Abstract
Mitochondrial Fission Factor (MFF) is part of a protein complex that promotes mitochondria and peroxisome fission. Hitherto, only 5 patients have been reported harboring mutations in MFF, all of them with the clinical features of a very early onset Leigh-like encephalopathy. We report on an 11-year-old boy with epileptic encephalopathy. He presented with neurological regression, epileptic myoclonic seizures, severe intellectual disability, microcephaly, tetraparesis, optic atrophy, and ophthalmoplegia. Brain MRI pattern was compatible with Leigh syndrome. NGS-based analysis of a gene panel for mitochondrial disorders revealed a homozygous c.892C>T (p. Arg298*) in the MFF gene. Fluorescence staining detected abnormal morphology of mitochondria and peroxisomes in fibroblasts from the patient; a strong reduction in MFF protein levels and the presence of truncated forms were observed. No biochemical alterations denoting peroxisomal disorders were found. As reported in other disorders affecting the dynamics of intracellular organelles, our patient showed clinical features suggesting both mitochondrial and peroxisomal impairment. High levels of lactate in our case suggested an involvement of the energetic metabolism but without clear respiratory chain deficiency, while biomarkers of peroxisomal dysfunction were normal. We confirm that MFF mutations are associated with epileptic encephalopathy with Leigh-like MRI pattern.
Highlights
Mitochondria are dynamic organelles and their morphology results from a finely tuned balance between fusion and fission events
Impairment in mitodynamics has been associated with diverse pathological conditions, including monogenetic forms of mitochondrial disorders caused by mutations affecting key players of this system
Mitochondrial Fission Factor (MFF) Mutation but it contributes to the division of peroxisomes (Li and Gould, 2003)
Summary
Mitochondria are dynamic organelles and their morphology results from a finely tuned balance between fusion and fission events. These processes are important for the maintenance of the cellular homeostasis: fission in particular allows quality control over the mitochondrial network, by separating defective mitochondria that are targeted to mitophagy, and it is mediated by a series of nuclear-encoded proteins. Dynamin-related protein 1 (DRP1, encoded by the DNM1L gene–MIM603850) is the main effector of mitochondrial fission. Several DRP1 receptors and recruitment factors on the outer mitochondrial membrane have been identified, including MFF (Mitochondrial fission factor–MIM614785), FIS1/TTC11 (Mitochondrial fission 1–MIM609003), GDAP1 (ganglioside-induced differentiation-associated protein 1– MIM606598) and MIEFs (Mitochondrial Elongation Factors; i.e., MIEF1-MIM615497 and MIEF2-MIM615498, known as MiD51/MiD49). Genetic defects in DNM1L result in phenotypes varying from autosomal dominant optic atrophy to severe early onset mitochondrial encephalopathy, while mutations in GDAP1 have been linked to forms of Charcot Marie Tooth Disease (Archer, 2013)
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