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Finn LS, Goldstein A, Hedrick HL. Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) Phenotype Associated With Unique Compound Heterozygous POLG Variants: Case Presentation and Review of the Literature. Pediatr Dev Pathol 2025:10935266251321317. [PMID: 39982139 DOI: 10.1177/10935266251321317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
We report a teenage patient with a delayed diagnosis of compound heterozygous POLG pathogenic variants [(POLG c. 1943 C>G, p.P648R) and (POLG c. 679 C>T, p.R227W)] who presented with fatigue and neuropathy, as well as long standing malnutrition and cachexia, erroneously attributed to an eating disorder. She experienced multiple bowel perforations and pathologic examination revealed jejunal diverticula and features of visceral neuromyopathy. In addition to ganglion cell mega-mitochondrial inclusions, there were multiple foci of interrupted muscularis mucosae, an alteration not previously recognized in the intestines of patients with primary mitochondrial disorders. We provide a detailed account of the gastrointestinal pathologic findings in this patient and compare with prior cases of Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) phenotypes.
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Affiliation(s)
- Laura S Finn
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA
| | - Amy Goldstein
- Division of Human Genetics, Mitochondrial Medicine Frontier Program, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Holly L Hedrick
- Division of General, Thoracic and Fetal Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Reitinger JC, Mackay DD. Optic Neuropathy Associated with POLG Mutations: A Case Series and Literature Review. J Neuroophthalmol 2024; 44:552-558. [PMID: 38294884 DOI: 10.1097/wno.0000000000002089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2024]
Abstract
BACKGROUND The clinical characteristics of patients with polymerase gamma ( POLG ) mutation-associated optic neuropathy remain incompletely characterized. METHODS We describe the clinical characteristics of 3 patients with POLG -associated optic neuropathy. We performed a literature review of optic neuropathy cases associated with POLG mutations and compared them with our cohort. RESULTS Many published cases of POLG -associated optic neuropathy in our literature review lacked details regarding severity of vision loss, visual field defects, and optical coherence tomography analysis. The clinical presentation of POLG mutations remains widely variable in age (from pediatric cases to adults) and associated systemic findings. All patients in our literature review presented with systemic symptoms, most commonly muscle weakness, ptosis, and ophthalmoplegia, whereas many young patients had severe systemic symptoms. In our case series, all 3 cases had isolated optic neuropathy affecting the papillomacular bundle, with signs such as reduced visual acuity and color vision, central visual field defects, temporal retinal nerve fiber layer loss with temporal optic disc pallor, and retinal ganglion cell complex loss. In addition, 2 of the 3 cases had added mitochondrial stressors in addition to the POLG mutation. CONCLUSIONS Clinicians should be aware that POLG mutations can present as isolated optic neuropathy primarily affecting the papillomacular bundle. With mitochondrial failure being the likely underlying pathogenic mechanism in POLG -associated optic neuropathy, helping affected patients eliminate mitochondrial stressors may be important in reducing the risk for progressive vision loss in this otherwise currently untreatable disorder.
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Affiliation(s)
- Jeremy C Reitinger
- Department of Ophthalmology (JCR), Indiana University School of Medicine, Indianapolis, Indiana; and Departments of Neurology (DDM), Ophthalmology, and Neurosurgery, Indiana University School of Medicine, Indianapolis, Indiana
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Sun YH, Bai XY, Guo T, Fan SY, Ruan GC, Zhou WX, Yang H. Rare digestive disease: Mitochondrial neurogastrointestinal encephalomyopathy, review of the literature. J Dig Dis 2024; 25:624-631. [PMID: 39694028 DOI: 10.1111/1751-2980.13317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 10/22/2024] [Accepted: 11/03/2024] [Indexed: 12/20/2024]
Abstract
The median age of patients at diagnosis of mitochondrial neurogastrointestinal encephalomyopathy was 25 years. The most common neurological symptoms were leukoencephalopathy (83.1%), polyneuropathy (68.5%), and ptosis/ophthalmoparesis (61.8%). And the most common digestive symptoms were weight loss/cachexia (71.9%), abdominal pain (58.4%), diarrhea (57.3%), vomiting (53.9%), and constipation (13.5%).
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Affiliation(s)
- Ying Hao Sun
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao Yin Bai
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Tao Guo
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Si Yuan Fan
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Ge Chong Ruan
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Xun Zhou
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Hong Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
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Salemi M, Lanza G, Salluzzo MG, Schillaci FA, Di Blasi FD, Cordella A, Caniglia S, Lanuzza B, Morreale M, Marano P, Tripodi M, Ferri R. A Next-Generation Sequencing Study in a Cohort of Sicilian Patients with Parkinson's Disease. Biomedicines 2023; 11:3118. [PMID: 38137339 PMCID: PMC10740523 DOI: 10.3390/biomedicines11123118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/20/2023] [Accepted: 11/21/2023] [Indexed: 12/24/2023] Open
Abstract
Parkinson's disease (PD) is a multisystem and multifactorial disorder and, therefore, the application of modern genetic techniques may assist in unraveling its complex pathophysiology. We conducted a clinical-demographic evaluation of 126 patients with PD, all of whom were Caucasian and of Sicilian ancestry. DNA was extracted from the peripheral blood for each patient, followed by sequencing using a Next-Generation Sequencing system. This system was based on a custom gene panel comprising 162 genes. The sample underwent further filtering, taking into account the allele frequencies of genetic variants, their presence in the Human Gene Mutation Database, and their association in the literature with PD or other movement/neurodegenerative disorders. The largest number of variants was identified in the leucine-rich repeat kinase 2 (LRRK2) gene. However, variants in other genes, such as acid beta-glucosidase (GBA), DNA polymerase gamma catalytic subunit (POLG), and parkin RBR E3 ubiquitin protein ligase (PRKN), were also discovered. Interestingly, some of these variants had not been previously associated with PD. Enhancing our understanding of the genetic basis of PD and identifying new variants possibly linked to the disease will contribute to improved diagnostic accuracy, therapeutic developments, and prognostic insights for affected individuals.
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Affiliation(s)
- Michele Salemi
- Oasi Research Institute—IRCCS, 94018 Troina, EN, Italy; (M.S.); (M.G.S.); (F.A.S.); (F.D.D.B.); (S.C.); (B.L.); (M.M.); (P.M.); (M.T.); (R.F.)
| | - Giuseppe Lanza
- Oasi Research Institute—IRCCS, 94018 Troina, EN, Italy; (M.S.); (M.G.S.); (F.A.S.); (F.D.D.B.); (S.C.); (B.L.); (M.M.); (P.M.); (M.T.); (R.F.)
- Department of Surgery and Medical-Surgical Specialties, University of Catania, 95123 Catania, CT, Italy
| | - Maria Grazia Salluzzo
- Oasi Research Institute—IRCCS, 94018 Troina, EN, Italy; (M.S.); (M.G.S.); (F.A.S.); (F.D.D.B.); (S.C.); (B.L.); (M.M.); (P.M.); (M.T.); (R.F.)
| | - Francesca A. Schillaci
- Oasi Research Institute—IRCCS, 94018 Troina, EN, Italy; (M.S.); (M.G.S.); (F.A.S.); (F.D.D.B.); (S.C.); (B.L.); (M.M.); (P.M.); (M.T.); (R.F.)
| | - Francesco Domenico Di Blasi
- Oasi Research Institute—IRCCS, 94018 Troina, EN, Italy; (M.S.); (M.G.S.); (F.A.S.); (F.D.D.B.); (S.C.); (B.L.); (M.M.); (P.M.); (M.T.); (R.F.)
| | - Angela Cordella
- Genomix4Life Srl, 84081 Baronissi, SA, Italy;
- Genome Research Center for Health—CRGS, 84081 Baronissi, SA, Italy
| | - Salvatore Caniglia
- Oasi Research Institute—IRCCS, 94018 Troina, EN, Italy; (M.S.); (M.G.S.); (F.A.S.); (F.D.D.B.); (S.C.); (B.L.); (M.M.); (P.M.); (M.T.); (R.F.)
| | - Bartolo Lanuzza
- Oasi Research Institute—IRCCS, 94018 Troina, EN, Italy; (M.S.); (M.G.S.); (F.A.S.); (F.D.D.B.); (S.C.); (B.L.); (M.M.); (P.M.); (M.T.); (R.F.)
| | - Manuela Morreale
- Oasi Research Institute—IRCCS, 94018 Troina, EN, Italy; (M.S.); (M.G.S.); (F.A.S.); (F.D.D.B.); (S.C.); (B.L.); (M.M.); (P.M.); (M.T.); (R.F.)
| | - Pietro Marano
- Oasi Research Institute—IRCCS, 94018 Troina, EN, Italy; (M.S.); (M.G.S.); (F.A.S.); (F.D.D.B.); (S.C.); (B.L.); (M.M.); (P.M.); (M.T.); (R.F.)
| | - Mariangela Tripodi
- Oasi Research Institute—IRCCS, 94018 Troina, EN, Italy; (M.S.); (M.G.S.); (F.A.S.); (F.D.D.B.); (S.C.); (B.L.); (M.M.); (P.M.); (M.T.); (R.F.)
| | - Raffaele Ferri
- Oasi Research Institute—IRCCS, 94018 Troina, EN, Italy; (M.S.); (M.G.S.); (F.A.S.); (F.D.D.B.); (S.C.); (B.L.); (M.M.); (P.M.); (M.T.); (R.F.)
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Kong LY, Wu YZ, Cheng RQ, Wang PH, Peng BW. Role of Mutations of Mitochondrial Aminoacyl-tRNA Synthetases Genes on Epileptogenesis. Mol Neurobiol 2023; 60:5482-5492. [PMID: 37316759 DOI: 10.1007/s12035-023-03429-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 06/05/2023] [Indexed: 06/16/2023]
Abstract
Mitochondria are the structures in cells that are responsible for producing energy. They contain a specific translation unit for synthesizing mitochondria-encoded respiratory chain components: the mitochondrial DNA (mt DNA). Recently, a growing number of syndromes associated with the dysfunction of mt DNA translation have been reported. However, the functions of these diseases still need to be precise and thus attract much attention. Mitochondrial tRNAs (mt tRNAs) are encoded by mt DNA; they are the primary cause of mitochondrial dysfunction and are associated with a wide range of pathologies. Previous research has shown the role of mt tRNAs in the epileptic mechanism. This review will focus on the function of mt tRNA and the role of mitochondrial aminoacyl-tRNA synthetase (mt aaRS) in order to summarize some common relevant mutant genes of mt aaRS that cause epilepsy and the specific symptoms of the disease they cause.
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Affiliation(s)
- Ling-Yue Kong
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Yi-Ze Wu
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Run-Qi Cheng
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Pei-Han Wang
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Bi-Wen Peng
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
- Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Donghu Rd185#, Wuhan, 430071, Hubei, China.
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Tafazoli A, Mikros J, Khaghani F, Alimardani M, Rafigh M, Hemmati M, Siamoglou S, Golińska AK, Kamiński KA, Niemira M, Miltyk W, Patrinos GP. Pharmacovariome scanning using whole pharmacogene resequencing coupled with deep computational analysis and machine learning for clinical pharmacogenomics. Hum Genomics 2023; 17:62. [PMID: 37452347 PMCID: PMC10347842 DOI: 10.1186/s40246-023-00508-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 07/03/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND This pilot study aims to identify and functionally assess pharmacovariants in whole exome sequencing data. While detection of known variants has benefited from pharmacogenomic-dedicated bioinformatics tools before, in this paper we have tested novel deep computational analysis in addition to artificial intelligence as possible approaches for functional analysis of unknown markers within less studied drug-related genes. METHODS Pharmacovariants from 1800 drug-related genes from 100 WES data files underwent (a) deep computational analysis by eight bioinformatic algorithms (overall containing 23 tools) and (b) random forest (RF) classifier as the machine learning (ML) approach separately. ML model efficiency was calculated by internal and external cross-validation during recursive feature elimination. Protein modelling was also performed for predicted highly damaging variants with lower frequencies. Genotype-phenotype correlations were implemented for top selected variants in terms of highest possibility of being damaging. RESULTS Five deleterious pharmacovariants in the RYR1, POLG, ANXA11, CCNH, and CDH23 genes identified in step (a) and subsequent analysis displayed high impact on drug-related phenotypes. Also, the utilization of recursive feature elimination achieved a subset of 175 malfunction pharmacovariants in 135 drug-related genes that were used by the RF model with fivefold internal cross-validation, resulting in an area under the curve of 0.9736842 with an average accuracy of 0.9818 (95% CI: 0.89, 0.99) on predicting whether a carrying individuals will develop adverse drug reactions or not. However, the external cross-validation of the same model indicated a possible false positive result when dealing with a low number of observations, as only 60 important variants in 49 genes were displayed, giving an AUC of 0.5384848 with an average accuracy of 0.9512 (95% CI: 0.83, 0.99). CONCLUSION While there are some technologies for functionally assess not-interpreted pharmacovariants, there is still an essential need for the development of tools, methods, and algorithms which are able to provide a functional prediction for every single pharmacovariant in both large-scale datasets and small cohorts. Our approaches may bring new insights for choosing the right computational assessment algorithms out of high throughput DNA sequencing data from small cohorts to be used for personalized drug therapy implementation.
