantation (AHSCT). In conclusion, LT promptly and stably normalizes nucleoside imbalance in MNGIE, stabilizing or improving some clinical parameters with marginal periprocedural mortality rate as compared to AHSCT. Nevertheless, restoring thymidine phosphorylase (TP) activity, achieved by both LT and AHSCT, does not allow a full clinical recovery, probably due to consolidated cellular damage and/or incomplete enzymatic tissue replacement.
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Affiliation(s)
- Roberto D'Angelo
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Interaziendale Clinica Neurologica Rete Metropolitana (NeuroMet), Neurologia AOU S. Orsola-Malpighi, Policlinico Sant'Orsola-Malpighi, Building #2, Via Albertoni, 15, 40138, Bologna, Italy.
| | - Elisa Boschetti
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.,Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Giulia Amore
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Roberta Costa
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Alessia Pugliese
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Leonardo Caporali
- UOC Clinica Neurologica, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Laura Ludovica Gramegna
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.,Functional and Molecular Neuroimaging Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Valentina Papa
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Luca Vizioli
- Department of Organ Insufficiency and Transplantation, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Mariantonietta Capristo
- UOC Clinica Neurologica, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Manuela Contin
- UOC Clinica Neurologica, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Susan Mohamed
- UOC Clinica Neurologica, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Giovanna Cenacchi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Raffaele Lodi
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Maria Cristina Morelli
- Department of Organ Insufficiency and Transplantation, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Luca Fasano
- Respiratory and Critical Care Unit, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Lara Pisani
- Respiratory and Critical Care Unit, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Matteo Cescon
- Department of Organ Insufficiency and Transplantation, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Caterina Tonon
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.,Functional and Molecular Neuroimaging Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Antonio Daniele Pinna
- Department of Organ Insufficiency and Transplantation, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Maria Teresa Dotti
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | - Francesco Sicurelli
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | | | - Massimiliano Filosto
- Center for Neuromuscular Diseases, Unit of Neurology, ASST "Spedali Civili", Brescia, Italy
| | - Carlo Casali
- Department of Medico-Surgical Sciences and Biotechnologies, University 'La Sapienza', Roma, Italy
| | - Loris Pironi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Valerio Carelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.,UOC Clinica Neurologica, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Roberto De Giorgio
- Department of Morphology, Surgery and Experimental Medicine, St. Anna Hospital, University of Ferrara, Ferrara, Italy
| | - Rita Rinaldi
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Interaziendale Clinica Neurologica Rete Metropolitana (NeuroMet), Neurologia AOU S. Orsola-Malpighi, Policlinico Sant'Orsola-Malpighi, Building #2, Via Albertoni, 15, 40138, Bologna, Italy
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7
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Kripps K, Nakayuenyongsuk W, Shayota BJ, Berquist W, Gomez-Ospina N, Esquivel CO, Concepcion W, Sampson JB, Cristin DJ, Jackson WE, Gilliland S, Pomfret EA, Kueht ML, Pettit RW, Sherif YA, Emrick LT, Elsea SH, Himes R, Hirano M, Van Hove JLK, Scaglia F, Enns GM, Larson AA. Successful liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Mol Genet Metab 2020; 130:58-64. [PMID: 32173240 PMCID: PMC8399858 DOI: 10.1016/j.ymgme.2020.03.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 03/02/2020] [Accepted: 03/03/2020] [Indexed: 12/19/2022]
Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal disorder characterized by progressive gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, skeletal myopathy, ophthalmoparesis, and ptosis. MNGIE stems from deficient thymidine phosphorylase activity (TP) leading to toxic elevations of plasma thymidine. Hematopoietic stem cell transplant (HSCT) restores TP activity and halts disease progression but has high transplant-related morbidity and mortality. Liver transplant (LT) was reported to restore TP activity in two adult MNGIE patients. We report successful LT in four additional MNGIE patients, including a pediatric patient. Our patients were diagnosed between ages 14 months and 36 years with elevated thymidine levels and biallelic pathogenic variants in TYMP. Two patients presented with progressive gastrointestinal dysmotility, and three demonstrated progressive peripheral neuropathy with two suffering limitations in ambulation. Two patients, including the child, had liver dysfunction and cirrhosis. Following LT, thymidine levels nearly normalized in all four patients and remained low for the duration of follow-up. Disease symptoms stabilized in all patients, with some manifesting improvements, including intestinal function. No patient died, and LT appeared to have a more favorable safety profile than HSCT, especially when liver disease is present. Follow-up studies will need to document the long-term impact of this new approach on disease outcome. Take Home Message: Liver transplantation is effective in stabilizing symptoms and nearly normalizing thymidine levels in patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and may have an improved safety profile over hematopoietic stem cell transplant.
