ArticlesRisk of developing a mitochondrial DNA deletion disorder
Introduction
Pathogenic mitochondrial DNA (mtDNA) mutations are found in at least one in 8000 individuals.1 Many patients harbour a single deleted species of mtDNA that causes chronic progressive external ophthalmoplegia, Kearns Sayre syndrome, or Pearson's syndrome.2, 3, 4, 5 These disorders are progressive, and often cause substantial disability and lead to premature death. No effective treatment for mtDNA disease is available, placing great emphasis on disease prevention.
Anecdotally, chronic progressive external ophthalmoplegia, Kearns Sayre syndrome, and Pearson's syndrome appear as sporadic cases,2, 3, 4, 5 but the factors that predispose an unaffected woman to have an affected child are not known. By contrast, autosomally inherited chronic progressive external ophthalmoplegia is known to be due to nuclear gene defects that compromise mtDNA maintenance and predispose to the formation of multiple secondary mtDNA deletions throughout life.6, 7, 8 Clinical recurrence of a single mtDNA deletion disorder has been noted in a small number of human pedigrees,9, 10, 11 and also in a mouse model of an mtDNA deletion disorder.12 Therefore, a genuine risk of disease recurrence exists in families with an affected individual, but the actual recurrence risks are not known.
Some patients with mtDNA deletion disorders also harbour an mtDNA duplication.13 The duplications are not thought to be pathogenic,14 but they may be transmitted from mother to child and lead to the formation of pathogenic deletions in the offspring of affected individuals.15 This mechanism might provide an explanation for the apparent transmission of mtDNA deletions in some human pedigrees,9, 10, 16 and in the mouse model,12 but in at least one instance the maternally transmitted species appears to be a deleted mtDNA molecule.11
To define and understand the recurrence risks for mtDNA deletion disorders, a very large cohort of affected individuals and their families need to be studied. mtDNA disorders are quite rare in the general population and detailed and reliable pedigree data are often not available in individual cases, making it difficult for any one centre to collect sufficient data to tackle this problem. We therefore formed a consortium of nine centres and identified 226 families with an mtDNA deletion disorder, enabling us to assess the risk factors and recurrence risks for single mtDNA deletion disorders.
Section snippets
Case ascertainment and molecular analysis
Patients with clinical, histochemical, and biochemical evidence of chronic progressive external opthalmoplegia, Kearns Sayre syndrome, and Pearson's syndrome were investigated in nine centres between 1990 and 2001 with standard molecular diagnostic techniques including a Southern blot of mtDNA.3, 17 Patients with multiple mtDNA deletions were excluded from subsequent analysis. Only patients with a single established mtDNA deletion in skeletal muscle were studied further. We deliberately
Results
We identified 226 nuclear families that contained at least one affected individual with chronic progressive external ophthalmoplegia, Kearns Sayre syndrome, or Pearson's syndrome. The clinical diagnosis was known for 219 index cases, and included 152 individuals with chronic progressive external ophthalmoplegia (with or without a proximal myopathy), 50 with Kearns Sayre syndrome, 11 with Pearson's syndrome, and six with diagnoses that did not fit into any of these established categories. These
Discussion
We have studied a large cohort of families affected by an mtDNA deletion disorder. Our observations not only provide robust clinical recurrence risks that can be used for genetic counselling, but also raise questions about the origin and transmission of mtDNA deletions that cause chronic progressive external ophthalmoplegia, Kearns Sayre syndrome, and Pearson's syndrome.
We noted no evidence of an association between maternal age and the risk of unaffected women having a child with an mtDNA
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