243rd ENMC international workshop: Developing guidelines for management of reproductive options for families with maternally inherited mtDNA disease, Amsterdam, the Netherlands, 22–24 March 2019

Poulton, Joanna; Steffann, Julie; Burgstaller, Joerg P.; McFarland, Robert

doi:10.1016/j.nmd.2019.08.004

Cited by 18 publications

(10 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An embryo with the lowest level of mtDNA mutation is then selected and transferred, providing the quality of the embryo is sufficiently high (Hellebrekers et al, 2012). It is also important to be aware that only a limited number of embryos will be available with mutation levels that are unlikely to result in severe mitochondrial disease, and PGD is only successful in approximately one-third of cycles due to inherent problems associated with IVF (Steffann et al, 2018;Poulton et al, 2019).…”

Section: Prevention Of Transmission Of Mitochondrial Diseasesmentioning

confidence: 99%

“…Recent studies in patients harboring the m.3243A > G mutation have highlighted the importance of collecting genetic data to allow mathematical modeling to predict the likelihood of the success of PGD (Pickett et al, 2019). An additional issue for mitochondrial donation is the availability of suitable donors who are prepared to provide oocytes, which in itself requires both hormonal treatment and oocyte collection (Poulton et al, 2019).…”

Section: Prevention Of Transmission Of Mitochondrial Diseasesmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial Diseases: Hope for the Future

Russell

Gorman

Lightowlers

et al. 2020

Cell

277

238

View full text Add to dashboard Cite

Section: Prevention Of Transmission Of Mitochondrial Diseasesmentioning

confidence: 99%

Section: Prevention Of Transmission Of Mitochondrial Diseasesmentioning

confidence: 99%

Mitochondrial Diseases: Hope for the Future

Russell

Gorman

Lightowlers

et al. 2020

Cell

277

238

View full text Add to dashboard Cite

“…A definitive genetic diagnosis benefits patients and families, 17 allowing tailored information about prognosis and treatment, genetic counselling, and access to reproductive options such as prenatal diagnosis (genetic testing during pregnancy, usually by chorionic villus sampling or amniocentesis), preimplantation genetic diagnosis (the use of assisted reproductive technology and genetic testing of embryos), and mitochondrial transfer (replacing the mother's mitochondria in an ovum or early embryo with healthy mitochondria from another woman's donor egg or embryo, used for disorders caused by mtDNA mutations). 18 Whole genome sequencing is a next generation sequencing technology that is used to sequence the entire genome of an individual. It has the added benefit of being able to diagnose pathogenic mutations affecting the mtDNA and the nuclear genome, 19 so it has the potential to make a diagnosis in more families and shorten the time to diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study

Schon

Horvath

Wei

et al. 2021

BMJ

View full text Add to dashboard Cite

Objective To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease. Design Cohort study. Setting National Health Service, England, including secondary and tertiary care. Participants 345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018. Intervention Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants. Main outcome measure Definite or probable genetic diagnosis. Results A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis. Conclusion Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.

show abstract

“…Prenatal diagnosis involves testing the variant level in foetal tissue obtained by chorionic villus biopsy or amniocentesis ( 74 , 75 ). The variant level detected in this tissue reflects that seen in tissues of offspring and provides valuable information.…”

Section: Introductionmentioning

confidence: 99%

“…This involves testing embryos before implanting an embryo with low levels of variant ( 74 , 75 ) and is a good option for women affected by variants that widely segregate in oocytes (e.g. m.8993T>G/C), since some oocytes will inherit variant levels well below disease-threshold ( 70 ).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA disorders: from pathogenic variants to preventing transmission

Gomes

Pickett

et al. 2021

Human Molecular Genetics

View full text Add to dashboard Cite

Mitochondrial DNA (mtDNA) disorders are recognised as one of the most common causes of inherited metabolic disorders. The mitochondrial genome occurs in multiple copies resulting in both homoplasmic and heteroplasmic pathogenic mtDNA variants. A biochemical defect arises when the pathogenic variant level reaches a threshold, which differs between variants. Moreover, variants can segregate, clonally expand, or be lost from cellular populations resulting in a dynamic and tissue-specific mosaic pattern of oxidative deficiency. MtDNA is maternally inherited but transmission patterns of heteroplasmic pathogenic variants are complex. During oogenesis, a mitochondrial bottleneck results in offspring with widely differing variant levels to their mother, whilst highly deleterious variants, such as deletions, are not transmitted. Complemented by a complex interplay between mitochondrial and nuclear genomes, these peculiar genetics produce marked phenotypic variation, posing challenges to the diagnosis and clinical management of patients. Novel therapeutic compounds and several genetic therapies are currently under investigation, but proven disease-modifying therapies remain elusive. Women who carry pathogenic mtDNA variants require bespoke genetic counselling to determine their reproductive options. Recent advances in in vitro fertilisation techniques, have greatly improved reproductive choices, but are not without their challenges. Since the first pathogenic mtDNA variants were identified over thirty years ago, there has been remarkable progress in our understanding of these diseases. However, many questions remain unanswered and future studies are required to investigate the mechanisms of disease progression and to identify new disease-specific therapeutic targets.

show abstract

243rd ENMC international workshop: Developing guidelines for management of reproductive options for families with maternally inherited mtDNA disease, Amsterdam, the Netherlands, 22–24 March 2019

Cited by 18 publications

References 52 publications

Mitochondrial Diseases: Hope for the Future

Mitochondrial Diseases: Hope for the Future

Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study

Mitochondrial DNA disorders: from pathogenic variants to preventing transmission

Contact Info

Product

Resources

About