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Affiliation(s)
- KimberlyA Kripps
- Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA
| | | | - Brian J Shayota
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - William Berquist
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Natalia Gomez-Ospina
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Carlos O Esquivel
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Waldo Concepcion
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Jacinda B Sampson
- Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA
| | - David J Cristin
- Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Whitney E Jackson
- Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Samuel Gilliland
- Department of Anesthesia, University of Colorado School of Medicine, Aurora, CO, USA
| | - Elizabeth A Pomfret
- Division of Transplant Surgery, University of Colorado School of Medicine, Aurora, CO, USA
| | - Michael L Kueht
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Rowland W Pettit
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Youmna A Sherif
- Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Lisa T Emrick
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Sarah H Elsea
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Ryan Himes
- Department of Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Houston, TX, USA
| | - Michio Hirano
- Department of Neurology, Columbia University Medical Center, New York City, NY, USA
| | - Johan L K Van Hove
- Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA
| | - Fernando Scaglia
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, USA; Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, ShaTin, Hong Kong
| | - Gregory M Enns
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Austin A Larson
- Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine, Aurora, CO, USA.
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8
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Bax BE. Mitochondrial neurogastrointestinal encephalomyopathy: approaches to diagnosis and treatment. JOURNAL OF TRANSLATIONAL GENETICS AND GENOMICS 2019; 4:1-16. [PMID: 32914088 PMCID: PMC7116056 DOI: 10.20517/jtgg.2020.08] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease caused by mutations in TYMP, the gene encoding for the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of thymidine and 2’-deoxyuridine and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. MNGIE is characterised by gastrointestinal dysmotility, cachexia, peripheral neuropathy, ophthalmoplegia, ptosis and leukoencephalopathy. The disease is progressively degenerative and leads to death at an average age of 37.6 years. Patients invariably encounter misdiagnoses, diagnostic delays, and non-specific clinical management. Despite its rarity, MNGIE has invoked much interest in the development of therapeutic strategies, mainly because it is one of the few mitochondrial disorders where the molecular abnormality is metabolically and physically accessible to manipulation. This review provides a resume of the current diagnosis and treatment approaches and aims to increase the clinical awareness of MNGIE and thereby facilitate early diagnosis and timely access to treatments, before the development of untreatable and irreversible organ damage.
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Affiliation(s)
- Bridget E Bax
- Institute of Molecular and Clinical Sciences, St. George's University of London, London, SW17 ORE, UK
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9
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Pacitti D, Levene M, Garone C, Nirmalananthan N, Bax BE. Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far. Front Genet 2018; 9:669. [PMID: 30627136 PMCID: PMC6309918 DOI: 10.3389/fgene.2018.00669] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 12/04/2018] [Indexed: 02/05/2023] Open
Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare metabolic autosomal recessive disease, caused by mutations in the nuclear gene TYMP which encodes the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of the deoxyribonucleosides thymidine and deoxyuridine, and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. Clinically, MNGIE is characterized by gastrointestinal and neurological manifestations, including cachexia, gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, ophthalmoplegia and ptosis. The disease is progressively degenerative and leads to death at an average age of 37.6 years. As with the vast majority of rare diseases, patients with MNGIE face a number of unmet needs related to diagnostic delays, a lack of approved therapies, and non-specific clinical management. We provide here a comprehensive collation of the available knowledge of MNGIE since the disease was first described 42 years ago. This review includes symptomatology, diagnostic procedures and hurdles, in vitro and in vivo disease models that have enhanced our understanding of the disease pathology, and finally experimental therapeutic approaches under development. The ultimate aim of this review is to increase clinical awareness of MNGIE, thereby reducing diagnostic delay and improving patient access to putative treatments under investigation.
