Selecting the right embryo in mitochondrial disorders

Mitochondrial disorders are among the most common inborn errors of metabolism. Based on genetic etiology, they can be divided into several subgroups, which require different approaches for reproductive counseling, addressing differences in recurrence risks and reproductive options. The majority are caused by mutations in nuclear genes, which are currently being rapidly resolved by whole-exome sequencing (wes) and which segregate in a mendelian way. Prenatal diagnosis (pnd) or preimplantation genetic diagnosis (pgd) is available for these families to prevent the birth of another severely affected child. In at least 15 % of cases, mitochondrial diseases are caused by mitochondrial dna (mtdna) mutations. Such mtdna mutations can (1) be the result of a nuclear gene defect (multiple mtdna deletions), (2) occur de novo (point mutations or large single mtdna rearrangements), or (3) be maternally inherited (generally point mutations). For the maternally inherited heteroplasmic mtdna mutations, the mitochondrial bottleneck is an important phenomenon defining the mtdna mutation load in the offspring, with an often high (or unpredictable) recurrence risk and consequently complex counseling. Pnd to enable testing for mtdna mutations is technically possible, but for many carriers of mtdna point mutations, this approach is not applicable given the limitations in predicting phenotype. A total of 44 cases of pnd performed in 35 mtdna mutation carriers (m.3243a>g, m.9176t>c, m.8993t>g/c, m.8344a>g, m.13513g>a, m.11777c>a, m.10191t>c, m.10158t>c, m.3688g>a) have been described in literature. One additional unpublished case is presented here (m.3303c>t). For mtdna point mutations which are most likely de novo in the affected child, the recurrence risk has been shown to be very low, and pnd can be offered for reassurance. We have performed pnd in four such cases, and six additional prenatal diagnoses were reported in literature. Pnd is also the most suitable option for female carriers with a low mutation load, demonstrating extreme skew such as mutations at nucleotide 8993. A fairly new option for preventing the transmission of mtdna diseases is preimplantation genetic diagnosis (pgd). Embryos with mutant load below a mutation-specific or, if not possible, general expression threshold are transferred. A systematic review showed ≥95 % probability of being unaffected at (muscle) mutant level of 18 % or less, irrespective of the mutation. A total of 14 pgd cycles in six female carriers of heteroplasmic mtdna mutations (m.3243a>g, m.8993t>g, m.8344a>g) have been completed at our center to date. All carriers produced oocytes below the threshold, and blastomere mutation load was representative for the whole embryo when two blastomeres were analyzed. A total of 12 pgd cycles in nine mtdna mutation carriers (m.3243a>g, m.8993t>g) have been reported elsewhere. A total of six children were born after pgd and one pregnancy is ongoing. So, pgd is currently the best reproductive option for most maternally transmitted heteroplasmic mtdna point mutations. Oocyte donation is a safe option to prevent the transmission of mtdna disease to a future child for couples who reject pgd. Nuclear genome transfer techniques are currently investigated in research settings and might offer additional reproductive options in specific cases of mtdna disease in the future.keywordsmitochondrial diseasemtdnareproductive counselingrecurrence riskreproductive optionsprenatal diagnosis (pnd)preimplantation genetic diagnosis (pgd).