title: Three families with 'de novo' m.3243A > G mutation.
abstract: The m.3243A > G mutation is the most prevalent, disease-causing mitochondrial DNA (mtDNA) mutation. In a national cohort study of 48 families harbouring the m.3243A > G mutation, we identified three families in which the mutation appeared to occur sporadically within these families. In this report we describe these three families. Based on detailed mtDNA analysis of three different tissues using two different quantitative pyrosequencing assays with sensitivity to a level of 1% mutated mtDNA, we conclude that the m.3243A > G mutation has arisen de novo in each of these families. The symptomatic carriers presented with a variety of symptoms frequently observed in patients harbouring the m.3243A > G mutation. A more severe phenotype is seen in the de novo families compared to recent cohort studies, which might be due to reporting bias. The observation that de novo m.3243A > G mutations exist is of relevance for both diagnostic investigations and genetic counselling. Firstly, even where there is no significant (maternal) family history in patients with stroke-like episodes, diabetes and deafness or other unexplained organ dysfunction, the m.3243A > G mutation should be screened as a possible cause of the disease. Second, analysis of maternally-related family members is highly recommended to provide reliable counselling for these families, given that the m.3243A > G mutation may have arisen de novo.
authors.affiliation: Radboud University Medical Center Amalia Children's Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: de Laat
authors.affiliation: Radboud University Medical Center Amalia Children's Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands; Radboud University Medical Center, Department of Internal Medicine, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands.
authors.forename: Mirian C H
authors.initials: MC
authors.lastname: Janssen
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Radboud University Medical Center Amalia Children's Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands.
authors.forename: Richard J T
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Radboud University Medical Center Amalia Children's Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands.
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
keywords: Genetic counselling; Inheritance; MELAS, mitochondrial myopathy, encephalopathy, lactate acidosis and stroke-like episodes; MERRF, myoclonic epilepsy with ragged-red fibres; MIDD, maternally inherited diabetes and deafness; Maternally inherited diabetes and deafness (MIDD); Mitochondrial myopathy, encephalopathy, lactate acidosis and stroke-like episodes (MELAS); m.3243A > G mutation; mtDNA, mitochondrial DNA