title: Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease.
abstract: OBJECTIVE
  Homoplasmic maternally inherited, m.14674T>C or m. 14674T>G mt-tRNA(Glu) mutations have recently been identified in reversible infantile cytochrome c oxidase deficiency (or 'benign COX deficiency'). This study sought other genetic defects that may give rise to similar presentations.
  
  
  METHODS
  Eight patients from seven families with clinicopathological features of infantile reversible cytochrome c oxidase deficiency were investigated.
  
  
  METHODS
  The study reviewed the diagnostic features and performed molecular genetic analyses of mitochondrial DNA and nuclear encoded candidate genes.
  
  
  RESULTS
  Patients presented with subacute onset of profound hypotonia, feeding difficulties and lactic acidosis within the first months of life. Although recovery was remarkable, a mild myopathy persisted into adulthood. Histopathological findings in muscle included increased lipid and/or glycogen content, ragged-red and COX negative fibres. Biochemical studies suggested more generalised abnormalities than pure COX deficiency. Clinical improvement was reflected by normalisation of lactic acidosis and histopathological abnormalities. The m.14674T>C mt-tRNA(Glu) mutation was identified in four families, but none had the m. 14674T>G mutation. Furthermore, in two families pathogenic mutations were also found in the nuclear TRMU gene which has not previously been associated with this phenotype. In one family, the genetic aetiology still remains unknown.
  
  
  CONCLUSIONS
  Benign COX deficiency is better described as 'reversible infantile respiratory chain deficiency'. It is genetically heterogeneous, and patients not carrying the m.14674T>C or T>G mt-tRNA(Glu) mutations may have mutations in the TRMU gene. Diagnosing this disorder at the molecular level is a significant advance for paediatric neurologists and intensive care paediatricians, enabling them to select children with an excellent prognosis for continuing respiratory support from those with severe mitochondrial presentation in infancy.
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, The Women's Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Uusimaa
authors.affiliation: Department of Clinical Neuroscience, King's College Hospital, London, UK.|Department of Paediatric Neurology - Neuromuscular Service, Evelina Children's Hospital, St Thomas' Hospital, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Jungbluth
authors.affiliation: Oxford Medical Genetics Lab, Churchill Hospital, Oxford, UK.
authors.forename: C
authors.initials: C
authors.lastname: Fratter
authors.affiliation: Servizio di Puericultura, Universita' di Cagliari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Crisponi
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Feng
authors.affiliation: Unit of Molecular Neurogenetics, "C. Besta" Neurological Institute - IRCCS Foundation, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: Department of Paediatric Neurology, Manchester Children's Hospital, Manchester, UK.
authors.forename: I
authors.initials: I
authors.lastname: Hughes
authors.affiliation: National Centre for Inherited Metabolic Disease, Children's University Hospital, Dublin Republic of Ireland.
authors.forename: E P
authors.initials: EP
authors.lastname: Treacy
authors.affiliation: Centre for Statistics in Medicine, University of Oxford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Birks
authors.affiliation: Department of Biochemistry, University of Oxford, UK.
authors.forename: G K
authors.initials: GK
authors.lastname: Brown
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
authors.forename: C A
authors.initials: CA
authors.lastname: Sewry
authors.affiliation: Our Lady's Hospital for Sick Children, Dublin, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: McDermott
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, The Women's Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Poulton
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003576:Electron Transport Complex IV / Q000235:genetics; D005145:Face / Q000473:pathology; D005190:Family; D005260:Female; D018740:Genetic Heterogeneity; D006651:Histocytochemistry; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009123:Muscle Hypotonia; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation / Q000235:genetics; D016415:Sequence Alignment; D012359:tRNA Methyltransferases / Q000235:genetics
chemical_list: D024101:Mitochondrial Proteins; D003576:Electron Transport Complex IV; D012359:tRNA Methyltransferases; C496706:TRMU protein, human