Complete elimination of a pathogenic homoplasmic mtDNA mutation in one generation

Mitochondrial DNA (mtDNA) mutations have been implicated in a wide variety of neurological conditions and are maternally inherited through a complex process which is not fully understood. Genetic counselling for mitochondrial conditions secondary to a mtDNA mutation can be challenging as it is not currently possible to accurately predict the mutational load/heteroplasmy of the mutation which could be passed to the offspring. In general, one expects that the higher the level of heteroplasmy the more likely that the same mtDNA mutation will be seen in the offspring. We report here a family which places a caveat on genetic counselling for mtDNA disorders. The proband is a 63 year old woman with m.14459G>A associated dystonia/spasticity/ataxia. The m.14459G>A mutation was detected at homoplasmic/near homoplasmic levels in her muscle tissue and fibroblasts, but did not appear to have been passed on to any of her offspring. To our knowledge, this is the first report of complete selection against a homoplasmic variant within maternally transmitted mtDNA. It is not clear if this novel phenomenon occurred by random chance or by another method of mitochondrial selection.