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.

Figure 1. Head and cervical spine MRI findings in patient 8

(A) Transverse axial T2 fluid-attenuated inversion recovery image of the head demonstrates multiple ovoid high-signal lesions in the periventricular white matter and juxtacortically. (B) Sagittal T2 image reveals lesions with an orientation resembling Dawson fingers. (C) Sagittal T2 image of the cervical spine demonstrates multiple high-signal lesions that are each less than one spinal segment. Taken together, these findings meet MRI diagnostic criteria for multiple sclerosis.

Figure 2. Visual examination and optical coherence tomography findings in patient 8

(A) Bilateral optic atrophy is demonstrated on fundoscopic examination (RE = right eye, LE = left eye). (B) Optical coherence tomography (OCT) measurements were obtained with the high-resolution spectral-domain Cirrus platform (Carl Zeiss Meditec, Dublin, CA). The average retinal nerve fiber layer (RNFL) thickness was 70 μm in the right eye (OD) and 66 μm in the left eye (OS). (C) The analysis software automatically selects the appropriate normative range for the patient, and the peripapillary RNFL measurements (dark traces) are represented within color-coded distribution centiles: i) red <1%, ii) yellow 1%–5%, and iii) green 5%–95%. The OCT measurements confirm significant RNFL thinning in keeping with the optic disc pallor. TSNIT = temporal-superior-nasal-inferior-temporal.