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Affiliation(s)
- Alireza Tafazoli
- Department of Analysis and Bioanalysis of Medicines, Faculty of Pharmacy With the Division of Laboratory Medicine, Medical University of Bialystok, 15-089, Białystok, Poland
- Laboratory of Pharmacogenomics, Department of Molecular Neuropharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Kraków, Poland
| | - John Mikros
- Laboratory of Pharmacogenomics and Individualized Therapy, Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece
| | - Faeze Khaghani
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran
| | - Maliheh Alimardani
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahboobeh Rafigh
- Medical Genetics Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahboobeh Hemmati
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Stavroula Siamoglou
- Laboratory of Pharmacogenomics and Individualized Therapy, Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece
| | | | - Karol A Kamiński
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Białystok, Poland
- Department of Cardiology, Medical University of Bialystok, Białystok, Poland
| | - Magdalena Niemira
- Clinical Research Centre, Medical University of Bialystok, Białystok, Poland
| | - Wojciech Miltyk
- Department of Analysis and Bioanalysis of Medicines, Faculty of Pharmacy With the Division of Laboratory Medicine, Medical University of Bialystok, 15-089, Białystok, Poland.
| | - George P Patrinos
- Laboratory of Pharmacogenomics and Individualized Therapy, Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece.
- Zayed Center for Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
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Venkadakrishnan J, Lahane G, Dhar A, Xiao W, Bhat KM, Pandita TK, Bhat A. Implications of Translesion DNA Synthesis Polymerases on Genomic Stability and Human Health. Mol Cell Biol 2023; 43:401-425. [PMID: 37439479 PMCID: PMC10448981 DOI: 10.1080/10985549.2023.2224199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 05/03/2023] [Accepted: 06/01/2023] [Indexed: 07/14/2023] Open
Abstract
Replication fork arrest-induced DNA double strand breaks (DSBs) caused by lesions are effectively suppressed in cells due to the presence of a specialized mechanism, commonly referred to as DNA damage tolerance (DDT). In eukaryotic cells, DDT is facilitated through translesion DNA synthesis (TLS) carried out by a set of DNA polymerases known as TLS polymerases. Another parallel mechanism, referred to as homology-directed DDT, is error-free and involves either template switching or fork reversal. The significance of the DDT pathway is well established. Several diseases have been attributed to defects in the TLS pathway, caused either by mutations in the TLS polymerase genes or dysregulation. In the event of a replication fork encountering a DNA lesion, cells switch from high-fidelity replicative polymerases to low-fidelity TLS polymerases, which are associated with genomic instability linked with several human diseases including, cancer. The role of TLS polymerases in chemoresistance has been recognized in recent years. In addition to their roles in the DDT pathway, understanding noncanonical functions of TLS polymerases is also a key to unraveling their importance in maintaining genomic stability. Here we summarize the current understanding of TLS pathway in DDT and its implication for human health.
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Affiliation(s)
| | - Ganesh Lahane
- Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Hyderabad Campus, Hyderabad, India
| | - Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Hyderabad Campus, Hyderabad, India
| | - Wei Xiao
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada
| | - Krishna Moorthi Bhat
- Department of Molecular Medicine, University of South Florida, Tampa, Florida, USA
| | - Tej K. Pandita
- Center for Genomics and Precision Medicine, Texas A&M College of Medicine, Houston, Texas, USA
| | - Audesh Bhat
- Center for Molecular Biology, Central University of Jammu, UT Jammu and Kashmir, India
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Altuntaş C, Uzunhan TA, Ertürk B, Petmezci MT, Çakar NE, Noyan B, Dokucu Aİ, Önal H. A very early onset MNGIE-like syndrome with POLG1 mutation and accompanying leukoencephalopathy. Clin Neurol Neurosurg 2023; 229:107712. [PMID: 37084649 DOI: 10.1016/j.clineuro.2023.107712] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 03/29/2023] [Accepted: 04/03/2023] [Indexed: 04/23/2023]
Abstract
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a well-known mitochondrial depletion syndrome. Since Van Goethem et al. described MNGIE syndrome with pathogenic POLG1 mutations in 2003, POLG1 gene became a target for MNGIE patients. Cases with POLG1 mutations strikingly differ from classic MNGIE patients due to a lack of leukoencephalopathy. Here we present a female patient with very early onset disease and leukoencephalopathy compatible with classic MNGIE disease who turned out to have homozygous POLG1 mutation compatible with MNGIE-like syndrome, mitochondrial depletion syndrome type 4b.
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Affiliation(s)
- Cansu Altuntaş
- Istinye University Medical Faculty, Pediatric Gastroenterology Department, Istanbul, Turkey.
| | - Tugce Aksu Uzunhan
- Prof Dr Cemil Taşçıoğlu City Hospital, Pediatric Neurology Department, Istanbul, Turkey
| | - Biray Ertürk
- Prof Dr Cemil Taşçıoğlu City Hospital, Medical Genetics Department, Istanbul, Turkey
| | - Mey Talip Petmezci
- Prof Dr Cemil Taşçıoğlu City Hospital, Pediatric Intensive Care Department, Istanbul, Turkey
| | - Nafiye Emel Çakar
- Prof Dr Cemil Taşçıoğlu City Hospital, Pediatric Metabolic Diseases Department, Istanbul, Turkey
| | - Bilge Noyan
- University of Health Sciences Başakşehir Çam Sakura City Hospital, Pediatric Metabolic Diseases Department, Istanbul, Turkey
| | - Ali İhsan Dokucu
- Prof Dr Cemil Taşçıoğlu City Hospital, Pediatric Surgery Department, Istanbul, Turkey
| | - Hasan Önal
- University of Health Sciences Başakşehir Çam Sakura City Hospital, Pediatric Metabolic Diseases Department, Istanbul, Turkey
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Ng YS, Gorman GS. Stroke-like episodes in adult mitochondrial disease. HANDBOOK OF CLINICAL NEUROLOGY 2023; 194:65-78. [PMID: 36813321 DOI: 10.1016/b978-0-12-821751-1.00005-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
Stroke-like episode is a paroxysmal neurological manifestation which affects a specific group of patients with mitochondrial disease. Focal-onset seizures, encephalopathy, and visual disturbances are prominent findings associated with stroke-like episodes, with a predilection for the posterior cerebral cortex. The most common cause of stroke-like episodes is the m.3243A>G variant in MT-TL1 gene followed by recessive POLG variants. This chapter aims to review the definition of stroke-like episode and delineate the clinical phenomenology, neuroimaging and EEG findings typically seen in patients. In addition, several lines of evidence supporting neuronal hyper-excitability as the key mechanism of stroke-like episodes are discussed. The management of stroke-like episodes should focus on aggressive seizure management and treatment for concomitant complications such as intestinal pseudo-obstruction. There is no robust evidence to prove the efficacy of l-arginine for both acute and prophylactic settings. Progressive brain atrophy and dementia are the sequalae of recurrent stroke-like episode, and the underlying genotype in part predicts prognosis.
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Affiliation(s)
- Yi Shiau Ng
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Gráinne S Gorman
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
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10
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Abstract
Progressive external ophthalmoplegia (PEO), characterized by ptosis and impaired eye movements, is a clinical syndrome with an expanding number of etiologically distinct subtypes. Advances in molecular genetics have revealed numerous pathogenic causes of PEO, originally heralded in 1988 by the detection of single large-scale deletions of mitochondrial DNA (mtDNA) in skeletal muscle of people with PEO and Kearns-Sayre syndrome. Since then, multiple point variants of mtDNA and nuclear genes have been identified to cause mitochondrial PEO and PEO-plus syndromes, including mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and sensory ataxic neuropathy dysarthria ophthalmoplegia (SANDO). Intriguingly, many of those nuclear DNA pathogenic variants impair maintenance of the mitochondrial genome causing downstream mtDNA multiple deletions and depletion. In addition, numerous genetic causes of nonmitochondrial PEO have been identified.
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Affiliation(s)
- Michio Hirano
- H. Houston Merritt Neuromuscular Research Center, Neuromuscular Medicine Division, Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States.
| | - Robert D S Pitceathly
- Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, United Kingdom
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Bianco F, Lattanzio G, Lorenzini L, Mazzoni M, Clavenzani P, Calzà L, Giardino L, Sternini C, Costanzini A, Bonora E, De Giorgio R. Enteric Neuromyopathies: Highlights on Genetic Mechanisms Underlying Chronic Intestinal Pseudo-Obstruction. Biomolecules 2022; 12:biom12121849. [PMID: 36551277 PMCID: PMC9776039 DOI: 10.3390/biom12121849] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/04/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Severe gut motility disorders are characterized by the ineffective propulsion of intestinal contents. As a result, the patients develop disabling/distressful symptoms, such as nausea and vomiting along with altered bowel habits up to radiologically demonstrable intestinal sub-obstructive episodes. Chronic intestinal pseudo-obstruction (CIPO) is a typical clinical phenotype of severe gut dysmotility. This syndrome occurs due to changes altering the morpho-functional integrity of the intrinsic (enteric) innervation and extrinsic nerve supply (hence neuropathy), the interstitial cells of Cajal (ICC) (mesenchymopathy), and smooth muscle cells (myopathy). In the last years, several genes have been identified in different subsets of CIPO patients. The focus of this review is to cover the most recent update on enteric dysmotility related to CIPO, highlighting (a) forms with predominant underlying neuropathy, (b) forms with predominant myopathy, and (c) mitochondrial disorders with a clear gut dysfunction as part of their clinical phenotype. We will provide a thorough description of the genes that have been proven through recent evidence to cause neuro-(ICC)-myopathies leading to abnormal gut contractility patterns in CIPO. The discovery of susceptibility genes for this severe condition may pave the way for developing target therapies for enteric neuro-(ICC)-myopathies underlying CIPO and other forms of gut dysmotility.
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Affiliation(s)
- Francesca Bianco
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | - Giulia Lattanzio
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
| | - Luca Lorenzini
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
| | - Maurizio Mazzoni
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
| | - Paolo Clavenzani
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
| | - Laura Calzà
- IRET Foundation, 40064 Ozzano Emilia, Italy
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Luciana Giardino
- Department of Veterinary Sciences, University of Bologna, 40064 Ozzano Emilia, Italy
- IRET Foundation, 40064 Ozzano Emilia, Italy
| | - Catia Sternini
- UCLA/DDRC, Division of Digestive Diseases, Departments Medicine and Neurobiology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90001, USA
| | - Anna Costanzini
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
| | - Elena Bonora
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
- Correspondence: (E.B.); (R.D.G.); Tel.: +39-051-2094761 (E.B.); +39-0532-236631 (R.D.G.)
| | - Roberto De Giorgio
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
- Correspondence: (E.B.); (R.D.G.); Tel.: +39-051-2094761 (E.B.); +39-0532-236631 (R.D.G.)
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12
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Elwan M, Schaefer AM, Craig K, Hopton S, Falkous G, Blakely EL, Taylor RW, Warren N. Changing faces of mitochondrial disease: autosomal recessive POLG disease mimicking myasthenia gravis and progressive supranuclear palsy. BMJ Neurol Open 2022; 4:e000352. [PMID: 36518302 PMCID: PMC9743281 DOI: 10.1136/bmjno-2022-000352] [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] [Subscribe] [Scholar Register] [Accepted: 11/22/2022] [Indexed: 12/13/2022] Open
Abstract
Background Mitochondrial disorders are known to cause diverse neurological phenotypes which cause a diagnostic challenge to most neurologists. Pathogenic polymerase gamma (POLG) variants have been described as a cause of chronic progressive external ophthalmoplegia, which manifests with ptosis, horizontal and vertical eye movement restriction and myopathy. Autosomal dominant progressive external ophthalmoplegia is rarely associated with Parkinsonism responsive to levodopa. Methods We report a case of a 58-year-old man who presented with an eye movement disorder then Parkinsonism who made his way through the myasthenia then the movement disorder clinic. Results A diagnostic right tibialis anterior biopsy revealed classical hallmarks of mitochondrial disease, and genetic testing identified compound heterozygous pathogenic gene variants in the POLG gene. The patient was diagnosed with autosomal recessive POLG disease. Conclusions It is important to maintain a high index of suspicion of pathogenic POLG variants in patients presenting with atypical Parkinsonism and ophthalmoplegia. Patients with POLG-related disease will usually have ptosis, and downgaze is typically preserved until late in the disease. Accurate diagnosis is essential for appropriate prognosis and genetic counselling.
