Prenatal diagnosis of myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome: contribution to understanding mitochondrial DNA segregation during human embryofetal development.
BACKGROUND
Myopathy, encephalopathy, lactic acidosis, and stroke-like (MELAS) syndrome, a maternally inherited disorder that is among the most common mitochondrial DNA (mtDNA) diseases, is usually associated with the m.3242A>G mutation of the mitochondrial tRNA(leu) gene. Very few data are available with respect to prenatal diagnosis of this serious disease. The rate of mutant versus wild-type mtDNA (heteroplasmy) in fetal DNA is indeed considered to be a poor indicator of postnatal outcome.


METHODS
Taking advantage of a novel semi-quantitative polymerase chain reaction test for m.3243A>G mutant load assessment, we carried out nine prenatal diagnoses in five unrelated women, using two different fetal tissues (chorionic villi v amniocytes) sampled at two or three different stages of pregnancy.


RESULTS
Two of the five women, although not carrying m.3243A>G in blood or extra-blood tissues, were, however, considered at risk for transmission of the mutation, as they were closely related to MELAS-affected individuals. The absence of 3243A>G in the blood of first degree relatives was associated with no mutated mtDNA in the cardiovascular system (CVS) or amniocytes, and their three children are healthy, with a follow-up of 3 months-3 years. Among the six fetuses from the three carrier women, three were shown to be homoplasmic (0% mutant load), the remaining three being heteroplasmic, with a mutant load ranging from 23% to 63%. The fetal mutant load was fairly stable at two or three different stages of pregnancy in CVS and amniocytes. Although pregnancy was terminated in the case of the fetus with a 63% mutant load, all other children are healthy with a follow-up of 3 months-6 years.


CONCLUSIONS
These data suggest that a prenatal diagnosis for MELAS syndrome might be helpful for at-risk families.
Bouchet
C
C
Department of Genetics, Hôpital Necker-Enfants Malades, Paris, France.
Steffann
J
J
Corcos
J
J
Monnot
S
S
Paquis
V
V
Rötig
A
A
Lebon
S
S
Levy
P
P
Royer
G
G
Giurgea
I
I
Gigarel
N
N
Benachi
A
A
Dumez
Y
Y
Munnich
A
A
Bonnefont
J P
JP
D000140:Acidosis, Lactic / Q000175:diagnosis / Q000196:embryology / Q000235:genetics; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial; D005190:Family; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D050259:Genes, Mitochondrial / Q000235:genetics*; D006801:Humans; D007223:Infant; D017241:MELAS Syndrome / Q000175:diagnosis* / Q000196:embryology / Q000235:genetics; D008297:Male; D017237:Mitochondrial Encephalomyopathies / Q000175:diagnosis / Q000196:embryology / Q000235:genetics; D009135:Muscular Diseases / Q000175:diagnosis / Q000196:embryology / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D012356:RNA, Transfer, Leu / Q000235:genetics; D020521:Stroke / Q000175:diagnosis / Q000196:embryology / Q000235:genetics
D004272:DNA, Mitochondrial; D012356:RNA, Transfer, Leu