Secondary Post-Geniculate Involvement in Leber’s Hereditary Optic Neuropathy

Giovanni Rizzo,Alfredo A Sadun,Kevin R Tozer,Raffaele Lodi,Valerio Carelli,Ruvdeep S Randhawa,Piero Barboni,David Manners,Maria Lucia Valentino,Claudia Testa,Caterina Tonon,Emil Malucelli,Chiara La Morgia,Fred N Ross-Cisneros

doi:10.1371/journal.pone.0050230

Abstract

Leber’s hereditary optic neuropathy (LHON) is characterized by retinal ganglion cell (RGC) degeneration with the preferential involvement of those forming the papillomacular bundle. The optic nerve is considered the main pathological target for LHON. Our aim was to investigate the possible involvement of the post-geniculate visual pathway in LHON patients. We used diffusion-weighted imaging for in vivo evaluation. Mean diffusivity maps from 22 LHON visually impaired, 11 unaffected LHON mutation carriers and 22 healthy subjects were generated and compared at level of optic radiation (OR). Prefrontal and cerebellar white matter were also analyzed as internal controls. Furthermore, we studied the optic nerve and the lateral geniculate nucleus (LGN) in post-mortem specimens obtained from a severe case of LHON compared to an age-matched control. Mean diffusivity values of affected patients were higher than unaffected mutation carriers (P<0.05) and healthy subjects (P<0.01) in OR and not in the other brain regions. Increased OR diffusivity was associated with both disease duration (B = 0.002; P<0.05) and lack of recovery of visual acuity (B = 0.060; P<0.01). Post-mortem investigation detected atrophy (41.9% decrease of neuron soma size in the magnocellular layers and 44.7% decrease in the parvocellular layers) and, to a lesser extent, degeneration (28.5% decrease of neuron density in the magnocellular layers and 28.7% decrease in the parvocellular layers) in the LHON LGN associated with extremely severe axonal loss (99%) in the optic nerve. The post-geniculate involvement in LHON patients is a downstream post-synaptic secondary phenomenon, reflecting de-afferentation rather than a primary neurodegeneration due to mitochondrial dysfunction of LGN neurons.

Highlights

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by retinal ganglion cells (RGCs) degeneration due to maternally inherited point mutations in mitochondrial DNA that affect the respiratory complex I [1,2]
In this study we have demonstrated increased diffusivity in the optic radiations (OR) of patients with LHON using diffusionweighted imaging (DWI)
DWI changes in OR of LHON affected patients were more severe in those who failed to recover visual acuity and had longer disease duration, whereas they were not detected in unaffected LHON mutation carriers

Summary

Introduction

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by retinal ganglion cells (RGCs) degeneration due to maternally inherited point mutations in mitochondrial DNA (mtDNA) that affect the respiratory complex I [1,2]. LHON affects prevalently young males, who suffer an acute/ subacute loss of central vision that leads to rapid decrease of visual acuity due to central scotoma. This acute phase consolidates in a chronic state in about one year after the onset of visual loss, leaving the patients with optic atrophy and usually permanent blindness [1,2]. Some of the patients may experience various degrees of visual function recovery, with gain of visual acuity and shrinkage or fenestration of the central scotoma at visual field [1,2] This recovery may occur spontaneously, most frequently with one of the common mutations at position 14484/ND6 and if the age at disease onset is precocious, irrespectively the mutation type. Long-lasting chronic cases may suffer further slow rate loss of RGCs, as documented by a few cases studied post-mortem, supporting a long-range neurodegenerative activity [1,3]

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