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Affiliation(s)
- Menatalla Elwan
- Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
| | - Andrew M Schaefer
- Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Kate Craig
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Sila Hopton
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Gavin Falkous
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Emma L Blakely
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Robert W Taylor
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
- NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle University, Newcastle upon Tyne, UK
| | - Naomi Warren
- Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
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13
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Bonora E, Bianco F, Giorgio RD. Comment to the Description of a Novel Cohesinopathy in Chronic Intestinal Pseudo Obstruction. J Neurogastroenterol Motil 2022; 28:501-502. [PMID: 35799243 PMCID: PMC9274473 DOI: 10.5056/jnm22017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Affiliation(s)
- Elena Bonora
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Italy
| | - Francesca Bianco
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Italy
- Department of Veterinary Medical Sciences, University of Bologna, Italy
| | - Roberto De Giorgio
- Department of Translational Medicine, St. Anna Hospital, University of Ferrara, Italy
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14
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Zada A, Kuil LE, de Graaf BM, Kakiailatu N, Windster JD, Brooks AS, van Slegtenhorst M, de Koning B, Wijnen RMH, Melotte V, Hofstra RMW, Brosens E, Alves MM. TFAP2B Haploinsufficiency Impacts Gastrointestinal Function and Leads to Pediatric Intestinal Pseudo-obstruction. Front Cell Dev Biol 2022; 10:901824. [PMID: 35874825 PMCID: PMC9304996 DOI: 10.3389/fcell.2022.901824] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/14/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Pediatric Intestinal Pseudo-obstruction (PIPO) is a congenital enteric disorder characterized by severe gastrointestinal (GI) dysmotility, without mechanical obstruction. Although several genes have been described to cause this disease, most patients do not receive a genetic diagnosis. Here, we aim to identify the genetic cause of PIPO in a patient diagnosed with severe intestinal dysmotility shortly after birth. Methods: Whole exome sequencing (WES) was performed in the patient and unaffected parents, in a diagnostic setting. After identification of the potential disease-causing variant, its functional consequences were determined in vitro and in vivo. For this, expression constructs with and without the causing variant, were overexpressed in HEK293 cells. To investigate the role of the candidate gene in GI development and function, a zebrafish model was generated where its expression was disrupted using CRISPR/Cas9 editing. Results: WES analysis identified a de novo heterozygous deletion in TFAP2B (NM_003221.4:c.602-5_606delTCTAGTTCCA), classified as a variant of unknown significance. In vitro studies showed that this deletion affects RNA splicing and results in loss of exon 4, leading to the appearance of a premature stop codon and absence of TFAP2B protein. Disruption of tfap2b in zebrafish led to decreased enteric neuronal numbers and delayed transit time. However, no defects in neuronal differentiation were detected. tfap2b crispants also showed decreased levels of ednrbb mRNA, a downstream target of tfap2b. Conclusion: We showed that TFAP2B haploinsufficiency leads to reduced neuronal numbers and GI dysmotility, suggesting for the first time, that this gene is involved in PIPO pathogenesis.
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Affiliation(s)
- Almira Zada
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
- *Correspondence: Almira Zada, ; Maria M. Alves,
| | - Laura E. Kuil
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Bianca M. de Graaf
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Naomi Kakiailatu
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Jonathan D. Windster
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
- Department of Pediatric Surgery, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Alice S. Brooks
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Marjon van Slegtenhorst
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Barbara de Koning
- Department of Pediatric Gastroenterology, Erasmus University Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - René M. H. Wijnen
- Department of Pediatric Surgery, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Veerle Melotte
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Robert M. W. Hofstra
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Erwin Brosens
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
| | - Maria M. Alves
- Department of Clinical Genetics, Erasmus Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands
- *Correspondence: Almira Zada, ; Maria M. Alves,
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15
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Hou Y, Zhao X, Xie Z, Yu M, Lv H, Zhang W, Yuan Y, Wang Z. Novel and recurrent nuclear gene variations in a cohort of Chinese progressive external ophthalmoplegia patients with multiple mtDNA deletions. Mol Genet Genomic Med 2022; 10:e1921. [PMID: 35289132 PMCID: PMC9034679 DOI: 10.1002/mgg3.1921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/30/2021] [Accepted: 02/25/2022] [Indexed: 11/07/2022] Open
Abstract
Objectives This study aimed to investigate the clinical and genetic spectrum in Chinese patients with multiple mtDNA deletions presenting with autosomal‐inherited mitochondrial progressive external ophthalmoplegia (PEO). Methods Long‐range polymerase chain reaction and massively parallel sequencing of the mitochondrial genome were performed to detect deletions in muscle mtDNA of 274 unrelated families. Then, targeted next generation sequencing was used to detect nuclear gene variations in patients with multiple mtDNA deletions. Results A total of 40 Chinese PEO patients (10 males and 30 females) from 20 families were found to have multiple mtDNA deletions in this study, and the median age at onset was 35 (1–70) years. PEO and positive family history were the two prominent features of these patients, and ataxia, neuropathy, and hypogonadism were also present as onset symptoms in some patients. Fifteen of 20 probands with multiple mtDNA deletions were identified to carry nuclear gene variants; eight (40.0%) probands had variants within POLG, two (10.0%) within TWNK, two (10.0%) within RRM2B, two (10.0%) within TK2, and one (5.0%) within POLG2. A total of 24 variants were found in these five nuclear genes, of which 19 were novel. The causal nuclear genetic factors in five pedigrees remain undetermined. Conclusions The POLG gene is the most common disease‐causing gene in this group of PEO patients with multiple mtDNA deletions. While inherited PEO is the most prominent symptoms in these patients, genotypic and phenotypic heterogeneity still exist, for example in onset age, initial symptoms, and accompanying manifestations.
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Affiliation(s)
- Yue Hou
- Department of Neurology, Peking University First Hospital, Beijing, China.,Department of Geriatrics, Peking University First Hospital, Beijing, China
| | - Xutong Zhao
- Department of Neurology, Peking University First Hospital, Beijing, China
| | - Zhiying Xie
- Department of Neurology, Peking University First Hospital, Beijing, China
| | - Meng Yu
- Department of Neurology, Peking University First Hospital, Beijing, China
| | - He Lv
- Department of Neurology, Peking University First Hospital, Beijing, China
| | - Wei Zhang
- Department of Neurology, Peking University First Hospital, Beijing, China
| | - Yun Yuan
- Department of Neurology, Peking University First Hospital, Beijing, China
| | - Zhaoxia Wang
- Department of Neurology, Peking University First Hospital, Beijing, China.,Beijing Key Laboratory of Neurovascular Disease Discovery, Beijing, China
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16
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NGS in Hereditary Ataxia: When Rare Becomes Frequent. Int J Mol Sci 2021; 22:ijms22168490. [PMID: 34445196 PMCID: PMC8395181 DOI: 10.3390/ijms22168490] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/03/2021] [Accepted: 08/04/2021] [Indexed: 12/17/2022] Open
Abstract
The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.
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17
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Bender F, Timmann D, van de Warrenburg BP, Adarmes-Gómez AD, Bender B, Thieme A, Synofzik M, Schöls L. Natural History of Polymerase Gamma-Related Ataxia. Mov Disord 2021; 36:2642-2652. [PMID: 34288125 DOI: 10.1002/mds.28713] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/31/2021] [Accepted: 06/16/2021] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Mutations in the mitochondrial DNA polymerase gamma are causing a wide phenotypic spectrum including ataxia as one of the most common presentations. OBJECTIVE The objective of this study was to determine the course of disease of polymerase gamma-related ataxia. METHODS In a prospective natural history study, we assessed 24 adult ataxia patients with biallelic polymerase gamma mutations for (1) severity of cerebellar dysfunction using the Scale for the Assessment and Rating of Ataxia score, (2) presence of nonataxia signs using the Inventory of Non-Ataxia Symptoms, (3) gray- and white-matter changes in brain MRI, and (4) findings in nerve conduction studies. RESULTS Assessment included follow-up visits up to 11.6 years. The Scale for the Assessment and Rating of Ataxia showed a mean annual increase of 1.02 ± 0.78 points/year. Disease progression was faster in patients with age at onset ≤ 30 years (1.5 Scale for the Assessment and Rating of Ataxia points/year) than with later onset (0.5 points/year); P = 0.008. The Inventory of Non-Ataxia Symptoms count increased by 0.30 ± 0.4 points/year. External ophthalmoplegia, brain stem oculomotor signs, areflexia, and sensory deficits were the most common nonataxic features. On MRI cerebellar atrophy was mild. T2 signal alterations affected mostly cerebellar white matter, middle cerebellar peduncles, thalamus, brain stem, and occipital and frontal white matter. Within 4 years, progression was primarily observed in the context of repeated epileptic seizures. Nerve conduction studies revealed axonal sensory peripheral neuropathy with mild motor nerve involvement. Exploratory sample size calculation implied 38 patients per arm as sufficient to detect a reduction of progression by 50% in hypothetical interventions within a 1-year trial. CONCLUSION The results recommend the Scale for the Assessment and Rating of Ataxia as a primary outcome measure for future interventional trials in polymerase gamma-related ataxia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Friedemann Bender
- Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Tuebingen, Germany.,German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany
| | - Dagmar Timmann
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Bart P van de Warrenburg
- Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Astrid D Adarmes-Gómez
- Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Benjamin Bender
- Department of Diagnostics and Interventional Neuroradiology, University of Tuebingen, Tuebingen, Germany
| | - Andreas Thieme
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Matthis Synofzik
- Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Tuebingen, Germany.,German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany
| | - Ludger Schöls
- Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tuebingen, Tuebingen, Germany.,German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany
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18
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Holland AM, Bon-Frauches AC, Keszthelyi D, Melotte V, Boesmans W. The enteric nervous system in gastrointestinal disease etiology. Cell Mol Life Sci 2021; 78:4713-4733. [PMID: 33770200 PMCID: PMC8195951 DOI: 10.1007/s00018-021-03812-y] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/20/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023]
Abstract
A highly conserved but convoluted network of neurons and glial cells, the enteric nervous system (ENS), is positioned along the wall of the gut to coordinate digestive processes and gastrointestinal homeostasis. Because ENS components are in charge of the autonomous regulation of gut function, it is inevitable that their dysfunction is central to the pathophysiology and symptom generation of gastrointestinal disease. While for neurodevelopmental disorders such as Hirschsprung, ENS pathogenesis appears to be clear-cut, the role for impaired ENS activity in the etiology of other gastrointestinal disorders is less established and is often deemed secondary to other insults like intestinal inflammation. However, mounting experimental evidence in recent years indicates that gastrointestinal homeostasis hinges on multifaceted connections between the ENS, and other cellular networks such as the intestinal epithelium, the immune system, and the intestinal microbiome. Derangement of these interactions could underlie gastrointestinal disease onset and elicit variable degrees of abnormal gut function, pinpointing, perhaps unexpectedly, the ENS as a diligent participant in idiopathic but also in inflammatory and cancerous diseases of the gut. In this review, we discuss the latest evidence on the role of the ENS in the pathogenesis of enteric neuropathies, disorders of gut-brain interaction, inflammatory bowel diseases, and colorectal cancer.
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Affiliation(s)
- Amy Marie Holland
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Ana Carina Bon-Frauches
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Daniel Keszthelyi
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, NUTRIM-School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Veerle Melotte
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Werend Boesmans
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.
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19
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Bonora E, Chakrabarty S, Kellaris G, Tsutsumi M, Bianco F, Bergamini C, Ullah F, Isidori F, Liparulo I, Diquigiovanni C, Masin L, Rizzardi N, Cratere MG, Boschetti E, Papa V, Maresca A, Cenacchi G, Casadio R, Martelli P, Matera I, Ceccherini I, Fato R, Raiola G, Arrigo S, Signa S, Sementa AR, Severino M, Striano P, Fiorillo C, Goto T, Uchino S, Oyazato Y, Nakamura H, Mishra SK, Yeh YS, Kato T, Nozu K, Tanboon J, Morioka I, Nishino I, Toda T, Goto YI, Ohtake A, Kosaki K, Yamaguchi Y, Nonaka I, Iijima K, Mimaki M, Kurahashi H, Raams A, MacInnes A, Alders M, Engelen M, Linthorst G, de Koning T, den Dunnen W, Dijkstra G, van Spaendonck K, van Gent DC, Aronica EM, Picco P, Carelli V, Seri M, Katsanis N, Duijkers FAM, Taniguchi-Ikeda M, De Giorgio R. Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy. Brain 2021; 144:1451-1466. [PMID: 33855352 DOI: 10.1093/brain/awab056] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 11/13/2020] [Accepted: 12/09/2020] [Indexed: 12/11/2022] Open
Abstract
Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities.
