Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.
Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as 'benign cytochrome c oxidase deficiency myopathy' is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.
Horvath
Rita
R
Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. rita.horvath@ncl.ac.uk
Kemp
John P
JP
Tuppen
Helen A L
HA
Hudson
Gavin
G
Oldfors
Anders
A
Marie
Suely K N
SK
Moslemi
Ali-Reza
AR
Servidei
Serenella
S
Holme
Elisabeth
E
Shanske
Sara
S
Kollberg
Gittan
G
Jayakar
Parul
P
Pyle
Angela
A
Marks
Harold M
HM
Holinski-Feder
Elke
E
Scavina
Mena
M
Walter
Maggie C
MC
Coku
Jorida
J
Günther-Scholz
Andrea
A
Smith
Paul M
PM
McFarland
Robert
R
Chrzanowska-Lightowlers
Zofia M A
ZM
Lightowlers
Robert N
RN
Hirano
Michio
M
Lochmüller
Hanns
H
Taylor
Robert W
RW
Chinnery
Patrick F
PF
Tulinius
Mar
M
DiMauro
Salvatore
S
D001483:Base Sequence; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003937:Diagnosis, Differential; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008967:Molecular Biology; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology; D009690:Nucleic Acid Conformation; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011379:Prognosis