Risk of developing a mitochondrial DNA deletion disorder.
BACKGROUND
Pathogenic mitochondrial DNA (mtDNA) mutations are found in at least one in 8000 individuals. No effective treatment for mtDNA disorders is available, making disease prevention important. Many patients with mtDNA disease harbour a single pathogenic mtDNA deletion, but the risk factors for new cases and disease recurrence are not known.


METHODS
We did a multicentre study of 226 families in which a single mtDNA deletion had been identified in the proband, including patients with chronic progressive external ophthalmoplegia, Kearns Sayre syndrome, or Pearson's syndrome. We studied the relation between maternal age and the risk of unaffected mothers having an affected child, and determined the recurrence risks among the siblings and offspring of affected individuals.


RESULTS
We noted no relation between maternal age and the risk of unaffected mothers having children with an mtDNA deletion disorder. None of the 251 siblings of the index cases developed clinical features of mtDNA disease. Risk of recurrence among the offspring of affected women was 4.11% (95% CI 0.86-11.54, or one in 117 to one in nine births). Only one of the mothers who had an affected child had a duplication of mtDNA in skeletal muscle.


CONCLUSIONS
Unlike nuclear chromosomal rearrangements, incidence of mtDNA deletion disorders does not increase with maternal age, and unaffected mothers are unlikely to have more than one affected child. Affected women were previously thought to have a negligible chance of having clinically affected offspring, but the actual risk is, on average, about one in 24 births.
Neurology, University of Newcastle upon Tyne, Newcastle upon Tyne, UK. P.F.Chinnery@ncl.ac.uk
Patrick F
PF
Chinnery
Salvatore
S
DiMauro
Sara
S
Shanske
Eric A
EA
Schon
Massimo
M
Zeviani
Caterina
C
Mariotti
Fanco
F
Carrara
Anne
A
Lombes
Pascal
P
Laforet
Helène
H
Ogier
Michaela
M
Jaksch
Hanns
H
Lochmüller
Rita
R
Horvath
Marcus
M
Deschauer
David R
DR
Thorburn
Laurence A
LA
Bindoff
Joanna
J
Poulton
Robert W
RW
Taylor
John N S
JN
Matthews
Douglass M
DM
Turnbull
D000328:Adult; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007625:Kearns-Sayre Syndrome / Q000235:genetics; D008297:Male; D008423:Maternal Age; D028361:Mitochondrial Diseases / Q000235:genetics*; D009154:Mutation; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics; D010375:Pedigree; D012307:Risk Factors; D013577:Syndrome
D004272:DNA, Mitochondrial