Preventing transmission of maternally inherited mitochondrial DNA diseases

  title={Preventing transmission of maternally inherited mitochondrial DNA diseases},
  author={Joanna Poulton and Stephen Kennedy and Pippa Oakeshott and Dagan Wells},
  journal={BMJ : British Medical Journal},
#### Summary points #### Methods We used our personal archive of references, Medline searches, and consultation with other experts in the field to produce this review. It is derived from 22 years of research and 11 years of genetic counselling in mitochondrial DNA diseases. Maternally inherited mutations of mitochondrial DNA can be asymptomatic or cause illnesses such as developmental regression, deafness, blindness, neuropathy, diabetes, cardiomyopathy, and liver failure. Families who have… 

Preimplantation genetic diagnosis in mitochondrial DNA disorders: challenge and success

PGD provides carriers of mtDNA mutations the opportunity to conceive healthy offspring through preimplantation genetic diagnosis, which circumvents these problems by transferring an embryo below the threshold of clinical expression.

Preventing the transmission of pathogenic mitochondrial DNA mutations: can we achieve long-term benefits from germ-line gene transfer?

A model of mtDNA heteroplasmy inheritance was developed by studying 87 mother–child pairs, and predicted the likely outcome of different levels of ‘mutant mtDNA leakage’ on subsequent maternal generations, and showed that reducing the proportion of mutant mtDNA to <5% dramatically reduces the chance of disease recurrence in subsequent generations.

Information for genetic management of mtDNA disease: sampling pathogenic mtDNA mutants in the human germline and in placenta

Background Families with a child who died of severe, maternally inherited mitochondrial DNA (mtDNA) disease need information on recurrence risk. Estimating this risk is difficult because of (a)

PGD and heteroplasmic mitochondrial DNA point mutations: a systematic review estimating the chance of healthy offspring.

The data show, for the first time, that carriers of heteroplasmic mtDNA mutations will have a fair chance of having healthy offspring, by applying PGD, and these conclusions are partly based on estimations and do not provide absolute certainty.

Assisted Reproductive Technologies: The Potential to Prevent the Transmission of Mutant mtDNA from One Generation to the Next

Encouraging studies in non-human models have developed micromanipulation approaches to reduce the transmission of mutant mtDNA between generations, however, these methodologies require further experimental validation to determine whether assisted reproductive technologies can prevent the Transmission of Mutant mtDNA.

Mitochondrial donation – birth of a policy

Mitochondrial donation (or mitochondrial replacement techniques, MRT) is a special form of in vitro fertilisa­ tion involving the mitochondrial DNA (mtDNA) of a third (donor) party. This technique

Avoiding transgenerational risks of mitochondrial DNA disorders: a morally acceptable reason for sex selection?

It is concluded that if PGD is already part of the procedure, either as the central technology or as a back-up test after NT, preferentially transferring male embryos could in principle be a morally acceptable way of reducing possible burdens and risks.

Segregation of mitochondrial DNA mutations in the human placenta: implication for prenatal diagnosis of mtDNA disorders

Data indicate that mutant load determined from CVS has to be interpreted with caution for PND of some mtDNA disorders and should be associated with/substituted by a mutant load measurement on amniocytes.

Mitochondrial Gene Replacement in Primate Offspring and Embryonic Stem Cells

It is demonstrated here that the mitochondrial genome can be efficiently replaced in mature non-human primate oocytes (Macaca mulatta) by spindle–chromosomal complex transfer from one egg to an enucleated, mitochondrial-replete egg.



PGD to reduce reproductive risk: the case of mitochondrial DNA disorders.

It is concluded that none of them supplies convincing moral arguments to regard risk-reducing PGD as unacceptable, Nevertheless, introducing this new application of PGD in clinical practice will raise further complex issues of determining conditions for its responsible use.

Evidence from human oocytes for a genetic bottleneck in an mtDNA disease.

Oocytes from a patient with Kearn-Sayre syndrome caused by mtDNA rearrangements are examined to present direct evidence that the number of segregating units (n) is three to five orders of magnitude less than thenumber of mitochondria in the human female oocyte.

Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993.

The severity of symptoms to the mutant load and predicted the clinical outcome of a given mutant load were related to the available data to generate empirical recurrence risks for genetic counseling, which may be used in conjunction with prenatal diagnosis.

A functionally dominant mitochondrial DNA mutation.

A novel mtDNA mutation is reported that contradicts this rule, since it caused a severe multisystem disorder and respiratory chain deficiency even at low levels of heteroplasmy in a 13-year-old boy with clinical, radiological and biochemical evidence of a mitochondrial disorder.

Dealing with uncertainties: ethics of prenatal diagnosis and preimplantation genetic diagnosis to prevent mitochondrial disorders.

The ethical issues regarding prenatal diagnosis and preimplantation genetic diagnosis (PGD) of mitochondrial disorders are addressed and the acceptability of suboptimal genetic testing, the value and research use of embryos, the evaluation of late abortion, and the ethics of PGD for disorders with an incomplete penetrance and variable expression are addressed.

A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes

It is shown that the partitioning of mtDNA molecules into different cells before and after implantation, followed by the segregation of replicating mtDNA between proliferating primordial germ cells, is responsible for the different levels of heteroplasmy seen in the offspring ofheteroplasmic female mice.

Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation.

  • A. SatoT. Kono J. Hayashi
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2005
Nuclear transplantation of zygotes of transmitochondria mice was carried out and was shown to rescue all of the F(0) progeny from expression of respiration defects throughout their lives, applicable to patients with mitochondrial diseases for preventing their children from developing the diseases.

Decrease of 3243 A-->G mtDNA mutation from blood in MELAS syndrome: a longitudinal study.

Results suggest that mutant mtDNA is slowly selected from rapidly dividing blood cells in MELAS, and that changes in the distribution of mutant mtDNAs underlie the progressive nature of mtDNA diseases.

A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle.

This study, which reports a mutation involving tRNALeu(CUN), demonstrates clearly that mtDNA point mutations can accumulate over time and may be restricted in their tissue distribution.