Sporadic intragenic inversion of the mitochondrial DNA MTND1 gene causing fatal infantile lactic acidosis.
Mutations of mitochondrial DNA (mtDNA) are an important cause of genetic disease, yet rarely present in the neonatal period. Here we report the clinical, biochemical, and molecular genetic findings of an infant who died at the age of 1 mo with marked biventricular hypertrophy, aortic coarctation, and severe lactic acidosis due to a previously described but unusual mtDNA mutation, a 7-bp intragenic inversion within the mitochondrial gene encoding ND1 protein of complex I (MTND1). In direct contrast to the previous case, an adult with exercise intolerance who only harbored the mutation in muscle, the MTND1 inversion in our patient was present at high levels in several tissues including the heart, muscle, liver, and cultured skin fibroblasts. There was no evidence of the mutation or respiratory complex I defect in a muscle biopsy from the patient's mother. Transmitochondrial cytoplasmic hybrids (cybrids) containing high mutant loads of the inversion expressed the biochemical defect but apparently normal levels of the assembled complex. Our report highlights the enormous phenotypic diversity that exists among pathogenic mtDNA mutations and reemphasizes the need for appropriate genetic counseling for families affected by mtDNA disease.
Blakely
Emma L
EL
Mitochindrial Research Group, School of Neurlogy, Neurobiology and Psychiatry, The University of Newcastle upon Tyne, UK.
Rennie
Katherine J
KJ
Jones
Linda
L
Elstner
Mattias
M
Chrzanowska-Lightowlers
Zofia M A
ZM
White
Christopher B
CB
Shield
Julian P H
JP
Pilz
Daniela T
DT
Turnbull
Douglass M
DM
Poulton
Joanna
J
Taylor
Robert W
RW
D000140:Acidosis, Lactic / Q000235:genetics* / Q000401:mortality; D000328:Adult; D001017:Aortic Coarctation / Q000235:genetics; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics; D017380:Hypertrophy, Right Ventricular / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D009245:NADH Dehydrogenase / Q000235:genetics*; D017354:Point Mutation
D004272:DNA, Mitochondrial; D042967:Electron Transport Complex I; D009245:NADH Dehydrogenase; C515075:NADH dehydrogenase subunit 1, human