Introduction: Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder that typically presents with painless, central visual loss, hyperaemia of the optic nerve head, and peripapillary telangiectasias. Most LHON cases are due to one of three variants, but several less common variants also exist. We describe a clinical case of LHON associated with the variant m.3866T>C, which is possibly linked to LHON. Case Presentation: A 59-year-old Caucasian woman experienced acute, bilateral, and painless visual loss. She reported cigarette smoking, and elevated phosphatidylethanol suggested harmful alcohol consumption. Her best-corrected visual acuity (BCVA) was 20/100 for the right eye and 20/50 for the left eye. She could only read the Ishihara demonstration plate, and threshold perimetry demonstrated reduced central sensitivity bilaterally. Her optic nerve heads were hyperaemic, with peripapillary telangiectasias. The visual symptoms and clinical findings suggested LHON. Magnetic resonance imaging demonstrated a tuberculum sella meningioma and two cerebral aneurysms, which we regarded as incidental findings. Genetic testing did not identify common LHON variants but a rare homoplasmic variant, m.3866T>C, which studies suggest might cause LHON or act in synergy with other variants to increase the disease penetrance. After initiating test-of-treatment with idebenone 900 mg per day, the patient’s BCVA improved to 20/32 for both eyes and then stabilized. Conclusion: This case strengthens the evidence for m.3866T>C as a causative LHON variant. The case also raises the question as to whether this particular variant can respond favourably to treatment with idebenone.

Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder that typically presents with painless, central visual loss, hyperaemia of the optic nerve head, and peripapillary telangiectasias. Most LHON cases are due to one of three variants, m.11778G>A, m.3460G>A, and m.14484T>C, altering the structure and function of mitochondrial complex I, but several less common variants also exist [1]. With regard to treatment of LHON, one randomized controlled trial suggests benefit of idebenone [2]. Accordingly, the European Medicines Agency has authorized Raxone (Chiesi Farmaceutici, Parma, Italy) for treatment of visual impairment in adolescent and adult LHON patients. We report a patient with a variant, m.3866T>C, possibly linked to LHON; the clinical presentation and response to idebenone suggest it caused LHON in this case. We have also completed the CARE Checklist for the case report, which is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000539445).

Our patient was a 59-year-old Caucasian woman. Her family history was negative for optic nerve disorders. She received treatment for hypertension (hydrochlorothiazide, valsartan, and metoprolol), hypothyroidism (levothyroxine), obstructive pulmonary disease (budesonide-formoterol inhaler), and mixed anxiety-depressive disorder (sertraline). She reported smoking 15–20 cigarettes per day and drinking about eight units of alcohol per week; elevated phosphatidylethanol suggested harmful alcohol consumption. She had experienced acute, bilateral, and painless visual loss 4 weeks prior to examination at our neuro-ophthalmology unit. Her best-corrected visual acuity (BCVA) was 20/100 for the right eye and 20/50 for the left eye. She could only read the Ishihara demonstration plate for each eye. Threshold perimetry demonstrated reduced sensitivity centrally, in particular for the right eye (Fig. 1a). Her optic nerve heads were hyperaemic, with peripapillary telangiectasias (Fig. 1b). There was normal peripapillary nerve fibre layer thickness on optical coherence tomography; the mean value was 100 μm for the right eye and 93 μm for the left eye. Magnetic resonance imaging revealed a tuberculum sellae meningioma lifting the prechiasmatic optic nerves, a 4-mm anterior communicating artery aneurysm, and a 14-mm right posterior communicating artery aneurysm (Fig. 2).

Fig. 1.

Threshold perimetry (a) and fundus photography (b) of the patient. There is reduced sensitivity in the central visual field, in particular for the right eye. The optic nerve heads appear hyperaemic, and there are peripapillary telangiectasias.

Fig. 1.

Threshold perimetry (a) and fundus photography (b) of the patient. There is reduced sensitivity in the central visual field, in particular for the right eye. The optic nerve heads appear hyperaemic, and there are peripapillary telangiectasias.

Close modal
Fig. 2.