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Affiliation(s)
- Elena Bonora
- Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, 40138, Italy
| | - Sanjiban Chakrabarty
- Department of Molecular Genetics, Erasmus MC, Rotterdam, 3000 CA, The Netherlands
| | - Georgios Kellaris
- Center for Human Disease Modeling, Duke University, Durham, NC 27710, USA
| | - Makiko Tsutsumi
- Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Aichi, 470-1192, Japan
| | - Francesca Bianco
- Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, 40138, Italy
| | - Christian Bergamini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy
| | - Farid Ullah
- Center for Human Disease Modeling, Duke University, Durham, NC 27710, USA
| | - Federica Isidori
- Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, 40138, Italy
| | - Irene Liparulo
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy
| | - Chiara Diquigiovanni
- Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, 40138, Italy
| | - Luca Masin
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy
| | - Nicola Rizzardi
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy
| | - Mariapia Giuditta Cratere
- Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, 40138, Italy.,Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, 20132, Italy
| | - Elisa Boschetti
- Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, 40138, Italy
| | - Valentina Papa
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 40123, Italy
| | - Alessandra Maresca
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, 40139, Italy
| | - Giovanna Cenacchi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 40123, Italy
| | - Rita Casadio
- Biocomputing Group, Department of Biological, Geological, Environmental Sciences, University of Bologna, Bologna, 40126, Italy
| | - Pierluigi Martelli
- Biocomputing Group, Department of Biological, Geological, Environmental Sciences, University of Bologna, Bologna, 40126, Italy
| | - Ivana Matera
- IRCCS Istituto Giannina Gaslini, Genova, 16128, Italy
| | | | - Romana Fato
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy
| | - Giuseppe Raiola
- Department of Paediatrics, Pugliese-Ciaccio Hospital, Catanzaro, 88100, Italy
| | - Serena Arrigo
- IRCCS Istituto Giannina Gaslini, Genova, 16128, Italy
| | - Sara Signa
- IRCCS Istituto Giannina Gaslini, Genova, 16128, Italy
| | | | | | | | | | - Tsuyoshi Goto
- Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, 611-0011, Japan
| | - Shumpei Uchino
- Department of Pediatrics, Teikyo University School of Medicine, Tokyo, 173-8605, Japan.,Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Yoshinobu Oyazato
- Department of Pediatrics, Kakogawa Central City Hospital, Kakogawa, Hyogo, 675-8611, Japan
| | - Hisayoshi Nakamura
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan
| | - Sushil K Mishra
- Glycoscience Group, National University of Ireland, Galway, H91 CF50, Ireland
| | - Yu-Sheng Yeh
- Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, 611-0011, Japan
| | - Takema Kato
- Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Aichi, 470-1192, Japan
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan
| | - Jantima Tanboon
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan
| | - Ichiro Morioka
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, 173-8610, Japan
| | - Ichizo Nishino
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan
| | - Tatsushi Toda
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Yu-Ichi Goto
- Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan
| | - Akira Ohtake
- Department of Pediatrics & Clinical Genomics, Faculty of Medicine, Saitama Medical University, Saitama, 350-0495, Japan
| | - Kenjiro Kosaki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, 160-8582, Japan
| | - Yoshiki Yamaguchi
- Laboratory of Pharmaceutical Physical Chemistry, Tohoku Medical and Pharmaceutical University, Miyagi, 981-8558, Japan
| | - Ikuya Nonaka
- Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan
| | - Kazumoto Iijima
- Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan
| | - Masakazu Mimaki
- Department of Pediatrics, Teikyo University School of Medicine, Tokyo, 173-8605, Japan
| | - Hiroki Kurahashi
- Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Aichi, 470-1192, Japan
| | - Anja Raams
- Department of Molecular Genetics, Erasmus MC, Rotterdam, 3000 CA, The Netherlands
| | - Alyson MacInnes
- Department of Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, 1100 DD, The Netherlands
| | - Mariel Alders
- Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, 1100 DD, The Netherlands
| | - Marc Engelen
- Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, 1100 DD, The Netherlands
| | - Gabor Linthorst
- Department of Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, 1100 DD, The Netherlands
| | - Tom de Koning
- Department of Metabolic Diseases, UMCG, Groningen, 9700 RB, The Netherlands
| | | | - Gerard Dijkstra
- Department of Gastroenterology, UMCG, Groningen, 9700 RB, The Netherlands
| | - Karin van Spaendonck
- Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, 1100 DD, The Netherlands
| | - Dik C van Gent
- Department of Molecular Genetics, Erasmus MC, Rotterdam, 3000 CA, The Netherlands
| | - Eleonora M Aronica
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, 1100 DD, The Netherlands
| | - Paolo Picco
- IRCCS Istituto Giannina Gaslini, Genova, 16128, Italy
| | - Valerio Carelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 40123, Italy.,IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, 40139, Italy
| | - Marco Seri
- Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, 40138, Italy
| | - Nicholas Katsanis
- Center for Human Disease Modeling, Duke University, Durham, NC 27710, USA
| | - Floor A M Duijkers
- Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, 1100 DD, The Netherlands
| | - Mariko Taniguchi-Ikeda
- Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Aichi, 470-1192, Japan.,Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan.,Department of Clinical Genetics, Fujita Health University Hospital, Aichi, 470-1192, Japan
| | - Roberto De Giorgio
- Department of Morphology, Surgery and Experimental Medicine, St. Anna Hospital, University of Ferrara, Ferrara, 44124, Italy
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20
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Zhu CZ, Zhao HW, Lin HW, Wang F, Li YX. Latest developments in chronic intestinal pseudo-obstruction. World J Clin Cases 2020. [DOI: 10.12998/wjcc.v8.i23.5850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
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21
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Zhu CZ, Zhao HW, Lin HW, Wang F, Li YX. Latest developments in chronic intestinal pseudo-obstruction. World J Clin Cases 2020; 8:5852-5865. [PMID: 33344584 PMCID: PMC7723695 DOI: 10.12998/wjcc.v8.i23.5852] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 10/02/2020] [Accepted: 10/19/2020] [Indexed: 02/05/2023] Open
Abstract
Chronic intestinal pseudo-obstruction (CIPO) is a type of intestinal dysfunction presenting as symptoms of intestinal obstruction but without actual mechanical obstruction. An extremely low incidence, non-specific clinical symptoms, strong heterogeneity, and no definitive cause in some patients make CIPO very difficult to diagnose correctly. Imaging and gastrointestinal manometry are commonly used. Most patients have progressive worsening of their symptoms and require intervention, and nutritional assessment and treatment are very important to determine the prognosis. With improvements in surgical techniques, small bowel transplantation is a feasible treatment option for patients with advanced CIPO; however, the long-term prognosis for CIPO patients remains unsatisfactory. Generally, the disease is rare and difficult to diagnose, which leads to clinicians' lack of understanding of the disease and results in a high rate of misdiagnosis. This review describes the characteristics of CIPO and the latest developments in diagnosis and treatment, in detail. The goal of our review is to improve clinicians' understanding of CIPO so that the disease is identified quickly and accurately, and treated as early as possible to improve patients' quality of life.
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Affiliation(s)
- Chang-Zhen Zhu
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Hong-Wei Zhao
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Hong-Wei Lin
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Feng Wang
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yuan-Xin Li
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
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22
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Abstract
Mitochondrial disease presenting in childhood is characterized by clinical, biochemical and genetic complexity. Some children are affected by canonical syndromes, but the majority have nonclassical multisystemic disease presentations involving virtually any organ in the body. Each child has a unique constellation of clinical features and disease trajectory, leading to enormous challenges in diagnosis and management of these heterogeneous disorders. This review discusses the classical mitochondrial syndromes presenting most frequently in childhood and then presents an organ-based perspective including systems less frequently linked to mitochondrial disease, such as skin and hair abnormalities and immune dysfunction. An approach to diagnosis is then presented, encompassing clinical evaluation and biochemical, neuroimaging and genetic investigations, and emphasizing the problem of phenocopies. The impact of next-generation sequencing is discussed, together with the importance of functional validation of novel genetic variants never previously linked to mitochondrial disease. The review concludes with a brief discussion of currently available and emerging therapies. The field of mitochondrial medicine has made enormous strides in the last 30 years, with approaching 400 different genes across two genomes now linked to primary mitochondrial disease. However, many important questions remain unanswered, including the reasons for tissue specificity and variability of clinical presentation of individuals sharing identical gene defects, and a lack of disease-modifying therapies and biomarkers to monitor disease progression and/or response to treatment.
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Affiliation(s)
- S Rahman
- Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, UK
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23
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Hu C, Li X, Zhao L, Shi Y, Zhou S, Wu B, Wang Y. Clinical and molecular characterization of pediatric mitochondrial disorders in south of China. Eur J Med Genet 2020; 63:103898. [PMID: 32348839 DOI: 10.1016/j.ejmg.2020.103898] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/15/2020] [Accepted: 02/19/2020] [Indexed: 12/30/2022]
Abstract
Mitochondrial disorders (MDs) are genetic ailments affecting all age groups. Epidemiological data and frequencies of gene mutations in pediatric patients in China are scarce. This retrospective study assessed 101 patients with suspected MDs treated at the Neurology Department of Children's Hospital, Fudan University, in 2011-2017. Mitochondrial (mtDNA) and nuclear (nDNA) samples were assessed by long-range polymerase chain reaction (PCR)-based whole mtDNA sequencing and whole exome sequencing (WES) for identifying pathogenic mutations. Muscle samples underwent various staining protocols and immunofluorescence for detecting selected proteins. Seventeen mutations in the MT-TL1, MT-COX2, MT-ND4, MT, tRNA TRNE, MT-TN, MT-TK, MT-ATP6, MT-ND6, MT-ND3 and MT-CO3 genes were identified in 39 patients, of which m.3243A > G, m.3303C > T, m.8993T > C/G, m.9176T > C, and m.10191T > C were most common. Mitochondrial myopathy and MELAS were most common for m.3243A > G mutation. Four novel mutations were detected, including m.9478insT, m.5666T > C, m.8265T > C, and m.8380-13600 deletion mutations related to Leigh syndrome, mitochondrial myopathy and KSS, respectively. Thirty-three mutations in the TK2, POLG, IBA57, HADHB, FBXL4, ALDH5A1, FOXRED1, TPK1, NDUFAF5, NDUFAF7, NDUFV1, CARS2, PDHA1, and HIBCH genes were identified in 19 patients, including 23 currently unknown. Higher rates of TK2, POLG, IBA57, and HADHB mutations were found in nDNA-mutated MD compared with the remaining individuals. Besides, IBA57 c.286T > C (p.Y96H), TK2 c.497A > T (p.D166V) founder mutations critically contributed to MDs. Comprehensive genomic analysis plays a critical role in pediatric MD diagnosis. These data summarize the relative frequencies of different gene mutations in a large Chinese population, and identified 23 novel MD-associated nDNA and 4 novel mtDNA mutations.
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Affiliation(s)
- Chaoping Hu
- Department of Neurology, Children's Hospital of Fudan University, Shanghai, China
| | - Xihua Li
- Department of Neurology, Children's Hospital of Fudan University, Shanghai, China.
| | - Lei Zhao
- Department of Neurology, Children's Hospital of Fudan University, Shanghai, China
| | - Yiyun Shi
- Department of Neurology, Children's Hospital of Fudan University, Shanghai, China
| | - Shuizhen Zhou
- Department of Neurology, Children's Hospital of Fudan University, Shanghai, China
| | - Bingbing Wu
- Translational Research Center for Development and Disease, Children's Hospital of Fudan University, Shanghai, China
| | - Yi Wang
- Department of Neurology, Children's Hospital of Fudan University, Shanghai, China.
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24
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Hoyos-Gonzalez N, Trasviña-Arenas CH, Degiorgi A, Castro-Lara AY, Peralta-Castro A, Jimenez-Sandoval P, Diaz-Quezada C, Lodi T, Baruffini E, Brieba LG. Modeling of pathogenic variants of mitochondrial DNA polymerase: insight into the replication defects and implication for human disease. Biochim Biophys Acta Gen Subj 2020; 1864:129608. [PMID: 32234506 DOI: 10.1016/j.bbagen.2020.129608] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 03/07/2020] [Accepted: 03/25/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Mutations in human gene encoding the mitochondrial DNA polymerase γ (HsPolγ) are associated with a broad range of mitochondrial diseases. Here we studied the impact on DNA replication by disease variants clustered around residue HsPolγ-K1191, a residue that in several family-A DNA polymerases interacts with the 3' end of the primer. METHODS Specifically, we examined the effect of HsPolγ carrying pathogenic variants in residues D1184, I1185, C1188, K1191, D1196, and a stop codon at residue T1199, using as a model the yeast mitochondrial DNA polymerase protein, Mip1p. RESULTS The introduction of pathogenic variants C1188R (yV945R), and of a stop codon at residue T1199 (yT956X) abolished both polymerization and exonucleolysis in vitro. HsPolγ substitutions in residues D1184 (yD941), I1185 (yI942), K1191 (yK948) and D1196 (yD953) shifted the balance between polymerization and exonucleolysis in favor of exonucleolysis. HsPolγ pathogenic variants at residue K1191 (yK948) and D1184 (yD941) were capable of nucleotide incorporation albeit with reduced processivity. Structural analysis of mitochondrial DNAPs showed that residue HsPolγ-N864 is placed in an optimal distance to interact with the 3' end of the primer and the phosphate backbone previous to the 3' end. Amino acid changes in residue HsPolγ-N864 to Ala, Ser or Asp result in enzymes that did not decrease their polymerization activity on short templates but exhibited a substantial decrease for processive DNA synthesis. CONCLUSION Our data suggest that in mitochondrial DNA polymerases multiple amino acids are involved in the primer-stand stabilization.
