Leber Hereditary Optic Neuropathy Caused by a Mitochondrial DNA 10663T>C Point Mutation and Its Response to Idebenone Treatment

Letters to the Editor depression; a key one being in the treatment of chronic headaches. Antidepressants may inadvertently undermine a patient's attempts at losing weight. By no means do we suggest withholding or suddenly withdrawing antidepressants from patients who truly need them. However, when faced with a patient who struggles to lose weight, we would encourage a careful review of the patient's medications. In addition, in treating chronic intractable headaches, clinicians should weigh the risks and benefits before prescribing a tricyclic, as in the long-term management of patients with IIH, these drugs may cause more of a headache than you bargained for. Anna M. Gruener, BMedSci(Hons), BMBS, MSc, FRCOphth Department of Ophthalmology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom Neuro-Ophthalmology Division, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland Alexander D. Jolly, BMBS, MRCPsych Urgent Medical Mental Health Line, Nottinghamshire Healthcare NHS Foundation Trust, Nottingham, United Kingdom James M. A. Ellison, BMedSci(Hons), BMBS, PGDip, MRCPsych Department of Examinations and Assessments, University of Nottingham School of Medicine, Nottingham, United Kingdom Michael A. Burdon, MBBS, FRCP, FRCOphth Department of Ophthalmology, University of Birmingham Hospitals NHS Foundation Trust, Birmingham, United Kingdom The authors report no conflicts of interest. REFERENCES 1. Subramaniam S, Fletcher WA. Obesity and weight loss in idiopathic intracranial hypertension: a narrative review. J Neuroophthalmol. 2017;37:197-205. Leber Hereditary Optic Neuropathy Caused by a Mitochondrial DNA 10663T.C Point Mutation and Its Response to Idebenone Treatment W e read with interest the consensus report by Carelli et al (1) describing the value of idebenone in the treatment of patients with Leber hereditary optic neuropathy Letters to the Editor: J Neuro-Ophthalmol 2018; 38: 122-133 2. Jung SJ, Woo HT, Cho S, Park K, Jeong S, Lee YJ, Kang D, Shin A. Association between body size, weight change and depression: systematic review and meta-analysis. Br J Psychiatry. 2017;211:14-21. 3. Kesler A, Mosek A, Fithlicher N, Gidron Y. Psychological correlates of idiopathic intracranial hypertension. Isr Med Assoc J. 2005;7:627-630. 4. Lee SH, Paz-Filho G, Mastronardi C, Licinio J, Wong ML. Is increased antidepressant exposure a contributory factor to the obesity pandemic? Transl Psychiatry. 2016;6:e759. 5. Himmerich H, Minkwitz J, Kirkby KC. Weight gain and metabolic changes during treatment with antipsychotics and antidepressants. Endocr Metab Immune Disord Drug Targets. 2015;15:252-260. 6. Carbone F, Vanuytsel T, Tack J. The effect of mirtazapine on gastric accommodation, gastric sensitivity to distention, and nutrient tolerance in healthy subjects. Neurogastroenterol Motil. [published online ahead of print July 11, 2017] doi: 10.1111/nmo.13146. 7. Salvi V, Mencacci C, Barone-Adesi F. H1-histamine receptor affinity predicts weight gain with antidepressants. Eur Neuropsychopharmacol J. 2016;26:1673-1677. 8. Badowski M, Pandit NS. Pharmacologic management of human immunodeficiency virus wasting syndrome. Pharmacotherapy. 2014;34:868-881. 9. Hilas O, Avena-Woods C. Potential role of mirtazapine in underweight older adults. Consult Pharm J Am Soc Consult Pharm. 2014;29:124-130. 10. Xu XM, Liu Y, Dong MX, Zou DZ, Wei YD. Tricyclic antidepressants for preventing migraine in adults. Medicine (Baltimore). 2017;96:e6989. 11. Krishnan A, Silver N. Headache (chronic tension-type). BMJ Clin Evid. 2009;2009:1205. 12. Uguz F, Sahingoz M, Gungor B, Aksoy F, Askin R. Weight gain and associated factors in patients using newer antidepressant drugs. Gen Hosp Psychiatry. 2015;37:46-48. 13. Mahmood S, Booker I, Huang J, Coleman CI. Effect of topiramate on weight gain in patients receiving atypical antipsychotic agents. J Clin Psychopharmacol. 2013;33:90-94. 14. Chan JW. Current concepts and strategies in the diagnosis and management of idiopathic intracranial hypertension in adults. J Neurol. 2017;264: 1622-1633. 15. Sinclair AJ, Burdon MA, Nightingale PG, Ball AK, Good P, Matthews TD, Jacks A, Lawden M, Clarke CE, Stewart PM, Walker EA, Tomlinson JW, Rauz S. Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study. BMJ. 2010;341:c2701. 16. Manfield JH, Yu KKH, Efthimiou E, Darzi A, Athanasiou T, Ashrafian H. Bariatric surgery or non-surgical weight loss for idiopathic intracranial hypertension? A systematic review and comparison of meta-analyses. Obes Surg. 2017;27:513-521. 17. Moss HE. Bariatric surgery and the neuro-ophthalmologist. J Neuroophthalmol. 2016;36:78-84. (LHON). In addition, the Expanded Access Program (EAP) of patients with LHON with disease duration ,1 year found that the number of patients who recovered clinically relevant visual acuity (VA) increased with idebenone treatment duration, reaching almost 50% by 16 months (2). We describe a patient with LHON caused by an uncommon mitochondrial DNA 10663T.C point mutation and his response to idebenone. A 16-year-old boy developed acute and painless visual loss in both eyes 2 weeks apart. He was an only child with 129 Letters to the Editor no family history of visual loss. He had a medical history of mild exercise-induced asthma and used salbutamol inhalers as needed. He reported no tobacco or alcohol use. At initial examination, VA was 20/200 in the right eye and 20/100 in the left eye with profound dyschromatopsia bilaterally. Threshold perimetry identified central scotomas in both eyes. There was bilateral optic disc hyperemia with mild peripapillary telangiectasias. Postcontrast MRI demonstrated enhancement of both optic nerves and the optic chiasm without other evidence of white matter disease. The initial diagnosis was bilateral optic neuritis, but there was no improvement after treatment with intravenous methylprednisolone. The clinical picture and nonresponsiveness to corticosteroids raised the suspicion of LHON. Genetic analysis for the 3 common mitochondrial mutations proved negative. Nevertheless, the patient was prescribed idebenone 300 mg 3 times per day 10 months after symptom presentation. At that time, VA was 20/80 in the right eye and counting fingers in the left eye. There was bilateral optic disc pallor. After 2 months of idebenone treatment, VA was 20/50 in the right eye and 20/60 in the left eye; after 8 months, it was 20/25 in both eyes. At 2-year follow-up, VA was 20/20 bilaterally, and the patient was able to read the Ishihara pseudoisochromatic plates slowly with each eye. Whole mitochondrial genome sequencing performed at the Molecular Genetics Laboratory, Department of Clinical Genetics, Copenhagen University Hospital eventually detected a homoplasmic mutation, m.10663T.C (p.Val65Ala), in the ND4L gene; the mitochondrial DNA belonged to haplogroup J. The ND4L gene codes for a subunit of complex 1; replacement of alanine by valine at position 65 results in a partial complex 1 defect. Evidence suggests the mutation is pathogenic when co-occurring with haplogroup J (3,4). To our knowledge, this is the first report of idebenone treatment in LHON caused by a 10663C mutation. Treatment was started somewhat late, 10 months after visual loss, at which time there was evidence of bilateral optic atrophy. Regardless, our patient gradually experienced a remarkable improvement in vision. Some prognostic details of the natural history of LHON caused by the 10663C mutation co-occurring with haplogroup J are available. For affected males in one family, reported average end-point VA was 20/100 at the time of diagnosis, with subsequent spontaneous improvement to 20/60 (3). In another report, 2 10633Cpositive patients had VA of 20/200 to counting fingers (5). Thus, sparse evidence suggests that the mutation causes severe vision loss in affected individuals, and there is a potential for some spontaneous improvement. The 130 improvement in our patient exceeded the end-point of spontaneous improvement in VA. Rather, recovery in our patient corresponded to initiation of idebenone therapy and suggests a causal benefit of idebenone treatment. Furthermore, the improvement in VA surpasses that in the subgroup that recovered in the EAP. One intriguing fact is that the 10663C mutation alters a different structural subunit, NADH dehydrogenase 4L of complex I, rather than the common LHON mutations evaluated in the RHODOS trial (6) and the EAP. This raises the question as to whether structural changes in NADH dehydrogenase 4L harbor a higher potential for response to idebenone treatment than alterations in the prevailing LHON subunits. Øystein Kalsnes Jørstad, MD Eva Meling Ødegaard, MD Ketil Riddervold Heimdal, MD, PhD Emilia Kerty, MD, PhD Department of Ophthalmology, Oslo University Hospital, University of Oslo, Oslo, Norway The authors report no conflicts of interest. REFERENCES 1. Carelli V, Carbonelli M, de Coo IF, Kawasaki A, Klopstock T, Lagreze WA, La Morgia C, Newman NJ, Orssaud C, Pott JWR, Sadun AA, van Everdingen J, Vignal-Clermont C, Votruba M, Yu-Wai-Man P, Barboni P. International consensus statement on the clinical and therapeutic management of Leber heriditary optic neuropathy. J Neuroophthalmol. 2017;37:371-381. 2. Metz G, Hasham S, Catarino C, Klopstock T. Treatment of visual impairment in patients with Leber's Hereditary Optic Neuropathy (LHON) using idebenone (Raxone). Poster session presented at: Annual Meeting of The Association for Research in Vision and Ophthalmology; May 1-5, 2016; Seattle, WA. 3. Brown MD, Torroni A, Reckord CL, Wallace DC. Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations. Hum Mutat. 1995;6:311-325. 4. Brown MD, Starikovskaya E, Derbeneva O, Hosseini S, Allen JC, Mikhailovskaya IE, Sukernik RI, Wallace DC. The role of mtDNA background in disease expression: a new primary LHON mutation associated with Western Eurasian haplogroup J. Hum Genet. 2002;110:130-138. 5. Abu-Amero KK, Bosley TM. Mitochondrial abnormalities in patients with LHON-like optic neuropathies. Invest Ophthalmol Vis Sci. 2006;47:4211-4220. 6. Klopstock T, Yu-Wai-Man P, Dimitriadis K. Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A, Kernt M, Petraki D, Rummey C, Leinonen M, Metz G, Griffiths PG, Meier T, Chinnery PF. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain. 2011;134:2677-2686. Letters to the Editor: J Neuro-Ophthalmol 2018; 38: 122-133