74th ENMC International Workshop: Mitochondrial Diseases 19–20 November 1999, Naarden, The Netherlands

Article Outline

• 1. Introduction
  • 1.1. Current options
  • 1.2. Future options
• 2. Meeting outcome
  • 2.1. mtDNA rearrangements
  • 2.2. NARP or Leigh's syndrome – T8993G and T8993C
  • 2.3. MERRF A8344G
  • 2.4. MELAS A3243G
  • 2.5. 1555
  • 2.6. 11778, 3460 and 14484 mutations underlying Leber's hereditary optic neuropathy
  • 2.7. Private point mutations
  • 2.8. Website
• 3. Chairpersons
• 4. Participants
• Acknowledgements
• References
• Copyright

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1. Introduction 

Disease due to mtDNA defects is increasingly recognised and approximately 1 in 8000 persons carry these mutations. Despite significant scientific advances, there has been limited progress in the clinical management and genetic counselling of these patients [1]. Mitochondrial DNA (mtDNA) is maternally inherited. Thousands of copies of mtDNA are present in each nucleated somatic cell and in normal individuals these have a virtually identical sequence (homoplasmy). In many patients with mtDNA disease, there is a mixture of wild type and mutant genomes in the same cell – a situation termed heteroplasmy. The current workshop focussed specifically on the problems and solutions for genetic counselling of heteroplasmic mtDNA disorders.

Prenatal diagnosis and counselling of mtDNA diseases is difficult. The individual oocytes from women at risk of transmitting heteroplasmic mtDNA disease may contain markedly different levels of mutant mtDNA. An additional problem is that the amount of mutant mtDNA may vary between different tissues, and that it may vary with time. In practice, there are many asymptomatic women who feel unable to risk having children because of these uncertainties.

The important issues for both counselling and prenatal diagnosis include whether there is:

1.1. Current options 

1.2. Future options 

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2. Meeting outcome 

The meeting reached the following conclusions about counselling and prenatal diagnosis for heteroplasmic mtDNA mutations:

2.1. mtDNA rearrangements 

Recurrence risks for Kearns Sayre syndrome (KSS) are complex. For women with KSS due to mtDNA rearrangements, particularly those in whom rearrangements are detectable in blood (>5%), we recommend CVS. The analysis should be done by Southern blotting (PCR analysis may be misleading both because of contamination with maternal mtDNA and of problems with interpretation). For women with chronic progressive external ophthalmoplegia (CPEO) in whom only mtDNA deletions are detectable in muscle, we believe that the risk of transmitting the disease is very low and that no special precautions are essential. For healthy women with a single affected child with KSS or Pearson's syndrome and no detectable deletion in blood, the risk of another affected child is probably very low. CVS analysis may be an option.

2.2. NARP or Leigh's syndrome – T8993G and T8993C 

There is a relationship between mutatant load in the mother and the risk of an affected offspring [2]. Both mutations fulfil the criteria above for prenatal diagnosis and therefore CVS is likely to be informative. Our recommendations are:

2.3. MERRF A8344G 

There is a relationship between mtDNA mutant load in the mother and the risk of an affected offspring. Severe disease is rare in offspring of mothers with a load of <40% mutant mtDNA in blood, and this fact should be considered when offering CVS. We believe that CVS should be offered to mothers with levels of >40%. Pre-implantation genetic diagnosis and oocyte donation should also be considered in mothers with high mutant load.

2.4. MELAS A3243G 

This is the most common and most problematic heteroplasmic mtDNA disorder. Available evidence suggests that there is a significant risk of an affected offspring for women known or suspected of carrying the mutation. The level of mutant mtDNA in blood falls with time and may be undetectable in women capable of transmitting the disorder. Sampling of other tissues, including oocytes, may be of value. Preimplantation genetic diagnosis and CVS probably predict mutation load in offspring. However, severity is less clearly related to mutatant load, and patients require very careful counselling before embarking on these procedures.

2.5. 1555 

As there is currently no way of predicting the clinical phenotype of patients with these mutations, which varies from normal to severe hearing impairment, prenatal diagnosis is not appropriate. However, making a molecular diagnosis is important in 1555 families as exposure to aminoglycoside antibiotics increases the penetrance and lowers the age of onset.

2.6. 11778, 3460 and 14484 mutations underlying Leber's hereditary optic neuropathy 

The clinical phenotype of patients with these mutations varies from normal to severe visual impairment. There is a slightly higher chance of blindness in patients who are homoplasmic than those who are heteroplasmic, but this is of little predictive value on an individual basis. Prenatal diagnosis is therefore not appropriate.

2.7. Private point mutations 

These also present major problems because extensive family data is rarely available. In this group of patients there is no good data available from which risk can be calculated. Sampling of several tissues in the mother, including oocyte sampling, may help. Individuals with a highly asymmetric tissue distribution (e.g. mutant mtDNA only found in muscle but absent in satellite cells) may be unlikely to transmit the disorder.

2.8. Website 

We intend to set up a website to collate information on our combined experience with prenatal diagnosis, and to establish a repository to evaluate the number of times rare mutations have been diagnosed. We urge diagnostic labs to make it a priority to submit this information. Contact person for database: Dr P.F. Chinnery (p.f.chinnery@ncl.ac.uk).

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3. Chairpersons 

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4. Participants 

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Acknowledgements 

This Workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors: Association Française contre les Myopathies (France), Deutsche Gesellschaft für Muskelkranke (Germany), Italian Telethon Committee (Italy), Muscular Dystrophy Group of Great Britain and Northern Ireland (UK), Muskelsvindfonden (Denmark), Prinses Beatrix Fonds (Netherlands), Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland), Verein zur Erforschung von Muskelkrankheiten bei Kindern (Austria), Vereniging Spierziekten Nederland (Netherlands) and ENMC associate member Muscular Dystrophy Association of Finland

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References 

1. Poulton J, Marchington DR. Progress in genetic counselling and prenatal diagnosis of maternally inherited mtDNA diseases. Neuromusc Disord 2000 (submitted for publication).
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2. White S, Collins V, R RW, et al.  Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am J Hum Genet. 1999;65:474–482
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