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Affiliation(s)
- Nallely Hoyos-Gonzalez
- Laboratorio Nacional de Genómica para la Biodiversidad, Centro de Investigación y de Estudios Avanzados del IPN, Apartado Postal 629, CP 36821 Irapuato, Guanajuato, Mexico
| | - Carlos H Trasviña-Arenas
- Laboratorio Nacional de Genómica para la Biodiversidad, Centro de Investigación y de Estudios Avanzados del IPN, Apartado Postal 629, CP 36821 Irapuato, Guanajuato, Mexico
| | - Andrea Degiorgi
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 11/A, 43124 Parma, Italy
| | - Atzimaba Y Castro-Lara
- Laboratorio Nacional de Genómica para la Biodiversidad, Centro de Investigación y de Estudios Avanzados del IPN, Apartado Postal 629, CP 36821 Irapuato, Guanajuato, Mexico
| | - Antolín Peralta-Castro
- Laboratorio Nacional de Genómica para la Biodiversidad, Centro de Investigación y de Estudios Avanzados del IPN, Apartado Postal 629, CP 36821 Irapuato, Guanajuato, Mexico
| | - Pedro Jimenez-Sandoval
- Laboratorio Nacional de Genómica para la Biodiversidad, Centro de Investigación y de Estudios Avanzados del IPN, Apartado Postal 629, CP 36821 Irapuato, Guanajuato, Mexico
| | - Corina Diaz-Quezada
- Laboratorio Nacional de Genómica para la Biodiversidad, Centro de Investigación y de Estudios Avanzados del IPN, Apartado Postal 629, CP 36821 Irapuato, Guanajuato, Mexico
| | - Tiziana Lodi
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 11/A, 43124 Parma, Italy
| | - Enrico Baruffini
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 11/A, 43124 Parma, Italy.
| | - Luis G Brieba
- Laboratorio Nacional de Genómica para la Biodiversidad, Centro de Investigación y de Estudios Avanzados del IPN, Apartado Postal 629, CP 36821 Irapuato, Guanajuato, Mexico.
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25
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Wright CM, Garifallou JP, Schneider S, Mentch HL, Kothakapa DR, Maguire BA, Heuckeroth RO. Dlx1/2 mice have abnormal enteric nervous system function. JCI Insight 2020; 5:131494. [PMID: 32017713 DOI: 10.1172/jci.insight.131494] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 01/22/2020] [Indexed: 12/31/2022] Open
Abstract
Decades ago, investigators reported that mice lacking DLX1 and DLX2, transcription factors expressed in the enteric nervous system (ENS), die with possible bowel motility problems. These problems were never fully elucidated. We found that mice lacking DLX1 and DLX2 (Dlx1/2-/- mice) had slower small bowel transit and reduced or absent neurally mediated contraction complexes. In contrast, small bowel motility seemed normal in adult mice lacking DLX1 (Dlx1-/-). Even with detailed anatomic studies, we found no defects in ENS precursor migration, or neuronal and glial density in Dlx1/2-/- or Dlx1-/- mice. However, RNA sequencing of Dlx1/2-/- ENS revealed dysregulation of many genes, including vasoactive intestinal peptide (Vip). Using immunohistochemistry and reporter mice, we then found that Dlx1/2-/- mice have reduced VIP expression and fewer VIP-lineage neurons in their ENS. Our study reveals what we believe is a novel connection between Dlx genes and Vip and highlights the observation that dangerous bowel motility problems can occur in the absence of easily identifiable ENS structural defects. These findings may be relevant for disorders like chronic intestinal pseudo-obstruction (CIPO) syndrome.
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Affiliation(s)
- Christina M Wright
- Department of Pediatrics.,Leonard and Madlyn Abramson Pediatric Research Center, Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - James P Garifallou
- Center for Applied Genomics, and.,Leonard and Madlyn Abramson Pediatric Research Center, Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sabine Schneider
- Department of Pediatrics.,Leonard and Madlyn Abramson Pediatric Research Center, Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Heather L Mentch
- Department of Pediatrics.,Leonard and Madlyn Abramson Pediatric Research Center, Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Deepika R Kothakapa
- Department of Pediatrics.,Leonard and Madlyn Abramson Pediatric Research Center, Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Beth A Maguire
- Department of Pediatrics.,Leonard and Madlyn Abramson Pediatric Research Center, Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Robert O Heuckeroth
- Department of Pediatrics.,Leonard and Madlyn Abramson Pediatric Research Center, Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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26
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Abstract
The POLG gene encodes the mitochondrial DNA polymerase that is responsible for replication of the mitochondrial genome. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. POLG-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. The six leading disorders caused by POLG mutations are Alpers-Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG-related disorders, focusing particularly on the neurological manifestations of these conditions.
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27
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Abstract
PURPOSE OF REVIEW The purpose of this review is to discuss current knowledge on pediatric intestinal pseudo-obstruction. We will also review new mutations that have been identified through advancement in genetic testing, allowing for a better understanding of the underlying mechanisms of intestinal dysmotility and potential etiologies. RECENT FINDINGS With the advancements in genetic testing, new mutations have been identified in the diagnosis of megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), a disorder leading to pediatric pseudo-obstruction. MYLK, LMOD1, MYL9, and MYH11 encode for various proteins within smooth muscle cells; abnormalities within these proteins lead to abnormal intestinal smooth muscle contractions. Chronic intestinal pseudo-obstruction (CIPO) is defined by symptoms of bowel obstruction in the absence of a lumen-occluding lesion. CIPO is a heterogeneous group of disorders caused by abnormalities in the enteric neurons, intestinal smooth muscle, and/or the interstitial cells of Cajal (ICC). Symptoms can be non-specific and etiologies include both primary and secondary causes of CIPO that contribute to the delay in recognizing this condition and making the correct diagnosis. Chronic intestinal pseudo-obstruction has been recognized in both adults and children with fundamental differences in the etiology, symptom onset, clinical features and natural history of this disorder. For this reason, it has been considered a separate entity referred to as pediatric intestinal pseudo-obstruction (PIPO).
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Affiliation(s)
- Heidi E Gamboa
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA.
| | - Manu Sood
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA
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28
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Infectious stress triggers a POLG-related mitochondrial disease. Neurogenetics 2019; 21:19-27. [PMID: 31655921 DOI: 10.1007/s10048-019-00593-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 09/22/2019] [Indexed: 01/22/2023]
Abstract
A 3-year-old girl presented with severe epilepsy in the context of Borrelia infection. After ceftriaxone/lidocaine administration, she showed secondarily generalized focal crises that led to neurological and motor sequelae. Genetic studies identified in the patient two heterozygous POLG mutations (c.2591A>G; p.Asn864Ser and c.3649G>C; p.Ala1217Pro). Through analysis of POLG activity in cultured fibroblasts, we confirmed that the mutations altered the mtDNA turnover. Moreover, patient fibroblasts were more sensitive than controls in the presence of a mitochondrial replication-affecting drug, the antiretroviral azidothymidine. To test if ceftriaxone treatment could worsen the deleterious effect of the patient mutations, toxicity assays were performed. Cell toxicity, without direct effect on mitochondrial respiratory function, was detected at different antibiotic concentrations. The clinical outcome, together with the different in vitro sensitivity to ceftriaxone among patient and control cells, suggested that the mitochondrial disease symptoms were hastened by the infection and were possibly worsened by the pharmacological treatment. This study underscores the benefit of early genetic diagnosis of the patients with mitochondrial diseases, since they may be a target group of patients especially vulnerable to environmental factors.
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29
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Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis. J Hum Genet 2019; 65:91-98. [PMID: 31645654 DOI: 10.1038/s10038-019-0689-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 09/03/2019] [Accepted: 10/04/2019] [Indexed: 12/21/2022]
Abstract
Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.
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30
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Huang H, Yang X, Liu L, Xu Y. Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalomyopathy-Like Syndrome with Polymerase-Gamma Mutations. Ann Indian Acad Neurol 2019; 22:325-327. [PMID: 31359948 PMCID: PMC6613405 DOI: 10.4103/aian.aian_34_18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome, caused by mutations in the thymidine phosphorylase gene, manifests as a multisystemic disorder characterized by severe gastrointestinal dysmotility, cachexia, ptosis and ophthalmoparesis, peripheral neuropathy, and leukoencephalopathy. These clinical manifestations, with the exception of leukoencephalopathy, are mimicked by MNGIE-like syndrome, linked to polymerase-gamma (POLG) gene. Here, we report a 49-year-old Chinese man with MNGIE-like syndrome involved leukoencephalopathy and was associated with novel POLG mutations. This case expands the clinical spectrum of MNGIE-like syndrome.
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Affiliation(s)
- Hongyan Huang
- Department of Neurology, West China Hospital, Sichuan University, Sichuan Province, PR China
| | - Xinglong Yang
- Department of Geriatric Neurology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, PR China
| | - Ling Liu
- Department of Neurology, West China Hospital, Sichuan University, Sichuan Province, PR China
| | - Yanming Xu
- Department of Neurology, West China Hospital, Sichuan University, Sichuan Province, PR China
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31
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Lindberg G. Pseudo-obstruction, enteric dysmotility and irritable bowel syndrome. Best Pract Res Clin Gastroenterol 2019; 40-41:101635. [PMID: 31594655 DOI: 10.1016/j.bpg.2019.101635] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 07/18/2019] [Indexed: 02/06/2023]
Abstract
New diagnostic techniques have advanced our knowledge about the irritable bowel syndrome. The majority of patients that we believed to have a psychosomatic disorder have received other diagnoses explaining their symptoms. Endoscopy makes it possible to diagnose celiac disease before it leads to malnutrition and allows the detection of microscopic colitis as a cause of watery diarrhea. At the severe end of the symptom spectrum enteric dysmotility marks the border at which IBS ceases to be a functional disorder and becomes a genuine motility disorder. Joint hypermobility or Ehlers-Danlos syndrome is present in a substantial proportion of patients with enteric dysmotility. Chronic intestinal pseudo-obstruction is the end-stage of a large number of very rare disorders in which failed peristalsis is the common denominator. Nutritional needs and symptom control are essential in the management of pseudo-obstruction. Home parenteral nutrition is life saving in more than half of patients with chronic intestinal pseudo-obstruction.
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Affiliation(s)
- Greger Lindberg
- Karolinska Institutet, Department of Medicine, Huddinge and Karolinska University Hospital Huddinge, Patient Area Gastroenterology, Dermatology, and Rheumatology, SE-14186, Stockholm, Sweden.
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32
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Yasuda K, Murase N, Yoshinaga K, Ohtani R, Goto YI, Takahashi R, Nakamura M. Leukoencephalopathy with a case of heterozygous POLG mutation mimicking mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). J Clin Neurosci 2019; 61:302-304. [DOI: 10.1016/j.jocn.2018.10.054] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Accepted: 10/06/2018] [Indexed: 01/21/2023]
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33
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Felhi R, Sfaihi L, Charif M, Desquiret-Dumas V, Bris C, Goudenège D, Ammar-Keskes L, Hachicha M, Bonneau D, Procaccio V, Reynier P, Amati-Bonneau P, Lenaers G, Fakhfakh F. Next generation sequencing in family with MNGIE syndrome associated to optic atrophy: Novel homozygous POLG mutation in the C-terminal sub-domain leading to mtDNA depletion. Clin Chim Acta 2018; 488:104-110. [PMID: 30395865 DOI: 10.1016/j.cca.2018.11.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 11/02/2018] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Mitochondrial diseases are a group of disorders caused mainly by the impairment of the mitochondrial oxidative phosphorylation process, due to mutations either in the mitochondrial or nuclear genome. Among them, the mitochondrial neuro-gastrointestinal encephalo-myopathy (MNGIE) syndrome affects adolescents or young adults, and is mostly caused by TYMP mutations encoding a cytosolic thymidine phosphorylase (TP). PATIENTS AND METHODS The present study reports the molecular investigation by next-generation re-sequencing of 281 nuclear genes, encoding mitochondrial proteins, of consanguineous family including two individuals with MNGIE syndrome associated to optic atrophy. Bioinformatic analysis was also performed in addition to mtDNA deletion screening and mtDNA copy number quantification in blood of the two patients which were carried out by solf clipping program and qPCR respectively. RESULTS Next-generation re-sequencing revealed a novel homozygous c.2391G > T POLG mutation (p.M797I) co-occurring with the hypomorphic c.1311A > G OPA1 variant (p.I437M). Analysis of the mitochondrial genome in the two patients disclosed mtDNA depletion in blood, but no deletion. Bio-informatics investigations supported the pathogenicity of the novel POLG mutation that is located in the C-terminal subdomain and might change POLG 3D structure, stability and function. CONCLUSION The novel homozygous p.M797I POLG mutation is responsible for MNGIE combined to optic atrophy and mtDNA depletion in the two patients.