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Affiliation(s)
- Dario Pacitti
- Molecular and Clinical Sciences Research Institute, St George's, University of London, London, United Kingdom
| | - Michelle Levene
- Molecular and Clinical Sciences Research Institute, St George's, University of London, London, United Kingdom
| | - Caterina Garone
- MRC Mitochondrial Biology Unit, Cambridge Biomedical, Cambridge, United Kingdom
| | | | - Bridget E. Bax
- Molecular and Clinical Sciences Research Institute, St George's, University of London, London, United Kingdom
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10
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Yadak R, Boot MV, van Til NP, Cazals-Hatem D, Finkenstedt A, Bogaerts E, de Coo IF, Bugiani M. Transplantation, gene therapy and intestinal pathology in MNGIE patients and mice. BMC Gastroenterol 2018; 18:149. [PMID: 30340467 PMCID: PMC6194683 DOI: 10.1186/s12876-018-0881-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 10/10/2018] [Indexed: 12/29/2022] Open
Abstract
Background Gastrointestinal complications are the main cause of death in patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Available treatments often restore biochemical homeostasis, but fail to cure gastrointestinal symptoms. Methods We evaluated the small intestine neuromuscular pathology of an untreated MNGIE patient and two recipients of hematopoietic stem cells, focusing on enteric neurons and glia. Additionally, we evaluated the intestinal neuromuscular pathology in a mouse model of MNGIE treated with hematopoietic stem cell gene therapy. Quantification of muscle wall thickness and ganglion cell density was performed blind to the genotype with ImageJ. Significance of differences between groups was determined by two-tailed Mann-Whitney U test (P < 0.05). Results Our data confirm that MNGIE presents with muscle atrophy and loss of Cajal cells and CD117/c-kit immunoreactivity in the small intestine. We also show that hematopoietic stem cell transplantation does not benefit human intestinal pathology at least on short-term. Conclusions We suggest that hematopoietic stem cell transplantation may be insufficient to restore intestinal neuropathology, especially at later stages of MNGIE. As interstitial Cajal cells and their networks play a key role in development of gastrointestinal dysmotility, alternative therapeutic approaches taking absence of these cells into account could be required.
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Affiliation(s)
- Rana Yadak
- Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.,Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Max V Boot
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
| | - Niek P van Til
- Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.,Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Armin Finkenstedt
- Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria
| | - Elly Bogaerts
- Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Irenaeus F de Coo
- Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.,Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Marianna Bugiani
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
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11
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Hegarty R, Deheragoda M, Fitzpatrick E, Dhawan A. Paediatric fatty liver disease (PeFLD): All is not NAFLD - Pathophysiological insights and approach to management. J Hepatol 2018; 68:1286-1299. [PMID: 29471012 DOI: 10.1016/j.jhep.2018.02.006] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 02/11/2018] [Accepted: 02/13/2018] [Indexed: 12/14/2022]
Abstract
The recognition of a pattern of steatotic liver injury where histology mimicked alcoholic liver disease, but alcohol consumption was denied, led to the identification of non-alcoholic fatty liver disease (NAFLD). Non-alcoholic fatty liver disease has since become the most common chronic liver disease in adults owing to the global epidemic of obesity. However, in paediatrics, the term NAFLD seems incongruous: alcohol consumption is largely not a factor and inherited metabolic disorders can mimic or co-exist with a diagnosis of NAFLD. The term paediatric fatty liver disease may be more appropriate. In this article, we summarise the known causes of steatosis in children according to their typical, clinical presentation: i) acute liver failure; ii) neonatal or infantile jaundice; iii) hepatomegaly, splenomegaly or hepatosplenomegaly; iv) developmental delay/psychomotor retardation and perhaps most commonly; v) the asymptomatic child with incidental discovery of abnormal liver enzymes. We offer this model as a means to provide pathophysiological insights and an approach to management of the ever more complex subject of fatty liver.