Coronal magnetic resonance imaging (MRI) of the patient. The most anterior MRI section (a) shows that the optic nerves (stars) straddle the tumour (T) without being encased. The most posterior MRI section (b) shows the tumour (T), the anterior communicating artery (ACOM) aneurysm, and the posterior communicating artery (PCOM) aneurysm, which compresses the medial temporal lobe.

Fig. 2.

Coronal magnetic resonance imaging (MRI) of the patient. The most anterior MRI section (a) shows that the optic nerves (stars) straddle the tumour (T) without being encased. The most posterior MRI section (b) shows the tumour (T), the anterior communicating artery (ACOM) aneurysm, and the posterior communicating artery (PCOM) aneurysm, which compresses the medial temporal lobe.

Close modal

The acute visual symptoms and clinical findings suggested LHON. On the other hand, there were no localizing signs suggesting optic neuropathy due to prechiasmatic compression. Initial genetic testing for m.11778G>A, m.3460G>A, and m.14484T>C was normal, and we therefore supplemented the workup with mitochondrial Sanger sequencing of positions 3,000–5,500 and 8,000–15,000, covering 19 primary LHON variants and 18 additional candidate variants listed in the MITOMAP human mitochondrial genome database. None of these variants were detected, but sequencing identified a homoplasmic variant, m.3866T>C, in the gene encoding the ND1 subunit of respiratory complex I; studies suggest the resulting substitution p.Ile187Thr might cause LHON or act in synergy with m.11778G>A to increase the penetrance of LHON in families carrying both variant [3‒5]. In consequence of the ambiguous genetic result, we opted for a test-of-treatment strategy with idebenone 900 mg per day, which was initiated 4 months after symptom debut. We also advised the patient to quit smoking and reduce her alcohol intake. At this point, the BCVA was 20/63 for the right eye and 20/50 for the left eye.

The patient returned after 11 weeks and reported improved eyesight after a few weeks of idebenone treatment. She had, however, not cut down on smoking or alcohol. The BCVA had improved to 20/32 for both eyes. Her optic nerve heads were still hyperaemic, but there was remission of the peripapillary telangiectasias. Optical coherence tomography revealed a 7-µm decline in mean peripapillary nerve fibre layer thickness for both eyes, most pronounced for the temporal (parvocellular) axons. Because of the improvement in BCVA after initiating idebenone treatment, the patient continued with idebenone 900 mg per day. After 6 months, she also underwent a craniotomy for the meningioma and aneurysms. She maintained stable BCVA and threshold perimetry over 10 months of idebenone treatment. Sadly, the patient then died in an unrelated accident.

The medical history and clinical findings of our female patient suggested LHON. The typical LHON patient is a young male, but LHON can affect both sexes and all age groups. In the case of our patient, whose disease debuted in her late 50s, it should be noted that she had a positive medical history for harmful alcohol consumption and smoking, both important risk factors for late-onset LHON [6]. We did not detect common LHON variants but identified a homoplasmic variant, m.3866T>C, possibly linked to LHON. This case thereby reinforces the evidence of m.3866T>C as a causative LHON variant. With regard to the tuberculum sellae meningioma, there were no localizing signs suggesting optic neuropathy due to prechiasmatic compression, and the improvement in visual function occurred before neurosurgery. We therefore considered the meningioma, and the aneurysms, as incidental findings. The case also raises the question as to whether m.3866T>C-associated LHON can respond favourably to idebenone treatment, but BCVA had slightly improved for the right eye before initiating treatment, pointing to a possible element of spontaneous recovery.

The patient gave verbal consent to publication of her case before she passed away. Written informed consent was obtained from the patient’s two sons for publication of the final case report and accompanying images. The data protection officer at Oslo University Hospital approved publication of the case report (Reference No. 24/00049).

Ø.K.J. has received lecture fees from Chiesi Farmaceutici. None of the other authors have financial disclosures in relation to this work.

The authors did not receive funding or grant support for this work.

Ø.K.J., S.S., H.S., O.R., R.T.B., and P.A.R. participated in the clinical workup of the patient. Ø.K.J. drafted the manuscript. Ø.K.J., S.S., H.S., O.R., R.T.B., and P.A.R. reviewed the manuscript and approved the final version.

All relevant data are included in the article. Further enquiries can be directed to the corresponding author.

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