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Affiliation(s)
- Rahma Felhi
- Molecular and Functional Genetics Laboratory, Faculty of Science of Sfax, University of Sfax, Tunisia.
| | - Lamia Sfaihi
- Department of Pediatry, University Hospital Hedi Chaker, Sfax, Tunisia
| | - Majida Charif
- MitoLab Team, Institut MitoVasc, UMR CNRS 6015, INSERM U1083, Angers University, Angers, France
| | - Valerie Desquiret-Dumas
- MitoLab Team, Institut MitoVasc, UMR CNRS 6015, INSERM U1083, Angers University, Angers, France; Department of Biochemistry and Genetics, University Hospital Angers, Angers, France
| | - Céline Bris
- MitoLab Team, Institut MitoVasc, UMR CNRS 6015, INSERM U1083, Angers University, Angers, France; Department of Biochemistry and Genetics, University Hospital Angers, Angers, France
| | - David Goudenège
- MitoLab Team, Institut MitoVasc, UMR CNRS 6015, INSERM U1083, Angers University, Angers, France; Department of Biochemistry and Genetics, University Hospital Angers, Angers, France
| | - Leila Ammar-Keskes
- Human Molecular Genetics Laboratory, Faculty of Medecine of Sfax, University of Sfax, Tunisia
| | - Mongia Hachicha
- Department of Pediatry, University Hospital Hedi Chaker, Sfax, Tunisia
| | - Dominique Bonneau
- MitoLab Team, Institut MitoVasc, UMR CNRS 6015, INSERM U1083, Angers University, Angers, France; Department of Biochemistry and Genetics, University Hospital Angers, Angers, France
| | - Vincent Procaccio
- MitoLab Team, Institut MitoVasc, UMR CNRS 6015, INSERM U1083, Angers University, Angers, France; Department of Biochemistry and Genetics, University Hospital Angers, Angers, France
| | - Pascal Reynier
- MitoLab Team, Institut MitoVasc, UMR CNRS 6015, INSERM U1083, Angers University, Angers, France; Department of Biochemistry and Genetics, University Hospital Angers, Angers, France
| | - Patrizia Amati-Bonneau
- MitoLab Team, Institut MitoVasc, UMR CNRS 6015, INSERM U1083, Angers University, Angers, France; Department of Biochemistry and Genetics, University Hospital Angers, Angers, France
| | - Guy Lenaers
- MitoLab Team, Institut MitoVasc, UMR CNRS 6015, INSERM U1083, Angers University, Angers, France
| | - Faiza Fakhfakh
- Molecular and Functional Genetics Laboratory, Faculty of Science of Sfax, University of Sfax, Tunisia.
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Paediatric Intestinal Pseudo-obstruction: Evidence and Consensus-based Recommendations From an ESPGHAN-Led Expert Group. J Pediatr Gastroenterol Nutr 2018; 66:991-1019. [PMID: 29570554 DOI: 10.1097/mpg.0000000000001982] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Chronic intestinal pseudo-obstructive (CIPO) conditions are considered the most severe disorders of gut motility. They continue to present significant challenges in clinical care despite considerable recent progress in our understanding of pathophysiology, resulting in unacceptable levels of morbidity and mortality. Major contributors to the disappointing lack of progress in paediatric CIPO include a dearth of clarity and uniformity across all aspects of clinical care from definition and diagnosis to management. In order to assist medical care providers in identifying, evaluating, and managing children with CIPO, experts in this condition within the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition as well as selected external experts, were charged with the task of developing a uniform document of evidence- and consensus-based recommendations. METHODS Ten clinically relevant questions addressing terminology, diagnostic, therapeutic, and prognostic topics were formulated. A systematic literature search was performed from inception to June 2017 using a number of established electronic databases as well as repositories. The approach of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was applied to evaluate outcome measures for the research questions. Levels of evidence and quality of evidence were assessed using the classification system of the Oxford Centre for Evidence-Based Medicine (diagnosis) and the GRADE system (treatment). Each of the recommendations were discussed, finalized, and voted upon using the nominal voting technique to obtain consensus. RESULTS This evidence- and consensus-based position paper provides recommendations specifically for chronic intestinal pseudo-obstruction in infants and children. It proposes these be termed paediatric intestinal pseudo-obstructive (PIPO) disorders to distinguish them from adult onset CIPO. The manuscript provides guidance on the diagnosis, evaluation, and treatment of children with PIPO in an effort to standardise the quality of clinical care and improve short- and long-term outcomes. Key recommendations include the development of specific diagnostic criteria for PIPO, red flags to alert clinicians to the diagnosis and guidance on the use of available investigative modalities. The group advocates early collaboration with expert centres where structured diagnosis and management is guided by a multi-disciplinary team, and include targeted nutritional, medical, and surgical interventions as well as transition to adult services. CONCLUSIONS This document is intended to be used in daily practice from the time of first presentation and definitive diagnosis PIPO through to the complex management and treatment interventions such as intestinal transplantation. Significant challenges remain to be addressed through collaborative clinical and research interactions.
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Rossi M, Anheim M, Durr A, Klein C, Koenig M, Synofzik M, Marras C, van de Warrenburg BP. The genetic nomenclature of recessive cerebellar ataxias. Mov Disord 2018; 33:1056-1076. [PMID: 29756227 DOI: 10.1002/mds.27415] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 03/15/2018] [Accepted: 03/25/2018] [Indexed: 12/17/2022] Open
Abstract
The recessive cerebellar ataxias are a large group of degenerative and metabolic disorders, the diagnostic management of which is difficult because of the enormous clinical and genetic heterogeneity. Because of several limitations, the current classification systems provide insufficient guidance for clinicians and researchers. Here, we propose a new nomenclature for the genetically confirmed recessive cerebellar ataxias according to the principles and criteria laid down by the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders. We apply stringent criteria for considering an association between gene and phenotype to be established. The newly proposed list of recessively inherited cerebellar ataxias includes 62 disorders that were assigned an ATX prefix, followed by the gene name, because these typically present with ataxia as a predominant and/or consistent feature. An additional 30 disorders that often combine ataxia with a predominant or consistent other movement disorder received a double prefix (e.g., ATX/HSP). We also identified a group of 89 entities that usually present with complex nonataxia phenotypes, but may occasionally present with cerebellar ataxia. These are listed separately without the ATX prefix. This new, transparent and adaptable nomenclature of the recessive cerebellar ataxias will facilitate the clinical recognition of recessive ataxias, guide diagnostic testing in ataxia patients, and help in interpreting genetic findings. © 2018 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Malco Rossi
- Movement Disorders Section, Neuroscience Department, Raul Carrea Institute for Neurological Research, Buenos Aires, Argentina
| | - Mathieu Anheim
- Département de Neurologie, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France.,Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, France.,Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
| | - Alexandra Durr
- Brain and Spine Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Pitié-Salpêtrière University Hospital, Paris, France.,Department of Genetics, AP-HP, Pitié-Salpêtrière University Hospital, 7501, Paris, France
| | - Christine Klein
- Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.,Department of Neurology, University Hospital Schleswig-Holstein, Campus Lübeck, Germany
| | - Michel Koenig
- Laboratoire de Génétique de Maladies Rares, EA7402, Institut Universitaire de Recherche Clinique, Université de Montpellier, CHU Montpellier, Montpellier, France
| | - Matthis Synofzik
- Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.,German Center for Neurodegenerative Diseases, Tübingen, Germany
| | - Connie Marras
- Toronto Western Hospital Morton, Gloria Shulman Movement Disorders Centre, and the Edmond J. Safra Program in Parkinson's Disease, University of Toronto, Toronto, Canada
| | - Bart P van de Warrenburg
- Department of Neurology, Donders Institute for Brain, Cognition & Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
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Abstract
Chronic intestinal pseudo-obstruction (CIP) is defined by either continuous or intermittent symptoms of bowel obstruction in the absence of fixed lumen excluding lesion. CIP includes a heterogeneous group of disorders which result either from diseases affecting the enteric neurons and smooth muscle lining or those involving the autonomic innervation of the bowel. Symptoms associated with CIP are nonspecific, which can sometimes contribute to the delay in recognizing the condition and making the correct diagnosis. The diagnostic workup should include imaging and manometry studies and, occasionally, full-thickness bowel biopsies for histopathological examination may be required. Multidisciplinary team approach for the management of these patients is recommended, and the team members should include a gastroenterologist, surgeon, chronic pain specialist, clinical nutritionist, and a psychologist. The treatment goals should include optimizing the nutritional status and preventing or delaying the development of intestinal failure. The majority of the patients require enteral or parenteral nutrition support, and chronic pain is a common and distressing symptom. Small bowel transplantation may be required if patients develop liver complications due to parenteral nutrition, have difficult central line access, or have poor quality of life and worsening pain despite aggressive medical management.
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Affiliation(s)
- Khalil El-Chammas
- Division of Pediatric Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Manu R Sood
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin.,Division of Pediatric Gastroenterology, Children's hospital of Wisconsin, Milwaukee, Wisconsin
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Mitochondrial Diseases as Model of Neurodegeneration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1007:129-155. [DOI: 10.1007/978-3-319-60733-7_8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations. Genet Med 2017; 19:1217-1225. [DOI: 10.1038/gim.2017.35] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 02/16/2017] [Accepted: 02/17/2017] [Indexed: 12/26/2022] Open
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El-Hattab AW, Craigen WJ, Scaglia F. Mitochondrial DNA maintenance defects. Biochim Biophys Acta Mol Basis Dis 2017; 1863:1539-1555. [PMID: 28215579 DOI: 10.1016/j.bbadis.2017.02.017] [Citation(s) in RCA: 193] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 01/31/2017] [Accepted: 02/14/2017] [Indexed: 01/12/2023]
Abstract
The maintenance of mitochondrial DNA (mtDNA) depends on a number of nuclear gene-encoded proteins including a battery of enzymes forming the replisome needed to synthesize mtDNA. These enzymes need to be in balanced quantities to function properly that is in part achieved by exchanging intramitochondrial contents through mitochondrial fusion. In addition, mtDNA synthesis requires a balanced supply of nucleotides that is achieved by nucleotide recycling inside the mitochondria and import from the cytosol. Mitochondrial DNA maintenance defects (MDMDs) are a group of diseases caused by pathogenic variants in the nuclear genes involved in mtDNA maintenance resulting in impaired mtDNA synthesis leading to quantitative (mtDNA depletion) and qualitative (multiple mtDNA deletions) defects in mtDNA. Defective mtDNA leads to organ dysfunction due to insufficient mtDNA-encoded protein synthesis, resulting in an inadequate energy production to meet the needs of affected organs. MDMDs are inherited as autosomal recessive or dominant traits, and are associated with a broad phenotypic spectrum ranging from mild adult-onset ophthalmoplegia to severe infantile fatal hepatic failure. To date, pathogenic variants in 20 nuclear genes known to be crucial for mtDNA maintenance have been linked to MDMDs, including genes encoding enzymes of mtDNA replication machinery (POLG, POLG2, TWNK, TFAM, RNASEH1, MGME1, and DNA2), genes encoding proteins that function in maintaining a balanced mitochondrial nucleotide pool (TK2, DGUOK, SUCLG1, SUCLA2, ABAT, RRM2B, TYMP, SLC25A4, AGK, and MPV17), and genes encoding proteins involved in mitochondrial fusion (OPA1, MFN2, and FBXL4).