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Affiliation(s)
- Robert Hegarty
- Paediatric Liver, GI and Nutrition Centre and Mowatlabs, King's College Hospital, London, United Kingdom
| | - Maesha Deheragoda
- Liver Histopathology, Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Emer Fitzpatrick
- Paediatric Liver, GI and Nutrition Centre and Mowatlabs, King's College Hospital, London, United Kingdom
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and Mowatlabs, King's College Hospital, London, United Kingdom.
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12
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Yadak R, Sillevis Smitt P, van Gisbergen MW, van Til NP, de Coo IFM. Mitochondrial Neurogastrointestinal Encephalomyopathy Caused by Thymidine Phosphorylase Enzyme Deficiency: From Pathogenesis to Emerging Therapeutic Options. Front Cell Neurosci 2017; 11:31. [PMID: 28261062 PMCID: PMC5309216 DOI: 10.3389/fncel.2017.00031] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 02/01/2017] [Indexed: 01/05/2023] Open
Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive metabolic disorder caused by thymidine phosphorylase (TP) enzyme deficiency. The lack of TP results in systemic accumulation of deoxyribonucleosides thymidine (dThd) and deoxyuridine (dUrd). In these patients, clinical features include mental regression, ophthalmoplegia, and fatal gastrointestinal complications. The accumulation of nucleosides also causes imbalances in mitochondrial DNA (mtDNA) deoxyribonucleoside triphosphates (dNTPs), which may play a direct or indirect role in the mtDNA depletion/deletion abnormalities, although the exact underlying mechanism remains unknown. The available therapeutic approaches include dialysis and enzyme replacement therapy, both can only transiently reverse the biochemical imbalance. Allogeneic hematopoietic stem cell transplantation is shown to be able to restore normal enzyme activity and improve clinical manifestations in MNGIE patients. However, transplant related complications and disease progression result in a high mortality rate. New therapeutic approaches, such as adeno-associated viral vector and hematopoietic stem cell gene therapy have been tested in Tymp-/-Upp1-/- mice, a murine model for MNGIE. This review provides background information on disease manifestations of MNGIE with a focus on current management and treatment options. It also outlines the pre-clinical approaches toward future treatment of the disease.
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Affiliation(s)
- Rana Yadak
- Department of Neurology, Erasmus University Medical Center Rotterdam, Netherlands
| | - Peter Sillevis Smitt
- Department of Neurology, Erasmus University Medical Center Rotterdam, Netherlands
| | - Marike W van Gisbergen
- Department of Radiation Oncology (MaastRO-Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre Maastricht, Netherlands
| | - Niek P van Til
- Laboratory of Translational Immunology, University Medical Center Utrecht Utrecht, Netherlands
| | - Irenaeus F M de Coo
- Department of Neurology, Erasmus University Medical Center Rotterdam, Netherlands
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13
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Abstract
Mitochondrial disorders (MIDs) due to respiratory-chain defects or nonrespiratory chain defects are usually multisystem conditions [mitochondrial multiorgan disorder syndrome (MIMODS)] affecting the central nervous system (CNS), peripheral nervous system, eyes, ears, endocrine organs, heart, kidneys, bone marrow, lungs, arteries, and also the intestinal tract. Frequent gastrointestinal (GI) manifestations of MIDs include poor appetite, gastroesophageal sphincter dysfunction, constipation, dysphagia, vomiting, gastroparesis, GI pseudo-obstruction, diarrhea, or pancreatitis and hepatopathy. Rare GI manifestations of MIDs include dry mouth, paradontosis, tracheoesophageal fistula, stenosis of the duodeno-jejunal junction, atresia or imperforate anus, liver cysts, pancreas lipomatosis, pancreatic cysts, congenital stenosis or obstruction of the GI tract, recurrent bowel perforations with intra-abdominal abscesses, postprandial abdominal pain, diverticulosis, or pneumatosis coli. Diagnosing GI involvement in MIDs is not at variance from diagnosing GI disorders due to other causes. Treatment of mitochondrial GI disease includes noninvasive or invasive measures. Therapy is usually symptomatic. Only for myo-neuro-gastro-intestinal encephalopathy is a causal therapy with autologous stem-cell transplantation available. It is concluded that GI manifestations of MIDs are more widespread than so far anticipated and that they must be recognized as early as possible to initiate appropriate diagnostic work-up and avoid any mitochondrion-toxic treatment.
