G.O.6: Lethal disorder of mitochondrial fission caused by mutations in DNM1L

Abstract

We describe two siblings, born to non-consanguineous Filipino parents after 12years of infertility, with profound hypotonia, absent respiratory effort, hepatic dysfunction and multiple abnormalities on neuropathological studies at autopsy. The first child, a female, died at 3weeks of age and the second child, a male, died at 5days of life after withdrawal of care. Array CGH, molecular testing of SMN1 , DMPK , POLG1 , and metabolic studies (plasma amino acids, urine organic acids, lactate, very long chain fatty acids, transferrin isoforms) were all normal. Neuropathological examination revealed many neurons in the brain and spinal cord with intracytoplasmic hyaline eosinophilic globules. Electron microscopy showed multiple giant mitochondria within hippocampal neurons which contained elongated cristae arranged parallel to each other. Examination of the spinal cord revealed marked reduction in myelin content and neurofilament immunostaining showed decreased numbers of axons. The posterior nerve roots and peripheral nerve also showed poor myelination with a marked reduction in numbers of myelinated axons. Exome sequencing of DNA from all family members revealed both children were compound heterozygous for a c.261dup in exon 3 and a c.385_386del mutation in exon 5 of the DNM1L gene. The parents were confirmed heterozygous carriers of one of the mutations. The protein encoded by DNM1L is a member of the dynamin superfamily of GTPases and has a critical role in regulating mitochondrial morphology through assembly of fission foci and distribution of mitochondrial tubules throughout the cytoplasm. Drp1 (DNM1L) knock-out mice die shortly after birth and have enlarged, abnormal mitochondria in neuronal cells, defective synaptic development and hepatic dysfunction, similar to our patients. To our knowledge, this is the first report of a mitochondrial fission defect caused by DNM1L deficiency in humans.