Are Leber’s mitochondial DNA mutations associated with aquaporin-4 autoimmunity?

Leber’s hereditary optic neuropathy (LHON) typically presents with a severe acute or subacute bilateral visual loss. ¹ However, some patients may develop a progressive myelopathy extending over multiple spinal levels, thus resembling neuromyelitis optica (NMO). ¹ The potential role of mtDNA in NMO pathogenesis has become increasingly intriguing. Until now, a coexistence of anti-aquaporin-4 (AQP4) antibody, a specific NMO biomarker, and a mtDNA mutation has been reported in two single cases.^2,3 In 32 NMO cases, the largest cohort examined for mtDNA mutations, no known mtDNA mutation was found. ¹ However, there have been no reports on the anti-AQP4 antibody status in a cohort of confirmed LHON cases.

We looked for anti-AQP4 antibodies in a series of 11 LHON patients in whom the diagnosis was confirmed by direct sequencing (The Big Dye Terminator Chemistry and Genetic Analyser ABI3500, Applied Biosystems, Foster City, CA, USA) in the Laboratory for Neurogenetics, Clinic of Neurology, Clinical Centre of Serbia, Belgrade, from 1 January 2010 to 31 December 2014. These patients were found to carry one of the three most frequent LHON mtDNA mutations (m.3460G>A, m.11778G>A, m.14484T>C). Serum anti-AQP4 antibodies were tested by indirect immunofluorescence (IIF) (Euroimmun AG, Lubeck, Germany) in the Neuroimmunology Laboratory, Clinic of Neurology, Clinical Centre of Serbia, Belgrade. Samples testing positive by IIF were also tested by enzyme-linked immunosorbent assay (ElisaRSRTM AQP4 Ab Version 2, RSR Limited, UK). All patients signed an informed consent prior to any study/diagnostic procedure. The study was approved by the Clinic of Neurology Institutional Review Board.

All 11 LHON patients (two female, nine male; median age, 23 years; age range, 11–47 years) had severe bilateral optic neuropathy and none had symptoms or signs of myelopathy. In a 31-year-old male patient, serum anti-AQP4 antibodies (confirmed by two methods) coexisted with a homoplasmic m.11778G>A mutation.

To the best of our knowledge, this is the first report on the analysis of anti-AQP4 antibodies in a LHON cohort. Until now, the coexistence of anti-AQP4 antibodies and mtDNA mutations has been reported in one NMO case with a homoplasmic m.11778G>A mutation ³ and in one patient with severe bilateral optic neuropathy and a heteroplasmic m.11778G>A mutation. ² In addition, a primary homoplasmic m.3460G>A mutation ⁴ and two homoplasmic secondary mtDNA mutations at nucleotide positions 4216 and 4917 ⁵ were reported in two NMO cases in whom anti-AQP4 antibodies were not analysed.^4,5 Similarly to other reports in small numbers of patients with a clinical diagnosis of NMO or in spinal specimens with NMO pathology, ¹ no known mtDNA mutation was found in 32 NMO cases. ¹

The association of anti-AQP4 antibodies and a mtDNA mutation suggests that LHON mtDNA mutations might be associated with AQP4-autoimmunity in a small subgroup of LHON patients and indicates that autoimmunity could, potentially, modulate clinical expression in LHON mutation carriers. The potential complex interplay between LHON mtDNA mutation-associated neurodegeneration and AQP4-associated central nervous system inflammation needs to be further investigated in larger multicentre studies, given the low prevalence of both conditions.