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Affiliation(s)
| | - Marlies Frank
- First Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria
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14
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De Giorgio R, Pironi L, Rinaldi R, Boschetti E, Caporali L, Capristo M, Casali C, Cenacchi G, Contin M, D'Angelo R, D'Errico A, Gramegna LL, Lodi R, Maresca A, Mohamed S, Morelli MC, Papa V, Tonon C, Tugnoli V, Carelli V, D'Alessandro R, Pinna AD. Liver transplantation for mitochondrial neurogastrointestinal encephalomyopathy. Ann Neurol 2016; 80:448-455. [DOI: 10.1002/ana.24724] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
- Roberto De Giorgio
- Department of Surgical and Medical SciencesUniversity of BolognaBologna Italy
| | - Loris Pironi
- Department of Surgical and Medical SciencesUniversity of BolognaBologna Italy
| | - Rita Rinaldi
- Neurology UnitSt. Orsola‐Malpighi HospitalBologna Italy
| | - Elisa Boschetti
- Department of Surgical and Medical SciencesUniversity of BolognaBologna Italy
| | | | | | - Carlo Casali
- Department of Medico‐Surgical Sciences and BiotechnologiesUniversity ‘La Sapienza’Rome Italy
| | - Giovanna Cenacchi
- Department of Biomedical and Neuromotor SciencesUniversity of BolognaBologna Italy
| | - Manuela Contin
- IRCCS Institute of Neurological Sciences of BolognaBologna Italy
- Department of Biomedical and Neuromotor SciencesUniversity of BolognaBologna Italy
| | - Roberto D'Angelo
- Department of Surgical and Medical SciencesUniversity of BolognaBologna Italy
- Neurology UnitSt. Orsola‐Malpighi HospitalBologna Italy
| | | | | | - Raffaele Lodi
- Department of Biomedical and Neuromotor SciencesUniversity of BolognaBologna Italy
| | | | - Susan Mohamed
- IRCCS Institute of Neurological Sciences of BolognaBologna Italy
| | | | - Valentina Papa
- Department of Biomedical and Neuromotor SciencesUniversity of BolognaBologna Italy
| | - Caterina Tonon
- Department of Biomedical and Neuromotor SciencesUniversity of BolognaBologna Italy
| | - Vitaliano Tugnoli
- Department of Biomedical and Neuromotor SciencesUniversity of BolognaBologna Italy
| | - Valerio Carelli
- IRCCS Institute of Neurological Sciences of BolognaBologna Italy
- Department of Biomedical and Neuromotor SciencesUniversity of BolognaBologna Italy
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15
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Cabrera-Pérez R, Torres-Torronteras J, Vila-Julià F, Ortega FJ, Cámara Y, Barquinero J, Martí R. Prospective therapeutic approaches in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Expert Opin Orphan Drugs 2015. [DOI: 10.1517/21678707.2015.1090307] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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16
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Halter JP, Michael W, Schüpbach M, Mandel H, Casali C, Orchard K, Collin M, Valcarcel D, Rovelli A, Filosto M, Dotti MT, Marotta G, Pintos G, Barba P, Accarino A, Ferra C, Illa I, Beguin Y, Bakker JA, Boelens JJ, de Coo IFM, Fay K, Sue CM, Nachbaur D, Zoller H, Sobreira C, Pinto Simoes B, Hammans SR, Savage D, Martí R, Chinnery PF, Elhasid R, Gratwohl A, Hirano M. Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy. Brain 2015; 138:2847-58. [PMID: 26264513 DOI: 10.1093/brain/awv226] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 06/19/2015] [Indexed: 12/18/2022] Open
Abstract
Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation should be considered for selected patients with an optimal donor.