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Affiliation(s)
- Ayman W El-Hattab
- Division of Clinical Genetics and Metabolic Disorders, Pediatrics Department, Tawam Hospital, Al-Ain, United Arab Emirates
| | - William J Craigen
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
| | - Fernando Scaglia
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
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40
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DeBalsi KL, Longley MJ, Hoff KE, Copeland WC. Synergistic Effects of the in cis T251I and P587L Mitochondrial DNA Polymerase γ Disease Mutations. J Biol Chem 2017; 292:4198-4209. [PMID: 28154168 DOI: 10.1074/jbc.m116.773341] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 01/26/2017] [Indexed: 01/28/2023] Open
Abstract
Human mitochondrial DNA (mtDNA) polymerase γ (Pol γ) is the only polymerase known to replicate the mitochondrial genome. The Pol γ holoenzyme consists of the p140 catalytic subunit (POLG) and the p55 homodimeric accessory subunit (POLG2), which enhances binding of Pol γ to DNA and promotes processivity of the holoenzyme. Mutations within POLG impede maintenance of mtDNA and cause mitochondrial diseases. Two common POLG mutations usually found in cis in patients primarily with progressive external ophthalmoplegia generate T251I and P587L amino acid substitutions. To determine whether T251I or P587L is the primary pathogenic allele or whether both substitutions are required to cause disease, we overproduced and purified WT, T251I, P587L, and T251I + P587L double variant forms of recombinant Pol γ. Biochemical characterization of these variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity, and compromised DNA processivity, even in the presence of the p55 accessory subunit. However, physical association with p55 was unperturbed, suggesting intersubunit affinities similar to WT. Notably, although the single mutants were similarly impaired, a dramatic synergistic effect was found for the double mutant across all parameters. In conclusion, our analyses suggest that individually both T251I and P587L substitutions functionally impair Pol γ, with greater pathogenicity predicted for the single P587L variant. Combining T251I and P587L induces extreme thermal lability and leads to synergistic nucleotide and DNA binding defects, which severely impair catalytic activity and correlate with presentation of disease in patients.
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Affiliation(s)
- Karen L DeBalsi
- From the Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709
| | - Matthew J Longley
- From the Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709
| | - Kirsten E Hoff
- From the Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709
| | - William C Copeland
- From the Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709
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DeBalsi KL, Hoff KE, Copeland WC. Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases. Ageing Res Rev 2017; 33:89-104. [PMID: 27143693 DOI: 10.1016/j.arr.2016.04.006] [Citation(s) in RCA: 117] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 04/19/2016] [Accepted: 04/19/2016] [Indexed: 12/19/2022]
Abstract
As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases. Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery. Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations. Clonal expansion of mtDNA mutations results in mitochondrial dysfunction, such as decreased electron transport chain (ETC) enzyme activity and impaired cellular respiration. We address the literature that mitochondrial dysfunction, in conjunction with altered mitochondrial dynamics, is a major driving force behind aging and age-related diseases. Additionally, interventions to improve mitochondrial function and attenuate the symptoms of aging are examined.
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Affiliation(s)
- Karen L DeBalsi
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - Kirsten E Hoff
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
| | - William C Copeland
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
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Di Nardo G, Di Lorenzo C, Lauro A, Stanghellini V, Thapar N, Karunaratne TB, Volta U, De Giorgio R. Chronic intestinal pseudo-obstruction in children and adults: diagnosis and therapeutic options. Neurogastroenterol Motil 2017; 29. [PMID: 27683196 DOI: 10.1111/nmo.12945] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 08/21/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Chronic intestinal pseudo-obstruction (CIPO) represents the most severe form of gastrointestinal dysmotility with debilitating and potentially lethal consequences. Symptoms can be non-specific, and result in this condition being diagnosed incorrectly or too late with consequences for morbidity and even mortality. PURPOSE The present article aims to provide pediatric and adult gastroenterologists with an up to date review about clinical features, diagnosis and therapeutic options for CIPO. Although pediatric and adult CIPO share many clinical aspects distinctive features can be identified. There is no single diagnostic test or pathognomonic finding of CIPO, thus a stepwise approach including radiology, endoscopy, laboratory, manometry, and histopathology should be considered in the diagnostic work-up. Treatment of patients with CIPO is challenging and requires a multidisciplinary effort with participation of appropriately experienced gastroenterologists, pathologists, dieticians, surgeons, psychologists, and other subspecialists based on the presence of comorbidities. Current treatment options invariably involve surgery and specialized nutritional support, especially in children. Medical therapies are mainly aimed to avoid complications such as sepsis or intestinal bacterial overgrowth and, where possible, restore intestinal propulsion. More efficacious therapeutic options are eagerly awaited for such difficult patients.
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Affiliation(s)
- G Di Nardo
- Pediatric Unit, Orvieto Hospital, Orvieto, Italy.,Pediatric Gastroenterology Unit, International Hospital Salvator Mundi, Rome, Italy
| | - C Di Lorenzo
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA
| | - A Lauro
- Liver and Multiorgan Transplant Unit, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - V Stanghellini
- Department of Medical and Surgical Sciences, Centro di Ricerca BioMedica Applicata (C.R.B.A.), University of Bologna, Bologna, Italy
| | - N Thapar
- Department of Gastroenterology, Great Ormond Street Hospital, Institute of Child Health, London, UK
| | - T B Karunaratne
- Department of Medical and Surgical Sciences, Centro di Ricerca BioMedica Applicata (C.R.B.A.), University of Bologna, Bologna, Italy
| | - U Volta
- Department of Medical and Surgical Sciences, Centro di Ricerca BioMedica Applicata (C.R.B.A.), University of Bologna, Bologna, Italy
| | - R De Giorgio
- Department of Medical and Surgical Sciences, Centro di Ricerca BioMedica Applicata (C.R.B.A.), University of Bologna, Bologna, Italy
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Demaria F, De Crescenzo F, Caramadre AM, D'Amico A, Diamanti A, Fattori F, Casini MP, Vicari S. Mitochondrial Neurogastrointestinal Encephalomyopathy Presenting as Anorexia Nervosa. J Adolesc Health 2016; 59:729-731. [PMID: 27743770 DOI: 10.1016/j.jadohealth.2016.08.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 07/19/2016] [Accepted: 08/04/2016] [Indexed: 01/21/2023]
Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystemic autosomal recessive disorder mainly caused by mutations in the nuclear gene TYMP, encoding thymidine phosphorylase. It generally appears in childhood and is clinically characterized by severe gastrointestinal dysmotility, cachexia, ptosis, progressive external ophthalmoplegia, peripheral neuropathy, and diffuse leukoencephalopathy on brain magnetic resonance imaging. The disease is clinically heterogeneous with the main symptoms being gastrointestinal, with an important weight loss. Symptoms might worsen rapidly, and a timely diagnosis is vital. However, patients report retrospectively their first symptoms before the age of 12 years, but the delay in diagnosis varies from 5 to 10 years. In the present study, we report a case of an adolescent with MNGIE, which was initially, and erroneously, diagnosed as anorexia nervosa. To make a timely and accurate differential diagnosis, we will discuss the clinical differences and similarities between MNGIE and anorexia nervosa and the importance of a multidisciplinary evaluation.
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Affiliation(s)
- Francesco Demaria
- Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, Italy.
| | - Franco De Crescenzo
- Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, Italy; Institute of Psychiatry and Psychology, Catholic University of Sacred Heart, Rome, Italy
| | | | - Adele D'Amico
- Neuromuscular and Neurodegenerative Disorders Unit, Bambino Gesù Children's Hospital, Rome, Italy
| | - Antonella Diamanti
- Artificial Nutrition Unit, Bambino Gesù Children's Hospital, Rome, Italy
| | - Fabiana Fattori
- Neuromuscular and Neurodegenerative Disorders Unit, Bambino Gesù Children's Hospital, Rome, Italy
| | - Maria Pia Casini
- Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, Italy
| | - Stefano Vicari
- Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, Italy
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Nascimento A, Ortez C, Jou C, O'Callaghan M, Ramos F, Garcia-Cazorla À. Neuromuscular Manifestations in Mitochondrial Diseases in Children. Semin Pediatr Neurol 2016; 23:290-305. [PMID: 28284391 DOI: 10.1016/j.spen.2016.11.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Mitochondrial diseases exhibit significant clinical and genetic heterogeneity. Mitochondria are highly dynamic organelles that are the major contributor of adenosine triphosphate, through oxidative phosphorylation. These disorders may be developed at any age, with isolated or multiple system involvement, and in any pattern of inheritance. Defects in the mitochondrial respiratory chain impair energy production and almost invariably involve skeletal muscle and peripheral nerves, causing exercise intolerance, cramps, recurrent myoglobinuria, or fixed weakness, which often affects extraocular muscles and results in droopy eyelids (ptosis), progressive external ophthalmoplegia, peripheral ataxia, and peripheral polyneuropathy. This review describes the main neuromuscular symptomatology through different syndromes reported in the literature and from our experience. We want to highlight the importance of searching for the "clue clinical signs" associated with inheritance pattern as key elements to guide the complex diagnosis process and genetic studies in mitochondrial diseases.
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Affiliation(s)
- Andrés Nascimento
- Department of Neurology, Neuromuscular Units, Hospital Sant Joan de Déu, Instituto de Salud Carlos III, Barcelona, Spain; Center for Biomedical Research on Rare Diseases (CIBERER), Institute of Pediatric Research Sant Joan de Déu, Madrid, Spain.
| | - Carlos Ortez
- Department of Neurology, Neuromuscular Units, Hospital Sant Joan de Déu, Instituto de Salud Carlos III, Barcelona, Spain
| | - Cristina Jou
- Department of Neurology, Neuromuscular Units, Hospital Sant Joan de Déu, Instituto de Salud Carlos III, Barcelona, Spain; Center for Biomedical Research on Rare Diseases (CIBERER), Institute of Pediatric Research Sant Joan de Déu, Madrid, Spain
| | - Mar O'Callaghan
- Center for Biomedical Research on Rare Diseases (CIBERER), Institute of Pediatric Research Sant Joan de Déu, Madrid, Spain; Department of Neurology, Neurometabolic Units, Hospital Sant Joan de Déu, Instituto de Salud Carlos III, Barcelona, Spain
| | - Federico Ramos
- Center for Biomedical Research on Rare Diseases (CIBERER), Institute of Pediatric Research Sant Joan de Déu, Madrid, Spain; Department of Neurology, Neurometabolic Units, Hospital Sant Joan de Déu, Instituto de Salud Carlos III, Barcelona, Spain
| | - Àngels Garcia-Cazorla
- Center for Biomedical Research on Rare Diseases (CIBERER), Institute of Pediatric Research Sant Joan de Déu, Madrid, Spain; Department of Neurology, Neurometabolic Units, Hospital Sant Joan de Déu, Instituto de Salud Carlos III, Barcelona, Spain
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Anagnostou ME, Ng YS, Taylor RW, McFarland R. Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG)
gene: A clinical and molecular genetic review. Epilepsia 2016; 57:1531-1545. [DOI: 10.1111/epi.13508] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2016] [Indexed: 01/01/2023]
Affiliation(s)
- Maria-Eleni Anagnostou
- Wellcome Trust Centre for Mitochondrial Research; Institute of Neuroscience; Newcastle University; Newcastle upon Tyne United Kingdom
| | - Yi Shiau Ng
- Wellcome Trust Centre for Mitochondrial Research; Institute of Neuroscience; Newcastle University; Newcastle upon Tyne United Kingdom
| | - Robert W. Taylor
- Wellcome Trust Centre for Mitochondrial Research; Institute of Neuroscience; Newcastle University; Newcastle upon Tyne United Kingdom
| | - Robert McFarland
- Wellcome Trust Centre for Mitochondrial Research; Institute of Neuroscience; Newcastle University; Newcastle upon Tyne United Kingdom
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Brosens E, Burns AJ, Brooks AS, Matera I, Borrego S, Ceccherini I, Tam PK, García-Barceló MM, Thapar N, Benninga MA, Hofstra RMW, Alves MM. Genetics of enteric neuropathies. Dev Biol 2016; 417:198-208. [PMID: 27426273 DOI: 10.1016/j.ydbio.2016.07.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 07/13/2016] [Accepted: 07/13/2016] [Indexed: 12/23/2022]
Abstract
Abnormal development or disturbed functioning of the enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, is associated with the development of neuropathic gastrointestinal motility disorders. Here, we review the underlying molecular basis of these disorders and hypothesize that many of them have a common defective biological mechanism. Genetic burden and environmental components affecting this common mechanism are ultimately responsible for disease severity and symptom heterogeneity. We believe that they act together as the fulcrum in a seesaw balanced with harmful and protective factors, and are responsible for a continuum of symptoms ranging from neuronal hyperplasia to absence of neurons.
