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Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations

Lookup NU author(s): Dr Gerald Pfeffer, Dr Ailbhe Burke, Dr Patrick Yu Wai Man, Professor Patrick Chinnery



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Pfeffer G, Burke A, Yu-Wai-Man P, Compston DAS, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Neurology

Year: 2013

Volume: 81

Issue: 24

Pages: 2073-2081

Print publication date: 10/12/2013

Online publication date: 06/11/2013

Acceptance date: 13/09/2013

Date deposited: 23/10/2014

ISSN (print): 0028-3878

ISSN (electronic): 1526-632X

Publisher: Lippincott Williams & Wilkins


DOI: 10.1212/01.wnl.0000437308.22603.43


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Funder referenceFunder name
Association Francaise contre les Myopathies
Canadian Institutes of Health Research
Medical Research Council (UK) Centre for Translational Muscle Disease research
Cambridge NIHR Biomedical Research Centre
Newcastle University
NIHR Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust
084980/Z/08/ZWellcome Trust Senior Fellow in Clinical Science
096919Z/ 11/ZWellcome Trust Centre for Mitochondrial Research
101876/Z/13/ZWellcome Trust