DNM1L-related mitochondrial fission defect presenting as spastic paraparesis and optic atrophy

DNM1L gene encodes the dynamin 1- like protein DNM1L (Drp1) which is crucial in the mitochondrial fusion process as well as fusion of peroxisomes. We describe a patient with novel heterozygous de novo DNM1L mutation c. 176C>T (p.Thr59Ile), which further expands the associated clinical spectrum. The patient exhibits axial hypotonia, spastic paraparesis, neo- and paleo-cerebellar syndrome and optic atrophy. Muscle biopsy revealed mild decrease in CI+III activity, increased SDH and decreased COX activity staining in 5% of muscle fibers. Protein analysis in cultured skin fibroblasts revealed altered amount of some OXPHOS subunits.   Furthermore, regular occurrence of “mega-mitochondria” along elongated mitochondrial network was found in cultured myoblasts which confirms impaired mitochondrial dynamic. Novel mutation c. 176C>T (p.Thr59Ile) in DNM1L gene was identified by exome sequencing and affects highly conserved Thr59 in the GTPase domain of the protein. Trp59 has been previously shown to be indispensable for GTPase reaction (Wenger et al 2013).  All previously described missense mutations in 3 patients with varied phenotype were localized in the middle domain important for the protein oligomerization. To conclude, our results further expand clinical phenotypes (including optic atrophy) associated with DNM1L mutations.