Genetic Features and Clinical Heterogeneity of Leber Hereditary Optic Neuropathy in Adolescent and Adult Patients: A Case Series on Arab Patients

Introduction

Leber hereditary optic neuropathy (LHON) is a rare disorder characterized by painless progressive visual loss resulting from optic nerve degeneration.^1–5 LHON is caused by maternally inherited mitochondrial DNA (mtDNA) point mutations, impairing the electron transport chain and subsequently reducing adenosine triphosphate (ATP) production.⁶ LHON disproportionately affects men. Around 90% of cases harbor one of the three identified point mutations: m.11778G>A, m.14484T>C, and m.3460G>A, all of which impairing complex I of the electron transport chain.^5,7,8

Mutations affecting complex I of the electron transport chain disrupt the normal electron transport to complex III, a process mediated by coenzyme Q10, a lipid-soluble electron carrier.⁹ In addition to mtDNA mutations, nuclear genes and environmental factors such as smoking¹⁰ and alcohol consumption are believed to influence disease expression and penetrance.¹¹ Less common risk factors including cyanide and carbon monoxide have also been associated with LHON presentation.¹² The complexity of genotype-phenotype association, in optic neuropathies, has been described underscoring the incomplete penetrance of the disease. Although some carriers do not manifest the disease, patients harboring the same mutations may exhibit different phenotypes.^13,14

While spontaneous vision recovery may occur in some patients depending on the specific mutation, with m.11778G>A associated with poorest prognosis and m.14484T>C with the most favorable,^15,16 many cases require treatment. Idebenone, a synthetic analog of coenzyme Q10, is currently approved therapy for LHON.^17,18 It enhances mitochondrial electron transport and may improve or stabilize vision in patients with LHON.^17,18

Yet, treatment initiation timing and follow-up duration contribute to variability in visual outcomes. Early treatment initiation, before 1 year of vision loss in the later eye, is associated with greater efficacy and enhanced visual improvement. Additionally, prolonged treatment showed considerable vision recovery even in patients with severe vision loss.^19,20

Despite global recognition of LHON, reports from Saudi Arabia and Yemen remain limited with few documented cases.^21,22

This manuscript presents a series of LHON cases of Saudi and Yemeni individuals, focusing on disease onset (adolescent versus adult onset), clinical evolution, and visual outcomes following treatment including Idebenone. It also explores potential factors that could trigger the manifestation of LHON in mutation carriers, challenges faced specifically in Yemen and Saudi Arabia including limited access to care, affordability barriers, and cultural risk factors exacerbating LHON manifestation.

Materials and Methods

Patients with LHON from Saudi Arabia and Yemen treated in Saudi Arabia and who benefited from a program sponsored by Biologix FZCO, Pharma, to determine the genetic variants confirming their disease, had their data described in this case series.

Patients in this case series were treated with Idebenone or other coenzyme Q10 according to drug availability and accessibility.

Data on disease onset (adolescent versus adult onset), clinical evolution, and visual outcomes following treatment with Idebenone, coenzyme Q10 (with different follow-up period) were collected.

The case series nature of the presented work impedes formal analysis with hypothesis testing or power calculations reducing the ability to assess therapeutic efficacy consistently.

Ethics Approval and Informed Consent

Institutional Review Board approval was obtained from King Fahad Armed Forces Hospital at Jeddah with alignemnt with the regulations of the National Committee of Bioethics at King Abdulaziz City for Science and Technology (NCBE-KACST Registration No. H-02-J-047) on July 1^st, 2025 (REC 820) to publish the case details.

Consent for Publication

Written informed consent was obtained from patients allowing their cases and any accompanying images to be described and published. For patients who were under 18 at the time of presentation (but were adult at the time of publication), written consent was obtained from both the patients and their parents. None of the reported data includes any information that can compromise patient confidentiality.

