title: Preimplantation genetic diagnosis in mitochondrial DNA disorders: challenge and success.
abstract: 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.
authors: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Limburg, Netherlands. suzanne.sallevelt@mumc.nl
authors: Suzanne C E H
authors: SC
authors: Sallevelt
authors: Joseph C F M
authors: JC
authors: Dreesen
authors: Marion
authors: M
authors: Drüsedau
authors: Sabine
authors: S
authors: Spierts
authors: Edith
authors: E
authors: Coonen
authors: Florence H J
authors: FH
authors: van Tienen
authors: Ronald J T
authors: RJ
authors: van Golde
authors: Irineus F M
authors: IF
authors: de Coo
authors: Joep P M
authors: JP
authors: Geraedts
authors: Christine E M
authors: CE
authors: de Die-Smulders
authors: Hubert J M
authors: HJ
authors: Smeets
mesh_terms: D000328:Adult; D001757:Blastomeres / Q000502:physiology; D004252:DNA Mutational Analysis / Q000379:methods*; D004272:DNA, Mitochondrial / Q000032:analysis* / Q000737:chemistry / Q000235:genetics; D004622:Embryo, Mammalian; D005260:Female; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D009865:Oocytes / Q000502:physiology; D010375:Pedigree; D011247:Pregnancy; D019836:Preimplantation Diagnosis / Q000379:methods*; D015053:Zygote / Q000502:physiology
chemical_list: D004272:DNA, Mitochondrial