title: Progressive myoclonic epilepsy as an adult-onset manifestation of Leigh syndrome due to m.14487T>C.
abstract: BACKGROUND
  m.14487T>C, a missense mutation (p.M63V) affecting the ND6 subunit of complex I of the mitochondrial respiratory chain, has been reported in isolated childhood cases with Leigh syndrome (LS) and progressive dystonia. Adult-onset phenotypes have not been reported.
  
  
  OBJECTIVE
  To determine the clinical-neurological spectrum and associated mutation loads in an extended m.14487T>C family.
  
  
  METHODS
  A genotype-phenotype correlation study of a Belgian five-generation family with 12 affected family members segregating m.14487T>C was carried out. Clinical and mutation load data were available for nine family members. Biochemical analysis of the respiratory chain was performed in three muscle biopsies.
  
  
  RESULTS
  Heteroplasmic m.14487T>C levels (36-52% in leucocytes, 97-99% in muscle) were found in patients with progressive myoclonic epilepsy (PME) and dystonia or progressive hypokinetic-rigid syndrome. Patients with infantile LS were homoplasmic (99-100% in leucocytes, 100% in muscle). We found lower mutation loads (between 8 and 35% in blood) in adult patients with clinical features including migraine with aura, Leber hereditary optic neuropathy, sensorineural hearing loss and diabetes mellitus type 2. Despite homoplasmic mutation loads, complex I catalytic activity was only moderately decreased in muscle tissue.
  
  
  CONCLUSIONS
  m.14487T>C resulted in a broad spectrum of phenotypes in our family. Depending on the mutation load, it caused severe encephalopathies ranging from infantile LS to adult-onset PME with dystonia. This is the first report of PME as an important neurological manifestation of an isolated mitochondrial complex I defect.
authors.affiliation: Department of Neurology, University Hospital Ghent, Ghent University, Ghent, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Dermaut
authors.forename: S
authors.initials: S
authors.lastname: Seneca
authors.forename: L
authors.initials: L
authors.lastname: Dom
authors.forename: K
authors.initials: K
authors.lastname: Smets
authors.forename: L
authors.initials: L
authors.lastname: Ceulemans
authors.forename: J
authors.initials: J
authors.lastname: Smet
authors.forename: B
authors.initials: B
authors.lastname: De Paepe
authors.forename: S
authors.initials: S
authors.lastname: Tousseyn
authors.forename: S
authors.initials: S
authors.lastname: Weckhuysen
authors.forename: M
authors.initials: M
authors.lastname: Gewillig
authors.forename: P
authors.initials: P
authors.lastname: Pals
authors.forename: P
authors.initials: P
authors.lastname: Parizel
authors.forename: J L
authors.initials: JL
authors.lastname: De Bleecker
authors.forename: P
authors.initials: P
authors.lastname: Boon
authors.forename: L
authors.initials: L
authors.lastname: De Meirleir
authors.forename: P
authors.initials: P
authors.lastname: De Jonghe
authors.forename: R
authors.initials: R
authors.lastname: Van Coster
authors.forename: W
authors.initials: W
authors.lastname: Van Paesschen
authors.forename: P
authors.initials: P
authors.lastname: Santens
mesh_terms: D000328:Adult; D017668:Age of Onset; D001530:Belgium; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics; D020821:Dystonic Disorders / Q000235:genetics; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007888:Leigh Disease / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; C507225:MT-ND6 protein, human; D009245:NADH Dehydrogenase