title: Disturbed mitochondrial and peroxisomal dynamics due to loss of MFF causes Leigh-like encephalopathy, optic atrophy and peripheral neuropathy.
abstract: BACKGROUND
  Mitochondria are dynamic organelles which undergo continuous fission and fusion to maintain their diverse cellular functions. Components of the fission machinery are partly shared between mitochondria and peroxisomes, and inherited defects in two such components (dynamin-related protein (DRP1) and ganglioside-induced differentiation-associated protein 1 (GDAP1)) have been associated with human disease. Deficiency of a third component (mitochondrial fission factor, MFF) was recently reported in one index patient, rendering MFF another candidate disease gene within the expanding field of mitochondrial and peroxisomal dynamics. Here we investigated three new patients from two families with pathogenic mutations in MFF.
  
  
  METHODS
  The patients underwent clinical examination, brain MRI, and biochemical, cytological and molecular analyses, including exome sequencing.
  
  
  RESULTS
  The patients became symptomatic within the first year of life, exhibiting seizures, developmental delay and acquired microcephaly. Dysphagia, spasticity and optic and peripheral neuropathy developed subsequently. Brain MRI showed Leigh-like patterns with bilateral changes of the basal ganglia and subthalamic nucleus, suggestive of impaired mitochondrial energy metabolism. However, activities of mitochondrial respiratory chain complexes were found to be normal in skeletal muscle. Exome sequencing revealed three different biallelic loss-of-function variants in MFF in both index cases. Western blot studies of patient-derived fibroblasts indicated normal content of mitochondria and peroxisomes, whereas immunofluorescence staining revealed elongated mitochondria and peroxisomes. Furthermore, increased mitochondrial branching and an abnormal distribution of fission-mediating DRP1 were observed.
  
  
  CONCLUSIONS
  Our findings establish MFF loss of function as a cause of disturbed mitochondrial and peroxisomal dynamics associated with early-onset Leigh-like basal ganglia disease. We suggest that, even if laboratory findings are not indicative of mitochondrial or peroxisomal dysfunction, the co-occurrence of optic and/or peripheral neuropathy with seizures warrants genetic testing for MFF mutations.
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Koch
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
authors.forename: René G
authors.initials: RG
authors.lastname: Feichtinger
authors.affiliation: Department of Pediatrics, Kreisklinken Reutlingen, Reutlingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Freisinger
authors.affiliation: Social Paediatric Center, Klinikum Frankfurt-Höchst, Frankfurt am Main, Germany.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Pies
authors.affiliation: Department of Ophthalmology and Optometry, Department of Anatomy, Department of Laboratory Medicine (HW), and First Department of Internal Medicine, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Falk
authors.initials: F
authors.lastname: Schrödl
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Arcangela
authors.initials: A
authors.lastname: Iuso
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
mesh_terms: D001480:Basal Ganglia Diseases / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D001927:Brain Diseases / Q000235:genetics / Q000503:physiopathology; D002675:Child, Preschool; D059472:Exome; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins; D009896:Optic Atrophy / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D020675:Peroxisomes / Q000235:genetics / Q000473:pathology
chemical_list: C118663:GDAP protein; D008565:Membrane Proteins; C533267:Mff protein, human; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins
keywords: Epilepsy and seizures; Genome-wide; Metabolic disorders; Molecular genetics; Neurology