Ewen W Sommerville1, Patrick F Chinnery2, Gráinne S Gorman1, Robert W Taylor1. 1. Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. 2. Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Abstract
BACKGROUND: Progressive external ophthalmoplegia (PEO) is an eye movement disorder characterised by paresis of the extra ocular muscles and muscle restricted multiple mitochondrial DNA (mtDNA) deletions. Classification of patients is particularly difficult due to overlapping phenotypes and a poor genotype-phenotype relationship. Despite the identification of several nuclear encoded genes causing PEO, over half of patients with clinically confirmed PEO do not have a genetic diagnosis. OBJECTIVE: To systematically review genotypic and phenotypic correlates of published cases of adult-onset PEO. METHODS: Patients were identified from interrogation of articles from Scopus, Medline via PubMed, and Genetic Abstracts databases using electronic searches (1st January 1970 to 8th November 2013). Reference lists and UniProt entries were also manually checked for additional articles. RESULTS: Twelve nuclear encoded genes were identified (TYMP, SLC25A4, POLG, C10ORF2, OPA1, POLG2, RRM2B, TK2, DGUOK, MPV17, MGME1, and DNA2) systematically from 583 patients. At the time of writing, mutations in SPG7 and AFG3L2 genes were reported to be associated with ophthalmoparesis and multiple mtDNA deletions in fourteen additional adult-onset PEO patients, bringing the total number of known genes to fourteen. CONCLUSIONS: Diagnostic yield is still critically dependent on the meticulous clinical and biochemical characterisation of patients. Understanding the intimate relationship between genotype and phenotype remains a fundamental challenge. The results of this systematic review provide guidance to both patients and clinician about future prognosis, and will serve, in future, to assess methods of disease prevention and evaluation of targeted therapeutic strategies.
BACKGROUND: Progressive external ophthalmoplegia (PEO) is an eye movement disorder characterised by paresis of the extra ocular muscles and muscle restricted multiple mitochondrial DNA (mtDNA) deletions. Classification of patients is particularly difficult due to overlapping phenotypes and a poor genotype-phenotype relationship. Despite the identification of several nuclear encoded genes causing PEO, over half of patients with clinically confirmed PEO do not have a genetic diagnosis. OBJECTIVE: To systematically review genotypic and phenotypic correlates of published cases of adult-onset PEO. METHODS:Patients were identified from interrogation of articles from Scopus, Medline via PubMed, and Genetic Abstracts databases using electronic searches (1st January 1970 to 8th November 2013). Reference lists and UniProt entries were also manually checked for additional articles. RESULTS: Twelve nuclear encoded genes were identified (TYMP, SLC25A4, POLG, C10ORF2, OPA1, POLG2, RRM2B, TK2, DGUOK, MPV17, MGME1, and DNA2) systematically from 583 patients. At the time of writing, mutations in SPG7 and AFG3L2 genes were reported to be associated with ophthalmoparesis and multiple mtDNA deletions in fourteen additional adult-onset PEOpatients, bringing the total number of known genes to fourteen. CONCLUSIONS: Diagnostic yield is still critically dependent on the meticulous clinical and biochemical characterisation of patients. Understanding the intimate relationship between genotype and phenotype remains a fundamental challenge. The results of this systematic review provide guidance to both patients and clinician about future prognosis, and will serve, in future, to assess methods of disease prevention and evaluation of targeted therapeutic strategies.
Authors: Ewen W Sommerville; Rachel L Jones; Steven A Hardy; Emma L Blakely; Angela Pyle; Andrew M Schaefer; Patrick F Chinnery; Douglass M Turnbull; Gráinne S Gorman; Robert W Taylor Journal: Neurol Genet Date: 2017-12-15
Authors: Lionel Van Maldergem; Arnaud Besse; Boel De Paepe; Emma L Blakely; Vivek Appadurai; Margaret M Humble; Juliette Piard; Kate Craig; Langping He; Pierre Hella; François-Guillaume Debray; Jean-Jacques Martin; Marion Gaussen; Patrice Laloux; Giovanni Stevanin; Rudy Van Coster; Robert W Taylor; William C Copeland; Eric Mormont; Penelope E Bonnen Journal: Ann Clin Transl Neurol Date: 2016-11-16 Impact factor: 4.511
Authors: Ewen W Sommerville; Ilaria Dalla Rosa; Masha M Rosenberg; Francesco Bruni; Kyle Thompson; Mariana Rocha; Emma L Blakely; Langping He; Gavin Falkous; Andrew M Schaefer; Patrick Yu-Wai-Man; Patrick F Chinnery; Lizbeth Hedstrom; Antonella Spinazzola; Robert W Taylor; Gráinne S Gorman Journal: Clin Genet Date: 2019-11-14 Impact factor: 4.296