Abstract
Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous report of DNM1L-related clinical disease: a female neonate with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF; OMIM #614388), a lethal disorder characterized by cerebral dysgenesis, seizures, lactic acidosis, elevated very long chain fatty acids, and abnormally elongated mitochondria and peroxisomes. Here, we describe a second individual, diagnosed via whole-exome sequencing, who presented with developmental delay, refractory epilepsy, prolonged survival, and no evidence of mitochondrial or peroxisomal dysfunction on standard screening investigations in blood and urine. EEG was nonspecific, showing background slowing with frequent epileptiform activity at the frontal and central head regions. Electron microscopy of skeletal muscle showed subtle, nonspecific abnormalities of cristal organization, and confocal microscopy of patient fibroblasts showed striking hyperfusion of the mitochondrial network. A panel of further bioenergetic studies in patient fibroblasts showed no significant differences versus controls. The proband’s de novo DNM1L variant, NM_012062.4:c.1085G>A; NP_036192.2:p.(Gly362Asp), falls within the middle (oligomerization) domain of DNM1L, implying a likely dominant-negative mechanism. This disorder, which presents nonspecifically and affords few diagnostic clues, can be diagnosed by means of DNM1L sequencing and/or confocal microscopy.
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Acknowledgements
We acknowledge the participation of the proband and his family, without whom this work would not be possible. This work was supported by MitoCanada Foundation and was performed, in part, under the Care4Rare Canada Consortium funded by Genome Canada, the Canadian Institutes of Health Research (CIHR), the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and CHEO Foundation. We thank Taila Hartley (Clinical Coordinator) and Chandree Beaulieu (Project Manager) at the Children’s Hospital of Eastern Ontario (CHEO) Research Institute for their contribution to the infrastructure of Care4Rare. This work was selected for study by the Care4Rare (Enhanced Care for Rare Genetic Diseases in Canada) Consortium Gene Discovery Steering Committee: Kym Boycott (lead; University of Ottawa), Alex MacKenzie (co-lead; University of Ottawa), Jacek Majewski (McGill University), Michael Brudno (University of Toronto), Dennis Bulman (University of Ottawa), and David Dyment (University of Ottawa). We acknowledge the contribution of the high-throughput sequencing platform of the McGill University and Génome Québec Innovation Centre, Montréal, Canada. MT received a post-doctoral fellowship from the CIHR. GA received a Vanier Canada Graduate Scholarship. M-EH is funded by the CIHR (INMD; MOP 57810). DAD is supported by the CIHR Institute of Genetics Clinical Investigatorship Award.
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Vanstone, J., Smith, A., McBride, S. et al. DNM1L-related mitochondrial fission defect presenting as refractory epilepsy. Eur J Hum Genet 24, 1084–1088 (2016). https://doi.org/10.1038/ejhg.2015.243
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DOI: https://doi.org/10.1038/ejhg.2015.243
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