Description of Adolescent Onset Cases

Case 1

At the age of 16, a male Saudi student, with no significant medical history besides asthma, presented with painless, progressive vision loss that started in the right eye (oculus dexter [OD]) preceded by the left eye (oculus sinister [OS]) two years before presentation. The patient had no known family history of vision loss but reported being a smoker. On initial examination, the visual acuity (VA) was 20/200 (1.0 LogMar) in both eyes (oculus uterque [OU]). Color vision revealed mild dyschromatopsia with 10/14 Ishihara plates OD and 7/14 OS. Fundus examination showed mild temporal pallor of the left optic disc, while the right disc appeared clinically normal (Figure 1A). The cup-to-disc (c/d) ratio was 0.5 in each eye. Visual field testing demonstrated generalized depression in both eyes. Optical coherence tomography of the retinal nerve fiber layer (OCT RNFL) revealed 109 µm OD and 94 µm OS (Figure 1B), suggesting early structural changes consistent with LHON, particularly in the right eye and optic atrophy in the left eye. Magnetic Resonance Imaging (MRI) of the brain and orbit with contrast was unremarkable, ruling out compressive or inflammatory optic neuropathies. He was placed on oral corticosteroids initially for suspected optic neuritis caused by demyelinating disease; however, no improvement was observed. Genetic testing later confirmed the m.11778G>A mutation in the MT-ND4 gene, the most common and often severe LHON-causing variant. The patient was subsequently started on Idebenone (900 mg/day) (self-purchased out-of-pocket from online vendors), nearly two years after the onset of vision loss in the left eye, and four months after onset in the right eye. Treatment continued for 12 months. After a 10-month follow-up, the patient showed significant functional improvement, with VA improving to 0.3 LogMar OD and 0.4 LogMar OS. Vision improvement allowed this young patient to successfully complete his school.

Figure 1 Investigations of case 1 at presentation. (A) Narrow fundus photo showing right normal optic disc at the acute stage and left temporal pallor and atrophy of the optic disc at the chronic stage. (B)Humphery visual feild 24-2 testing showing generalized depression in both eyes. (C) Optical coherence tomography of the RNFL that measures the thickness of the optic nerve fibers, right eye in the acute stage of vision loss showing slight inferior thickening reflecting mild optic disc sectoral edema and left eye after chronic vision loss showing temporal loss of nerve fiber layer with thinning. Optic Disc Cube 200×200. Abbreviations: OD, oculus dexter; OS, oculus sinister; RNFL, retinal nerve fiber layer; T, temporal; N, nasal; S, superior; I, inferior.

Case 2

At the age of 15, a Yemeni, otherwise healthy, presented with bilateral painless vision loss. On initial examination, VA was CF (1.9 LogMar) OD and 0.06 (1.2 LogMar) OS. Color vision testing revealed 0/16 OU Ishihara plates. Fundus examination showed bilateral optic disc pallor, most prominent temporally with c/d ratio of 0.1, consistent with optic atrophy. He reported a positive family history of LHON (brother of case 6) and disclosed frequent use of Khat (Catha edulis), a central nervous stimulant traditionally used for its euphoric and relaxing effects in some cultures.²³ Genetic testing demonstrated the m.11778G>A mutation in the MT-ND4 gene. Additional investigations, including MRI of the brain and orbits, were all within normal limits, helping exclude other inflammatory, vascular, or retinal causes of vision loss. He was started on coenzyme Q10 (over the counter supplements of ubidecarenone 900 mg daily) and corticosteroid therapy. Due to his socioeconomic conditions, he received coenzyme Q10 for 6 months instead of starting on Idebenone, which is associated with a substantially higher cost. The patient reported subjective improvement in vision; although no changes were observed on follow-up visual assessments.

Case 3

At the age of 17, a Saudi male university student, otherwise healthy, presented with painless progressive bilateral vision loss, with an interval of 8 months between eyes. He had no known family history of vision loss and no concomitant medical conditions. On initial examination, VA was CF (1.9 LogMar) OD and 20/400 (1.3 LogMar) OS. Color vision was severely impaired with 0/16 Ishihara plates in each eye and binocularly (OU), indicating complete dyschromatopsia. Fundus examination revealed bilateral optic disc pallor. MRI of the brain and orbits were normal. Genetic testing demonstrated the m.11778G>A mutation in the MT-ND4 gene. Since Idebenone was not available through either hospital pharmacies or online sources, the patient was started on co-enzyme Q10 for one year; however, no visual improvement was observed.

