MFN2, a new gene responsible for mitochondrial DNA depletion

Sir, we read with great interest the paper by Rouzier et al. (2012) reporting a novel dominant MFN2 missense mutation (c.629A>T, p.D210V) in a large family displaying an optic atrophy ‘plus’ phenotype. Importantly, the authors identified MFN2 as a new gene implicated in mitochondrial DNA instability as they found multiple mitochondrial DNA deletions in skeletal muscle of two adult patients. Moreover, they have shown that mitochondrial fusion is necessary to repair stress-induced damage to mitochondrial DNA. Here, we report a child with an early-onset progressive multi-systemic disorder and carrying a novel MFN2 missense mutation responsible for mitochondrial DNA depletion in skeletal muscle. This girl was the second child of healthy unrelated parents, born after an uneventful pregnancy. Her birth weight was 2700 g [−2 standard deviations (SD)], her length 45.5 cm (−2 SD) and her head circumference 35 cm (mean). At the age of 6 months she was examined because of developmental delay with hypotonia, decreased rate of growth in head circumference (−2 SD), failure to thrive and severe gastro-oesophageal reflux. Brain MRI, EEG, brainstem auditory evoked potentials, metabolic and genetic investigations were all normal. At 3 years of age, the patient could only stand up when aided and had no language acquisition although her level of understanding seemed good as did her social interaction and behaviour. Drooling, abnormal ocular pursuit, ataxia, dysmetria, areflexia, weakness of limbs and near permanent abnormal movements appeared progressively thereafter. EMG disclosed an axonal sensorimotor neuropathy. At 5 years of age, brainstem auditory evoked potentials revealed hearing loss on the right side and the amplitude of visual evoked responses was decreased while the electroretinogram was normal. Complementary aetiological explorations were negative. Orthopaedic …