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Affiliation(s)
- Joerg P Halter
- 1 Haematology, University Hospital Basel, Basel, Switzerland
| | - W Michael
- 1 Haematology, University Hospital Basel, Basel, Switzerland2 Department of Neurology, Inselspital, Berne University Hospital, and University of Bern, Switzerland3 Centre d'Investigation Clinique 9503, Institut du Cerveau et de la Moelle Épinière, Département de Neurologie, Université Pierre et Marie Curie-Paris 6 and INSERM, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France4 Rambam Medical Centre Haifa, Israel5 Dep. SBMC - Sapienza University Roma, Italy6 University Hospital Southampton, UK7 Newcastle University, Newcastle upon Tyne, UK8 University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain9 BMT Unit, MBBM Foundation, Paediatric Dept., University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy10 Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital "Spedali Civili", Brescia, Italy11 Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Italy12 Stem Cell Transplant and Cellular Therapy Unit, University Hospital, Siena, Italy13 Department of Paediatrics, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain14 Department of Haematology - Catalan Institute of Oncology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain15 Hospital de la Santa Creu i Sant Pau Universitat Autònoma Barcelona, Spain16 CHU Sart-Tilman Liege, Belgium17 Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Centre, Leiden, The Netherlands18 University Medical Centre Utrecht; Paediatric Blood and Marrow Transplantation Program, Utrecht, The Netherlands19 Department of Neurology and Child Neurology SKZ, Erasmus MC - University Medical Centre Rotterdam, The Netherlands20 Department of Haematology, Royal North Shore and St. Vincent Hospitals Sydney, Australia21 Department of Neurology, Royal North Shore Hospital, University of Sydney, Australia22 Medical University of Innsbruck, Departments of Medic
| | - M Schüpbach
- 2 Department of Neurology, Inselspital, Berne University Hospital, and University of Bern, Switzerland 3 Centre d'Investigation Clinique 9503, Institut du Cerveau et de la Moelle Épinière, Département de Neurologie, Université Pierre et Marie Curie-Paris 6 and INSERM, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France
| | | | | | | | | | - David Valcarcel
- 8 University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Attilio Rovelli
- 9 BMT Unit, MBBM Foundation, Paediatric Dept., University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy
| | - Massimiliano Filosto
- 10 Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital "Spedali Civili", Brescia, Italy
| | - Maria T Dotti
- 11 Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Italy
| | - Giuseppe Marotta
- 12 Stem Cell Transplant and Cellular Therapy Unit, University Hospital, Siena, Italy
| | - Guillem Pintos
- 13 Department of Paediatrics, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
| | - Pere Barba
- 8 University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Anna Accarino
- 8 University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Christelle Ferra
- 14 Department of Haematology - Catalan Institute of Oncology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
| | - Isabel Illa
- 15 Hospital de la Santa Creu i Sant Pau Universitat Autònoma Barcelona, Spain
| | | | - Jaap A Bakker
- 17 Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Centre, Leiden, The Netherlands
| | - Jaap J Boelens
- 18 University Medical Centre Utrecht; Paediatric Blood and Marrow Transplantation Program, Utrecht, The Netherlands
| | - Irenaeus F M de Coo
- 19 Department of Neurology and Child Neurology SKZ, Erasmus MC - University Medical Centre Rotterdam, The Netherlands
| | - Keith Fay
- 20 Department of Haematology, Royal North Shore and St. Vincent Hospitals Sydney, Australia
| | - Carolyn M Sue
- 21 Department of Neurology, Royal North Shore Hospital, University of Sydney, Australia
| | - David Nachbaur
- 22 Medical University of Innsbruck, Departments of Medicine II and V, Austria
