title: Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus.
abstract: OBJECTIVE
  To investigate the mechanisms underlying myoclonus in Leber hereditary optic neuropathy (LHON).
  
  
  METHODS
  Five patients and one unaffected carrier from two Italian families bearing the homoplasmic 11778/ND4 and 3460/ND1 mutations underwent a uniform investigation including neurophysiologic studies, muscle biopsy, serum lactic acid after exercise, and muscle ((31)P) and cerebral ((1)H) magnetic resonance spectroscopy (MRS). Biochemical investigations on fibroblasts and complete mitochondrial DNA (mtDNA) sequences of both families were also performed.
  
  
  RESULTS
  All six individuals had myoclonus. In spite of a normal EEG background and the absence of giant SEPs and C reflex, EEG-EMG back-averaging showed a preceding jerk-locked EEG potential, consistent with a cortical generator of the myoclonus. Specific comorbidities in the 11778/ND4 family included muscular cramps and psychiatric disorders, whereas features common to both families were migraine and cardiologic abnormalities. Signs of mitochondrial proliferation were seen in muscle biopsies and lactic acid elevation was observed in four of six patients. (31)P-MRS was abnormal in five of six patients and (1)H-MRS showed ventricular accumulation of lactic acid in three of six patients. Fibroblast ATP depletion was evident at 48 hours incubation with galactose in LHON/myoclonus patients. Sequence analysis revealed haplogroup T2 (11778/ND4 family) and U4a (3460/ND1 family) mtDNAs. A functional role for the non-synonymous 4136A>G/ND1, 9139G>A/ATPase6, and 15773G>A/cyt b variants was supported by amino acid conservation analysis.
  
  
  CONCLUSIONS
  Myoclonus and other comorbidities characterized our Leber hereditary optic neuropathy (LHON) families. Functional investigations disclosed a bioenergetic impairment in all individuals. Our sequence analysis suggests that the LHON plus phenotype in our cases may relate to the synergic role of mtDNA variants.
authors.affiliation: Dipartimento di Scienze Neurologiche, Università di Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy.
authors.forename: C
authors.initials: C
authors.lastname: La Morgia
authors.forename: A
authors.initials: A
authors.lastname: Achilli
authors.forename: L
authors.initials: L
authors.lastname: Iommarini
authors.forename: P
authors.initials: P
authors.lastname: Barboni
authors.forename: M
authors.initials: M
authors.lastname: Pala
authors.forename: A
authors.initials: A
authors.lastname: Olivieri
authors.forename: C
authors.initials: C
authors.lastname: Zanna
authors.forename: S
authors.initials: S
authors.lastname: Vidoni
authors.forename: C
authors.initials: C
authors.lastname: Tonon
authors.forename: R
authors.initials: R
authors.lastname: Lodi
authors.forename: R
authors.initials: R
authors.lastname: Vetrugno
authors.forename: B
authors.initials: B
authors.lastname: Mostacci
authors.forename: R
authors.initials: R
authors.lastname: Liguori
authors.forename: R
authors.initials: R
authors.lastname: Carroccia
authors.forename: P
authors.initials: P
authors.lastname: Montagna
authors.forename: M
authors.initials: M
authors.lastname: Rugolo
authors.forename: A
authors.initials: A
authors.lastname: Torroni
authors.forename: V
authors.initials: V
authors.lastname: Carelli
mesh_terms: D000255:Adenosine Triphosphate / Q000172:deficiency; D000328:Adult; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D004569:Electroencephalography; D004576:Electromyography; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009207:Myoclonus / Q000235:genetics* / Q000503:physiopathology; D029242:Optic Atrophy, Hereditary, Leber / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D012008:Recurrence
chemical_list: D004272:DNA, Mitochondrial; D000255:Adenosine Triphosphate