title: Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations.
abstract: OBJECTIVE
  To determine whether the association between multiple sclerosis (MS) and Leber hereditary optic neuropathy (LHON) (known as "Harding disease") is a chance finding, or the 2 disorders are mechanistically linked.
  
  
  METHODS
  We performed a United Kingdom-wide prospective cohort study of prevalent cases of MS with LHON mitochondrial DNA (mtDNA) mutations. The new cases were compared with published cases, enabling a comprehensive clinical description. We also performed a meta-analysis of studies screening patients with MS for LHON mtDNA mutations to find evidence of a genetic association.
  
  
  RESULTS
  Twelve new patients were identified from 11 pedigrees, and 44 cases were identified in the literature. The combined cohort had the following characteristics: multiple episodes of visual loss, predominance for women, and lengthy time interval before the fellow eye is affected (average 1.66 years), which is very atypical of LHON; conversely, most patients presented without eye pain and had a poor visual prognosis, which is unusual for optic neuritis associated with MS. The number of UK cases of LHON-MS fell well within the range predicted by the chance occurrence of MS and the mtDNA mutations known to cause LHON. There was no association between LHON mtDNA mutations and MS in a meta-analysis of the published data.
  
  
  CONCLUSIONS
  Although the co-occurrence of MS and LHON mtDNA mutations is likely to be due to chance, the resulting disorder has a distinct phenotype, implicating a mechanistic interaction. Patients with LHON-MS have a more aggressive course, and prognostication and treatment should be guarded.
authors.affiliation: From the Institute of Genetic Medicine (G.P., P.Y.-W.-M., P.F.C.), Newcastle; Institute of Neurology (A.B.), University College London; and Department of Clinical Neurosciences (D.A.S.C.), University of Cambridge, UK.
authors.forename: Gerald
authors.initials: G
authors.lastname: Pfeffer
authors.forename: Ailbhe
authors.initials: A
authors.lastname: Burke
authors.forename: Patrick
authors.initials: P
authors.lastname: Yu-Wai-Man
authors.forename: D Alastair S
authors.initials: DA
authors.lastname: Compston
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
mesh_terms: D000293:Adolescent; D000328:Adult; D015331:Cohort Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D011446:Prospective Studies; D006113:United Kingdom / Q000453:epidemiology; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial