Leber’s Hereditary Optic Neuropathy (LHON) is an inherited mitochondrial optic neuropathy causing acute, severe vision loss. When associated with the m.13513G>A mutation, Idebenone can potentially provide improvement, even after delayed treatment. This makes testing for this rare mutation essential.
LHON is the commonest mitochondrial disease, affecting one in 30,000 people.1 The mean age of onset of visual loss is 27.9 years, with male predominance.2 Classically, patients experience loss of colour vision in one eye followed by painless, subacute decrease in central visual acuity accompanied by an enlarging centrocaecal scotoma. Soon after, the contralateral eye is similarly affected. Here we present two cases of LHON associated with the rare m.13513G>A point mutation, who both improved significantly with Idebenone treatment.
Ali,* a 20-year-old left-handed man, presented with a six-week history of bilateral sequential vision loss. He initially described a central scotoma affecting his right eye, and four weeks later, noted similar symptoms in his left eye, which progressed to severe vision loss. He described headaches but no focal eye pain, pain on eye movements or systemic symptoms.
Ali had a history of migraine and depression. He did not take any regular medications but his social history was remarkable for smoking, occasional alcohol use and prior marijuana use. His family history was significant for albinism in a male cousin on the maternal side, and ulcerative colitis in his brother.
An initial examination revealed best corrected visual acuities (VA) of count fingers at 3m in the right eye, and 6/60 in the left. There was a small right relative afferent pupillary defect (RAPD). Fundoscopy revealed right-sided temporal pallor and mild bilateral disc swelling with peripapillary telangiectasias. Automated perimetry with a large target demonstrated enlarged blind spots with bilateral centrocaecal scotomata. Optical coherence tomography (OCT) was essentially normal, with a suggestion of some superior and inferior retinal nerve fibre layer (RNFL) thickening bilaterally. Neurological examination was otherwise normal.
Magnetic resonance imaging (MRI) showed an incidental finding of mega cisterna magna, and a focal T2 hyperintensity in the right frontal region, but no optic nerve pathology. MRI spectroscopy was normal. Electroencephalography, folate and vitamin B12 levels were normal. A panel testing for 22 mitochondrial mutations and sequencing of the POLG gene was requested. None of the three primary mutations for LHON were present. The test was positive for the m.13513G>A point mutation (mutant load 26%).
Ali was empirically treated with prednisone for one week. He took concentrated B vitamins with little effect. He was commenced on Idebenone (900mg daily) 15 months after initial vision loss. He experienced marked improvement in VA within two weeks of starting Idebenone to 6/9.5-1 in each eye.
Max,* a 54-year-old right-handed man, presented with a six-week history of progressive, sequential vision loss, initially affecting the left eye then the right eye two weeks later. A visual assessment, after his left eye became involved, found left acuity of 6/60 and right of 6/9. There were no headaches, focal eye pain, pain on eye movements or systemic symptoms.
Max had a history of IgA nephropathy with end stage renal failure requiring peritoneal dialysis, right cataract surgery, hypertension and hypercholesterolaemia. His family history was significant for a sister with epilepsy. He was a vegetarian, non-smoker, and drank alcohol occasionally.
On examination six weeks after symptom onset, Max’s right VA was 6/36 and left was 3/60. He had sluggish pupils bilaterally. There was a left relative afferent pupillary defect (RAPD). Fundoscopy revealed temporal pallor of each optic nerve head. Automated perimetry demonstrated bilateral centrocaecal scotomas. A non-contrast MRI of the brain was unremarkable (it was not possible to administer contrast due to renal failure). Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibodies were negative.
Max received three days of methylprednisolone with oral taper in case optic neuritis had not been detected on the non-contrast scan. After the initial review, LHON was thought to be most likely, so he was commenced on Idebenone. Genetic testing did not show any common LHON mutations, however full mitochondrial sequencing confirmed m.13513G>A point mutation.
At Max’s six-week review, his VA was counting fingers only bilaterally, and at his three-month review, his right VA was 2/60 and left 1/60. At a six-month review there was no improvement, despite Idebenone. One year after symptom onset, Max commenced haemodialysis. Six weeks later, he subjectively noticed improvement, and on examination his acuity was 6/18 in the right eye and 3/60 in the left. He had used Idebenone consistently since six weeks post his initial vision loss.
One of three pathogenic mutations of mitochondrial DNA (m.3460G>A, m.11778G>A, m.14484T>C) affecting complex I, can be found in over 90% of patients with LHON.3 The result is a defect of ATP synthesis and increased production of oxygen free radicals, leading to retinal ganglion cell loss and dysfunction. Numerous other mutations have been associated with LHON, however they are often only found in single families or individuals, and pathogenicity is not always certain.4 The m.13513G>A (p.D393N, ND5) mutation is clinically heterogenous and classically manifests as mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes (MELAS) and Leigh syndrome.5
Cases of isolated LHON with m.13513G>A mutation have rarely been reported, and mainly in cases of LHON plus. One patient with this mutation initially presented with LHON, however suffered stroke-like episodes within two years and made no significant visual recovery.6 Two patients with m.13513G>A have been identified with Leigh syndrome, optic atrophy and a Wolff-Parkinson-White syndrome.7 The only other case of isolated LHON, with the m.13513G>A mutation, occurred in a female with acute sequential optic neuropathy who made no visual recovery.8 LHON-like presentations may be missed if testing is limited to only the three primary mutations. With the increased availability of genetic testing, rarer genotypes are likely to be identified.
Treatment for LHON is limited, and has mainly been supportive with advice to avoid alcohol and tobacco.2 Recently Idebenone, a short-chain benzoquine structurally related to co-enzyme Q10, has been shown to be beneficial in LHON.9,10 It is a potent antioxidant and inhibitor of lipid peroxidation, facilitating mitochondrial electron flux in bypassing complex I.11 In nine patients treated for a year, Idebenone 135mg/day was associated with subjective improvement in visual acuity, with one patient showing arrest of progression to visual loss to the contralateral eye, and four demonstrating improvement in visual evoked potential.12 In a retrospective study of 103 patients who commenced Idebenone within one year, increased frequency of recovery of VA was shown in the Idebenone treated patients.13 Early treatment was most predictive of visual recovery. A doublemasked, randomised, placebo-controlled trial in 85 patients over 24 weeks,10 showed that Idebenone appeared to prevent further visual loss in patients with discordant visual acuities. The beneficial effect of Idebenone treatment for 24 weeks persisted following discontinuation.10
The temporal association between Idebenone use and visual improvement presented in our first case suggests that there may be a role for Idebenone in the mutation m.13513G>A, and also potential for it to provide rapid improvement in vision even after delayed treatment onset. Alternatively, the m.13513G>A mutation may produce a benign phenotype, with the chance of good visual outcome.
In summary, these are the first reported cases of isolated LHON associated with the m.13513G>A mutation, and demonstrate the importance of testing for this rare mutation. The cases also illustrate the potential for Idebenone to provide improvement, even after delayed treatment.
Dr Kate Ahmad is a neurologist specialising in neuro-ophthalmology and neurogenetics, particularly mitochondrial diseases. She works, and is involved in research, at Royal North Shore Hospital, Sydney, Australia.
Dr Cathy Cui MD/MBBS (Hons) undertook physician training at Royal North Shore Hospital. She is currently completing a clinical fellowship in movement disorders at the Brain and Mind Centre, Sydney.
A/Prof Mitchell Lawlor is a specialist in the medical and surgical treatment of optic nerve disease. He manages glaucoma and all other optic neuropathies at Sydney Eye Hospital, Royal Prince Alfred Hospital and Sydney Eye Surgeons.
Dr Natalie Palavra is a neurogenetics / movement disorder fellow at Royal North Shore Hospital in Sydney. Her research interests are in neurogenetics, particularly mitochondrial disorders, as well as Parkinson’s Disease.
Professor Carolyn Sue is a neurologist and head of neurogenetics at The Kolling Institute for Medical Research, specialising in mitochondrial disease.
*Patient names changed for anonymity.
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