TY - JOUR
T1 - Preimplantation genetic diagnosis in mitochondrial DNA disorders
T2 - challenge and success
AU - Sallevelt, Suzanne C. E. H.
AU - Dreesen, Joseph C. F. M.
AU - Drüsedau, Marion
AU - Spierts, Sabine
AU - Coonen, Edith
AU - van Tienen, Florence H. J.
AU - van Golde, Ronald J. T.
AU - de Coo, Irineus F. M.
AU - Geraedts, Joep P. M.
AU - de Die-Smulders, Christine E. M.
AU - Smeets, Hubert J. M.
PY - 2013/2
Y1 - 2013/2
N2 - Background Mitochondrial or oxidative phosphorylation diseases are relatively frequent, multisystem disorders; in about 15% of cases they are caused by maternally inherited mitochondrial DNA (mtDNA) mutations. Because of the possible severity of the phenotype, the lack of effective treatment, and the high recurrence risk for offspring of carrier females, couples wish to prevent the transmission of these mtDNA disorders to their offspring. Prenatal diagnosis is problematic for several reasons, and concern the often poor correlation between mutation percentages and disease severity and the uncertainties about the representativeness of a fetal sample. A new option for preventing transmission of mtDNA disorders is preimplantation genetic diagnosis (PGD), which circumvents these problems by transferring an embryo below the threshold of clinical expression.
Methods We present the data on nine PGD cycles in four female carriers of mitochondrial diseases: three mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) (m.3243A>G), and one Leigh (m.8993T>G). Our threshold for transfer after PGD is 15% for the m.3243A>G mutation and 30% for the m.8993T>G mutation.
Results All four female carriers produced embryos eligible for transfer. The m.8993T>G mutation in oocytes/embryos showed more skewing than the m.3243A>G. In about 80% of the embryos the mutation load in the individual blastomeres was fairly constant (interblastomere differences <10%). However, in around 11% (in embryos with the m.3243A>G mutation only), the mutation load differed substantially (>15%) between blastomeres of a single embryo, mostly as a result of one outlier. The m.8993T>G carrier became pregnant and gave birth to a healthy son.
Conclusions PGD provides carriers of mtDNA mutations the opportunity to conceive healthy offspring.
AB - Background Mitochondrial or oxidative phosphorylation diseases are relatively frequent, multisystem disorders; in about 15% of cases they are caused by maternally inherited mitochondrial DNA (mtDNA) mutations. Because of the possible severity of the phenotype, the lack of effective treatment, and the high recurrence risk for offspring of carrier females, couples wish to prevent the transmission of these mtDNA disorders to their offspring. Prenatal diagnosis is problematic for several reasons, and concern the often poor correlation between mutation percentages and disease severity and the uncertainties about the representativeness of a fetal sample. A new option for preventing transmission of mtDNA disorders is preimplantation genetic diagnosis (PGD), which circumvents these problems by transferring an embryo below the threshold of clinical expression.
Methods We present the data on nine PGD cycles in four female carriers of mitochondrial diseases: three mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) (m.3243A>G), and one Leigh (m.8993T>G). Our threshold for transfer after PGD is 15% for the m.3243A>G mutation and 30% for the m.8993T>G mutation.
Results All four female carriers produced embryos eligible for transfer. The m.8993T>G mutation in oocytes/embryos showed more skewing than the m.3243A>G. In about 80% of the embryos the mutation load in the individual blastomeres was fairly constant (interblastomere differences <10%). However, in around 11% (in embryos with the m.3243A>G mutation only), the mutation load differed substantially (>15%) between blastomeres of a single embryo, mostly as a result of one outlier. The m.8993T>G carrier became pregnant and gave birth to a healthy son.
Conclusions PGD provides carriers of mtDNA mutations the opportunity to conceive healthy offspring.
U2 - 10.1136/jmedgenet-2012-101172
DO - 10.1136/jmedgenet-2012-101172
M3 - Article
C2 - 23339111
SN - 0022-2593
VL - 50
SP - 125
EP - 132
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 2
ER -