Elsevier

The Journal of Pediatrics

Volume 171, April 2016, Pages 313-316.e2
The Journal of Pediatrics

Clinical and Laboratory Observations
Lethal Disorder of Mitochondrial Fission Caused by Mutations in DNM1L

Portions of the study were presented as an abstract at the World Muscle Society, Berlin, Germany, October 8, 2014.
https://doi.org/10.1016/j.jpeds.2015.12.060Get rights and content

We describe two infants with hypotonia, absent respiratory effort, and giant mitochondria in neurons due to compound heterozygosity for 2 nonsense mutations of DNM1L. DNM1L has a critical role in regulating mitochondrial morphology and function. This observation confirms the central role of mitochondrial fission to normal human development.

Section snippets

Methods

This study was approved by the Research Ethics Board of the Hospital for Sick Children and written consent was obtained from the family to participate in this study.

Patient A, a female, was born to a 37-year-old gravida 2 para 0 abortions 1 mother after 12 years of infertility. Parents were non-consanguineous and of Filipino background. Pregnancy was complicated by twin gestation with fetal death of the second twin at 21 weeks. Patient A was delivered by cesarean at 36 weeks for non-reassuring

Results

Both infants had detailed neuropathologic evaluation at autopsy and were found to have similar abnormalities (Figure 1). Many neurons in the brain and spinal cord contained intracytoplasmic hyaline eosinophilic globules. These globules were round, varied in size up to approximately 3 μm, and did not polarize. They were widespread and seen in neurons in all areas of the brain and spinal cord. Hyaline globules were not identified in glial or non-neuronal cells and were not associated with

Discussion

DNM1L is essential for normal embryonic development, and animal models of complete DNM1L deficiency have demonstrated absence of DNM1L is not compatible with life.7, 8 Neurons are particularly vulnerable to DNM1L dysfunction9 and DNM1L (Drp1) knock-out mice had smaller forebrains and marked hypoplasia of the white matter, in addition to giant mitochondria in neurons of the basal ganglia.7 Cerebellar development was defective in the knock-out mice, with Purkinje cells having abnormally shaped

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Funded by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute (OGI-049), Genome Quebec, Genome British Columbia, and the McLaughlin Center. S.S. serves as a paid scientific advisory board member of Population Diagnostics and Younique Genomics; receives royalty fees from Lineagen and Athena; serves on the scientific advisory board of Autism Speaks; and receives funding from GlaxoSmithKline. The other authors declare no conflicts of interest.

List of additional members of the FORGE Canada Consortium Steering Committee is available at www.jpeds.com (Appendix).

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