| | - Heinz Zoller
- 22 Medical University of Innsbruck, Departments of Medicine II and V, Austria
| | - Claudia Sobreira
- 23 Department of Neuroscience, Division of Neurology, Ribeirao Preto School of Medicine, Sao Paulo University, Brazil
| | - Belinda Pinto Simoes
- 24 Stem Cell Transplantation Unit, Internal Medicine Department, Ribeirao Preto School of Medicine, Sao Paulo University, Brazil
| | | | | | - Ramon Martí
- 8 University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain 27 Biomedical Network Research Centre on Rare Diseases (CIBERER) ISCIII, Barcelona, Spain
| | | | - Ronit Elhasid
- 28 Dana Children's Hospital, Sourasky Medical Centre, Tel Aviv, Israel
| | - Alois Gratwohl
- 1 Haematology, University Hospital Basel, Basel, Switzerland
| | - Michio Hirano
- 29 Department of Neurology, Columbia University Medical Centre, New York, NY, USA
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17
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Boschetti E, D’Alessandro R, Bianco F, Carelli V, Cenacchi G, Pinna AD, Gaudio MD, Rinaldi R, Stanghellini V, Pironi L, Rhoden K, Tugnoli V, Casali C, De Giorgio R. Liver as a source for thymidine phosphorylase replacement in mitochondrial neurogastrointestinal encephalomyopathy. PLoS One 2014; 9:e96692. [PMID: 24802030 PMCID: PMC4011889 DOI: 10.1371/journal.pone.0096692] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 04/10/2014] [Indexed: 01/22/2023] Open
Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive mitochondrial disease associated with mutations in the nuclear TYMP gene. As a result, the thymidine phosphorylase (TP) enzyme activity is markedly reduced leading to toxic accumulation of thymidine and therefore altered mitochondrial DNA. MNGIE is characterized by severe gastrointestinal dysmotility, neurological impairment, reduced life expectancy and poor quality of life. There are limited therapeutic options for MNGIE. In the attempt to restore TP activity, allogenic hematopoietic stem cell transplantation has been used as cellular source of TP. The results of this approach on ∼20 MNGIE patients showed gastrointestinal and neurological improvement, although the 5-year mortality rate is about 70%. In this study we tested whether the liver may serve as an alternative source of TP. We investigated 11 patients (7M; 35–55 years) who underwent hepatic resection for focal disorders. Margins of normal liver tissue were processed to identify, quantify and localize the TP protein by Western Blot, ELISA, and immunohistochemistry, and to evaluate TYMP mRNA expression by qPCR. Western Blot identified TP in liver with a TP/GAPDH ratio of 0.9±0.5. ELISA estimated TP content as 0.5±0.07 ng/μg of total protein. TP was identified in both nuclei and cytoplasm of hepatocytes and sinusoidal lining cells. Finally, TYMP mRNA was expressed in the liver. Overall, our study demonstrates that the liver is an important source of TP. Orthotopic liver transplantation may be considered as a therapeutic alternative for MNGIE patients.
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Affiliation(s)
- Elisa Boschetti
- Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | | | - Francesca Bianco
- Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy
| | - Valerio Carelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Giovanna Cenacchi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Antonio D. Pinna
- Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy
| | - Massimo Del Gaudio
- Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy
| | - Rita Rinaldi
- Neurology Unit, St. Orsola-Malpighi Hospital, Bologna, Italy
| | | | - Loris Pironi
- Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy
| | - Kerry Rhoden
- Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy
| | - Vitaliano Tugnoli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Carlo Casali
- Department of Medico-Surgical Sciences and Biotechnologies, University ‘La Sapienza’, Rome, Italy
| | - Roberto De Giorgio
- Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy
- * E-mail:
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