Leber's Hereditary Optic Neuropathy‐like syndrome in heteroplasmic mitochondrial mutations

Abstract

AbstractPurposeLeber's Plus syndromes have been well described in the literature. Intriguingly, an opposite effect occurs when heteroplasmy with more severe mitochondrial mutations present with an Leber's Hereditary Optic Neuropathy (LHON)‐like visual loss at a later age of onset. The small, unmyelinated papillomacular bundle (PMB) fibers are selectively affected first in these heteroplasmic mitochondrial mutations.MethodsCase report.ResultsTwenty‐year‐old woman with subacute bilateral sequential visual loss (CF @2 feet OD; 20/400+1 OS, no RAPD; central scotoma OU; temporal disc pallor OU; superior, temporal, and inferior RNFL thinning OU; diffuse GCL/IPL thinning OU) presented with an LHON‐like syndrome with a non‐LHON mutation, a pathogenic variant in MT‐ND3 m.10197G>A (p. Ala47Thr) with 51% heteroplasmy. Idebenone and vitamin C resulted in mild visual improvement.ConclusionsWe hypothesize that an LHON‐like presentation can be a form fruste of more severe heteroplasmic pathogenic mitochondrial mutations at a later age of onset, irrespective of the mitochondrial DNA (mtDNA) mutation type. Other factors can play a role in the clinical phenotype, including DNA haplotype, nuclear genetic background, environmental factors, etc. Although the mtDNA 10197G>A mutation has been associated with Leigh syndrome (LS), LHON/dystonia (LDYT), and MELAS/LS overlap syndrome,1 our 20‐year‐old woman had only LHON‐like visual loss at the onset of presentation. In all cases, the PMB is most vulnerable to oxidative damage.2 Although these mtDNA mutations affect different ND subunits of complex I, some electrons seem to be transferred through a parallel pathway to complex II, as shown in cybrid studies.3