Leber's hereditary optic neuropathy: Update on current diagnosis and treatment

Abstract

Leber's hereditary optic neuropathy (LHON) is a fairly prevalent mitochondrial disorder (1:50,000) arising from the dysfunction of the mitochondrial respiratory chain, which eventually leads to apoptosis of retinal ganglion cells. The usual presentation is that of a young male with a sequential reduction in visual acuity. OCT has been used to study the pattern of optic nerve involvement in LHON, showing early thickening of the inferior and superior retinal nerve fibre layer and ganglion cell layer thinning corresponding with the onset of symptoms. Of the three primary mutations for LHON, the m.14484T>C mutation has the best visual prognosis. Recent emerging therapeutic options for LHON include idebenone and the introduction of genetic vector therapy, which is currently in phase III clinical trials. Screening of family members and adequate advice to avoid environmental triggers, such as smoking and alcohol consumption, are also cornerstones in the management of LHON.

Keywords: Leber’s hereditary optic neuropathy; diagnostics; genetic vector therapy; idebenone; mitochondrial disorder.

Figure 1

Pathophysiology of LHON, showing the mutational defect in Complex 1 of the respiratory chain. IMS, Inter Membrane Space; IMM, Inner Mitochondrial Membrane; LHON, Lebers Hereditary Optic Neuropathy; C 1-5, Complex 1-5; CoQ, co-enzyme Q10; CytC, cytochrome c; NADH/NAD+, Nicotinamide adenine dinucleotide; FADH2/FAD+, flavin adenine dinucleotide; ADP, Adenosine Diphosphate; ATP, Adenosine Triphosphate; Pi, Phosphate; H+, Hydrogen; O2, Oxygen; H20, water.

Figure 2

Progression of perimetric and fundoscopic findings in patient A, an 18-year-old LHON patient. The patient presented with poor visual acuity at initial diagnosis: 20/400 OD & CF OS. Right eye later progressed to CF after 2 months. OD, Oculus dexter; OS, Oculus sinister; CF, Counting fingers.

Figure 3

OCT (Topcon 3DOCT-3000) findings in patient A, an 18-year-old LHON patient. The patient presented with poor visual acuity at initial diagnosis: 20/400 OD & CF OS. The right eye later progressed to CF after 2 months. This patient was homoplasmic for the mutation m.10663T>C p.ND4L: (Val65AIa). At initial diagnosis the patient presents with thinning of the RNFL in the left eye in the superior and nasal quadrant. At follow up there is significant reduction of RNFL thickness bilaterally, more seen in the superior and nasal quadrant and is more evident in the left eye. OD, Oculus dexter; OS, Oculus sinister; CF, Counting fingers; RNFL, Retinal nerve fiber layer.

Figure 4

OCT (Heidelberg, Spectralis) findings of patient B, a 20-year-old male patient presenting to the clinic with bilateral vision loss and bilateral central scotomas of 3-month duration. The thickness map shows thinning of GCL despite normal RNFLT in OD, and thinning of the temporal RNFT with corresponding GCL thinning in OS. OD, Oculus dexter; OS, Oculus sinister; GCL, Ganglion cell layer; RNFLT, Retinal nerve fiber layer thickness.

Figure 5

Findings of patient C, a 22-year-old male patient presenting to the clinic with progressive central visual loss OS for the duration of 5 months. His visual acuity was 2/200 OS and 20/400 OD. Fundoscopy showed a pale disc OS and peripapillary telangiectasias OD. The thickness map shows marked GCL thinning OS and early thinning of GCL OD, corresponding with deterioration of visual acuity. OD, Oculus dexter; OS, Oculus sinister; OU, Oculus uterque; GCL, Ganglion cell layer.

Figure 6

Algorithm proposed by Hage and Vignal-Clermont considering the statements of the Milan panel and gene therapy as part of a treatment guide for LHON (Hage & Vignal-Clermont, (39)).