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Affiliation(s)
- Erwin Brosens
- Department of Clinical Genetics, Erasmus University Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
| | - Alan J Burns
- Department of Clinical Genetics, Erasmus University Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands; Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Institute of Child Health, London, UK
| | - Alice S Brooks
- Department of Clinical Genetics, Erasmus University Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Ivana Matera
- UOC Medical Genetics, Istituto Giannina Gaslini, Genova, Italy
| | - Salud Borrego
- Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), Seville, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
| | | | - Paul K Tam
- Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine of the University of Hong Kong, Hong Kong, China
| | - Maria-Mercè García-Barceló
- State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Centre for Reproduction, Development, and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Nikhil Thapar
- Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Institute of Child Health, London, UK
| | - Marc A Benninga
- Pediatric Gastroenterology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands
| | - Robert M W Hofstra
- Department of Clinical Genetics, Erasmus University Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands; Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Institute of Child Health, London, UK
| | - Maria M Alves
- Department of Clinical Genetics, Erasmus University Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands
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Gurdziel K, Vogt KR, Walton KD, Schneider GK, Gumucio DL. Transcriptome of the inner circular smooth muscle of the developing mouse intestine: Evidence for regulation of visceral smooth muscle genes by the hedgehog target gene, cJun. Dev Dyn 2016; 245:614-26. [PMID: 26930384 DOI: 10.1002/dvdy.24399] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 01/29/2016] [Accepted: 02/16/2016] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Digestion is facilitated by coordinated contractions of the intestinal muscularis externa, a bilayered smooth muscle structure that is composed of inner circular muscles (ICM) and outer longitudinal muscles (OLM). We performed transcriptome analysis of intestinal mesenchyme tissue at E14.5, when the ICM, but not the OLM, is present, to investigate the transcriptional program of the ICM. RESULTS We identified 3967 genes enriched in E14.5 intestinal mesenchyme. The gene expression profiles were clustered and annotated to known muscle genes, identifying a muscle-enriched subcluster. Using publically available in situ data, 127 genes were verified as expressed in ICM. Examination of the promoter and regulatory regions for these co-expressed genes revealed enrichment for cJUN transcription factor binding sites, and cJUN protein was enriched in ICM. cJUN ChIP-seq, performed at E14.5, revealed that cJUN regulatory regions contain characteristics of muscle enhancers. Finally, we show that cJun is a target of Hedgehog (Hh), a signaling pathway known to be important in smooth muscle development, and identify a cJun genomic enhancer that is responsive to Hh. CONCLUSIONS This work provides the first transcriptional catalog for the developing ICM and suggests that cJun regulates gene expression in the ICM downstream of Hh signaling. Developmental Dynamics 245:614-626, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Katherine Gurdziel
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109.,Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109
| | - Kyle R Vogt
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109
| | - Katherine D Walton
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109
| | - Gary K Schneider
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109
| | - Deborah L Gumucio
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109
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Janssen W, Quaegebeur A, Van Goethem G, Ann L, Smets K, Vandenberghe R, Van Paesschen W. The spectrum of epilepsy caused by POLG mutations. Acta Neurol Belg 2016; 116:17-25. [PMID: 26104464 DOI: 10.1007/s13760-015-0499-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 06/08/2015] [Indexed: 12/21/2022]
Abstract
Mutations in POLG are increasingly recognized as a cause of refractory occipital lobe epilepsy (OLE) and status epilepticus (SE). Our aim was to describe the epilepsy syndrome in seven patients with POLG mutations. We retrospectively reviewed the medical records of seven patients with POLG mutations and epilepsy. Mutation analysis was performed by direct sequencing of the coding exons of the POLG gene. Disease onset was at a median age of 18 years (range 12-26). Epilepsy was the presenting problem in six patients. All had focal seizures, with motor (n = 6) and visual (n = 6) phenomena. Six patients had secondarily generalized seizures and two patients had myoclonic seizures. Six patients had one or more episodes of refractory SE, including focal (n = 5), subtle (n = 4), myoclonic (n = 2) and convulsive (n = 3) SE. During or after SE, brain MRI showed lesions affecting the occipital lobe in all patients, probably due to continuous epileptic activity. Five of the six patients with SE died during treatment of SE, one due to valproate-induced hepatotoxicity. Associated clinical symptoms were ataxia (n = 6), polyneuropathy (n = 6), progressive external ophthalmoplegia (PEO) (n = 3) and migraine (n = 3). Epilepsy may be the first and dominant neurological problem caused by POLG mutations. The epilepsy may be severe and the condition of the patient may end in fatal SE. Refractory OLE and SE in a patient with polyneuropathy, ataxia, PEO or migraine warrant screening for POLG mutations. In this clinical setting, valproate should not be given in view of the risk of fatal hepatotoxicity.
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Affiliation(s)
- Wouter Janssen
- Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000, Louvain, Belgium.
| | - Annelies Quaegebeur
- Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000, Louvain, Belgium
| | - Gert Van Goethem
- Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium
- Laboratory of Neurogenetics, Institute Born-Bunge, Antwerp, Belgium
- University of Antwerpen, Antwerp, Belgium
- Department of Neurology, University Hospital Antwerpen, Antwerp, Belgium
| | - Löfgren Ann
- Laboratory of Neurogenetics, Institute Born-Bunge, Antwerp, Belgium
- University of Antwerpen, Antwerp, Belgium
| | - Katrien Smets
- Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium
- Laboratory of Neurogenetics, Institute Born-Bunge, Antwerp, Belgium
- University of Antwerpen, Antwerp, Belgium
- Department of Neurology, University Hospital Antwerpen, Antwerp, Belgium
| | - Rik Vandenberghe
- Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000, Louvain, Belgium
| | - Wim Van Paesschen
- Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000, Louvain, Belgium.
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Waseem SH, Idrees MT, Croffie JM. Neuroenteric Staining as a Tool in the Evaluation of Pediatric Motility Disorders. Curr Gastroenterol Rep 2015; 17:30. [PMID: 26143629 DOI: 10.1007/s11894-015-0456-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
The diagnosis of enteric neuromuscular disorders has come a long way since the first description of an enteric neuropathic disorder by the Danish physician Harald Hirschsprung in 1886. Advances in specialized enteric histopathological staining techniques have made it possible to identify subtle neuropathies and myopathies that cause intestinal motility disorders, from the common and now better understood and relatively easily diagnosed Hirschsprung's disease to the less common and more severe and not well-characterized chronic idiopathic intestinal pseudoobstruction, which continues to present a diagnostic challenge to the gastroenterologist and histopathologist alike. This article will discuss the common gastrointestinal motility disorders and some of the specialized histological stains, such as the relatively common enzyme stain, acetylcholinesterase, used to diagnose Hirschsprung's disease; advanced tinctorial stains, such as Masson trichrome, which may aid in diagnosis of enteric myopathies causing pseudoobstruction; and immunohistochemical stains such as C-Kit or PG 9.5, which may aid in the diagnosis of enteric neuropathies causing pseudoobstruction.
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Affiliation(s)
- Shamaila H Waseem
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Indiana University School of Medicine, James Whitcomb Riley Hospital for Children, 705 Riley Hospital Drive #4210, Indianapolis, IN, 46202, USA,
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Tchikviladzé M, Gilleron M, Maisonobe T, Galanaud D, Laforêt P, Durr A, Eymard B, Mochel F, Ogier H, Béhin A, Stojkovic T, Degos B, Gourfinkel-An I, Sedel F, Anheim M, Elbaz A, Viala K, Vidailhet M, Brice A, Jardel C, Lombès A. A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity. J Neurol Neurosurg Psychiatry 2015; 86:646-54. [PMID: 25118206 DOI: 10.1136/jnnp-2013-306799] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 07/23/2014] [Indexed: 11/04/2022]
Abstract
OBJECTIVE Diseases due to mutations of POLG gene, encoding the mitochondrial DNA polymerase, are reputed to have very diverse clinical presentations and have been proposed to cause up to 25% adult mitochondrial diseases. Our objective was the evaluation of the specificity and sensitivity of the signs encountered with POLG mutations. DESIGN Forty-four patients out of 154 with sequenced POLG gene had mutations affecting either one (POLG(+/-) group) or two POLG alleles (POLG(+/+) group). Phenotyping included clinical signs, electroneuromyography and brain imaging while mitochondrial investigations encompassed muscle histochemistry, respiratory chain assays and search for multiple mitochondrial deletions. The specificity and sensitivity of the signs associated with POLG mutations were analysed by comparison between POLG(+/+) and patients without POLG mutation. RESULTS High sensitivity but low specificity was observed with single signs such as axonal sensory neuropathy, cerebellar syndrome, movement disorders and weakness involving ocular, pharyngeal, axial and/or limb muscles. Specificity was increased with combination of previous signs plus psychiatric symptoms, cognitive impairment and epilepsy. High specificity and sensitivity was only obtained with sensory neuronopathy associated with one of the following signs: weakness of ocular, pharyngeal, axial and/or limb muscles. Mitochondrial investigations did not suffice for diagnosis. The widespread neuromuscular signs were often present since disease onset and were the rule above 50 years of age leading to a very low probability of POLG mutations in patients with less than three signs and absent sensory neuropathy. CONCLUSIONS Phenotypes associated with POLG mutations follow a reproducible pattern, which allows establishing a diagnostic flow chart.
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Affiliation(s)
- Maya Tchikviladzé
- Department of Neurology, AP-HP, GHU Pitié-Salpêtrière, Paris, France INSERM CIC9503, GHU Pitié-Salpêtrière, Paris, France
| | - Mylène Gilleron
- INSERM U1016, Institut Cochin; CNRS UMR 8104, Paris, France Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, AP-HP, GHU Pitié-Salpêtrière, Paris, France UPMC Univ Paris 06, UMR_S975, Paris, France
| | - Thierry Maisonobe
- Department of Neurophysiology and Neuropathology, AP-HP, GHU Pitié-Salpêtrière, Paris, France
| | - Damien Galanaud
- Department of Neuroradiology, AP-HP, GHU Pitié-Salpêtrière, Paris, France
| | - Pascal Laforêt
- AP-HP, Centre de Référence de pathologie neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Paris, France
| | - Alexandra Durr
- UPMC Univ Paris 06, UMR_S975, Paris, France Department of Genetics, AP-HP, GHU Pitié-Salpêtrière, Paris, France INSERM UMR_S975, CRICM; CNRS UMR 7225, Paris, France ICM (Brain and Spine Institute) GH Pitié-Salpêtrière, Paris, France
| | - Bruno Eymard
- UPMC Univ Paris 06, UMR_S975, Paris, France AP-HP, Centre de Référence de pathologie neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Paris, France INSERM UMR_S975, CRICM; CNRS UMR 7225, Paris, France
| | - Fanny Mochel
- Department of Genetics, AP-HP, GHU Pitié-Salpêtrière, Paris, France INSERM UMR_S975, CRICM; CNRS UMR 7225, Paris, France Neurometabolic Unit, AP-HP, GH Pitié-Salpêtrière, Paris, France
| | - Hélène Ogier
- AP-HP, Maladies héréditaires du métabolisme, GH Robert Debré, Paris, France
| | - Anthony Béhin
- AP-HP, Centre de Référence de pathologie neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Paris, France
| | - Tanya Stojkovic
- AP-HP, Centre de Référence de pathologie neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Paris, France
| | - Bertrand Degos
- Department of Neurology, AP-HP, GHU Pitié-Salpêtrière, Paris, France
| | | | - Frederic Sedel
- Department of Genetics, AP-HP, GHU Pitié-Salpêtrière, Paris, France INSERM UMR_S975, CRICM; CNRS UMR 7225, Paris, France Neurometabolic Unit, AP-HP, GH Pitié-Salpêtrière, Paris, France
| | - Mathieu Anheim
- Department of Neurology, AP-HP, GHU Pitié-Salpêtrière, Paris, France
| | - Alexis Elbaz
- INSERM, CESP, Social and occupational determinants of health, U1018, Villejuif, France Université Versailles St-Quentin, UMRS 1018, Villejuif, France
| | - Karine Viala
- Department of Neurophysiology and Neuropathology, AP-HP, GHU Pitié-Salpêtrière, Paris, France
| | - Marie Vidailhet
- Department of Neurology, AP-HP, GHU Pitié-Salpêtrière, Paris, France INSERM UMR_S975, CRICM; CNRS UMR 7225, Paris, France ICM (Brain and Spine Institute) GH Pitié-Salpêtrière, Paris, France Neurometabolic Unit, AP-HP, GH Pitié-Salpêtrière, Paris, France
| | - Alexis Brice
- UPMC Univ Paris 06, UMR_S975, Paris, France Department of Genetics, AP-HP, GHU Pitié-Salpêtrière, Paris, France INSERM UMR_S975, CRICM; CNRS UMR 7225, Paris, France ICM (Brain and Spine Institute) GH Pitié-Salpêtrière, Paris, France
| | - Claude Jardel
- INSERM U1016, Institut Cochin; CNRS UMR 8104, Paris, France Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, AP-HP, GHU Pitié-Salpêtrière, Paris, France
| | - Anne Lombès
- INSERM U1016, Institut Cochin; CNRS UMR 8104, Paris, France Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, AP-HP, GHU Pitié-Salpêtrière, Paris, France Université Paris-Descartes-Paris5, Paris, France
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