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Stability of the m.8993T→G mtDNA mutation load during human embryofetal development has implications for the feasibility of prenatal diagnosis in NARP syndrome
  1. J Steffann1,
  2. N Gigarel1,
  3. J Corcos1,
  4. M Bonnière2,
  5. F Encha-Razavi2,
  6. M Sinico3,
  7. S Prevot4,
  8. Y Dumez,
  9. A Yamgnane,
  10. R Frydman5,
  11. A Munnich1,
  12. J P Bonnefont1
  1. 1Université Paris-Descartes, Faculté de Médecine; Unité INSERM U781 Institut de Recherche Necker-Enfants Malades; service de génétique médicale, Hôpital Necker-Enfants Malades (Assistance Publique-Hôpitaux de Paris), Paris, France
  2. 2Service d’histo-embryologie cytogénétique, Hôpital Necker-Enfants Malades (Assistance Publique-Hôpitaux de Paris), Paris, France
  3. 3Service d’anatomopathologie, Centre hospitalier intercommunal de Créteil, Créteil, France
  4. 4Service d’anatomopathologie, Hôpital Antoine Béclère (Assistance Publique-Hôpitaux de Paris), Clamart, France
  5. 5Service de gynécologie-obstétrique, Hôpital Antoine Béclère (Assistance Publique-Hôpitaux de Paris), Clamart, France
  1. Correspondence to:
 J Steffann
 service de génétique médicale, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris cedex 15, France; steffann{at}


Background: Mitochondrial DNA (mtDNA) mutations cause a wide range of serious genetic diseases with maternal inheritance. Because of the high transmission risk and the absence of therapy in these disorders, at-risk couples often ask for prenatal diagnosis (PND). However, because heteroplasmy load (coexistence of mutant and wild-type mtDNA) may vary among tissues and with time, the possibility that a single fetal sample may not reflect the whole neonate impedes prenatal diagnosis of mtDNA diseases.

Methods: We performed 13 prenatal diagnoses for the NARP (neurogenic weakness, ataxia, retinitis pigmentosa) m.8993T→G mtDNA mutation (p.Leu156Arg) in the ATP synthase subunit 6 gene. Analyses were performed on chorionic villous (CVS) and/or amniocyte samples carried out at various stages of pregnancy, using a method enabling quantification of low DNA amounts.

Results: Maternal mutant loads ranged from 0 to 75% in blood and had no predictive value for the fetus status, except for women with no detectable mutant DNA, whose fetuses were consistently mutation-free. In 8/13 PND, mutant load was <30%. These children are healthy at 2–7 years of age. In 5/13 PND, mutant load ranged from 65 to 100%, and parents preferred to terminate the pregnancies (15–22 weeks of gestation). Single-cell analysis of 20 trophoblastic cells and 21 amniocytes isolated from two affected fetuses found an average mutant load close to the overall CVS and amniocyte mutant load, despite striking intercellular variation. The m.8993T→G mutant loads, assessed in 7, 17, 11, and 5 different tissues from 4 terminations, respectively, were identical in all tissues from a given individual (mean (SD) 78 (1.2)%, 91 (0.7)%, 74 (2)%, and 63 (1.6)% for the 4 fetuses, respectively).

Conclusions: Our results indicate that the placental/amniotic mutant loads do reflect the NARP mutant mtDNA load in the whole fetus, even when the sample amount is small, and suggest that heteroplasmy level remains stable during pregnancy, at least after 10 weeks of gestation. Although these data establish the feasibility of PND for this mutation, assessing more precisely the correlation between mutant load and disease severity should further help in interpreting PND results.

  • MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes
  • NARP, neurogenic weakness, ataxia, retinitis pigmentosa
  • OMIM, Online Mendelian Inheritance in Man
  • PND, prenatal diagnosis
  • CVS, chorionic villus
  • NARP
  • neurogenic weakness
  • ataxia
  • retinitis pigmentosa syndrome
  • 8993T→G
  • heteroplasmy
  • mtDNA
  • fetus
  • prenatal diagnosis

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  • Competing interests: None declared.

  • Published Online First 1 June 2007