Description of Adult-Onset Cases

Case 4

At the age of 22, a Saudi female university student, presented with painless, progressive central vision loss in one eye followed by the other eye five months later. She had no family history of vision loss, but was diagnosed with bipolar disorder 3 years prior to presentation and was on risperidone, valproic acid and lamotrigine. She also had no history of smoking or alcohol use. On initial examination, VA was 20/400 (1.3 LogMar) in both eyes. Color vision was 0/14 Ishihara plates OD and 2/14 OS indicating severe dyschromatopsia. Fundus examination demonstrated bilateral optic disc pallor. Visual field testing revealed a cecocentral scotoma in both eyes, which is typical in LHON. The c/d ratio was 0.7 OD and 0.7 OS. OCT RNFL showed significant thinning with RNFL measurements of 59 µm OD and 58 µm OS, consistent with optic atrophy. MRI of the brain and orbits showed normal results. Genetic testing identified a heteroplasmic m.3395A>G mutation in the MT-ND1 gene. She did not receive any treatment throughout the entire follow-up period as she was no longer attending follow-up visits. She has recently been followed in a governmental hospital and applied for Saudi citizen–based medication eligibility and is currently awaiting approval of her medication request.

Case 5

At the age of 59, a Saudi housewife, presented with painless central vision loss in the right eye followed by the left eye after 7 months. She had a history of diabetes, hypertension, elevated intraocular pressure (IOP), as well as bipolar disorder and depression and was on valproic acid. Notably, she had a positive family history of LHON (her nephew). On examination after vision loss in the left eye, VA was count fingers (CF) (1.9 LogMar) in both eyes. Color vision was 0/21 OD and 0/21 OS and 0/16 binocularly (OU), indicating profound dyschromatopsia. Fundus examination revealed generalized optic disc pallor in the right eye, while the left eye showed a full disc with mild inferior swelling. Her c/d ratio was 0.2 OD. Visual field assessment demonstrated central scotoma in both eyes. Genetic testing confirmed the m.11778G>A mutation in the MT-ND4 gene. She initially used over-the-counter Idebenone (900 mg/day) (self-purchased out-of-pocket from online vendors) for 1.5 years, during which her vision remained CF near face (CFNF) and CF at one meter OS. Three months prior to the most recent follow-up, she transitioned to prescription Idebenone (Raxone, 900 mg/day) after becoming eligible, as a Saudi citizen, to receive treatment at a governmental hospital following approval by the expert committee. After 3 months of treatment, her vision improved to CF at 2 meters OD and CF at 1.5-meter OS, representing a mild but notable functional gain. Color vision remained 0/16. This patient regained the ability to lead an independent life, visit the gym, engage in social activities and travel.

Case 6

At the age of 34, a Yemeni construction worker, otherwise healthy, presented with bilateral painless, progressive vision loss. The patient reported a positive family history of LHON (brother of case 2). On initial examination, VA was CFNF approximately 1.9 LogMar in both eyes. Color vision testing revealed 0/16 Ishihara plates OD, OS and OU, indicating complete bilateral dyschromatopsia. Fundus examination showed bilateral optic disc pallor mainly temporal OU, indication chronic optic atrophy, a hallmark of LHON. The patient did not report a history of smoking or alcohol use; however, he reported regular use of Khat. Genetic testing detected the m.11778G>A mutation in the MT-ND4 gene. The patient was unable to afford Idebenone, therefore he initiated treatment with coenzyme Q10 (over the counter supplement of ubidecarenone 900 mg/day), a mitochondrial-targeted antioxidant. He received coenzyme Q10 for 6 months and reported subjective improvement in vision; although no changes were observed on follow-up visual assessments.

Case 7

At the age of 34, a male Yemeni construction worker, otherwise healthy, presented with bilateral painless vision loss. He reported no known family history of vision problems. At the time of presentation, VA was CF (1.9 LogMar) in both eyes. Color vision was 0/16 Ishihara plates OD and OS and binocularly (OU), indicating complete dyschromatopsia. Optic nerve head (ONH) was swollen in both eyes, suggesting early LHON. The patient reported frequent use of Khat. Genetic testing showed the presence of m.11778G>A mutation in the MT-ND4 gene. He did not receive any treatment throughout his brief follow-up period and is no longer attending follow-up visits.

Summary of LHON Presentation

Table 1 below recapitulates patients’ characteristics including age of onset, mutation type, received treatments, follow-up period, and visual acuity before and after treatment.

Table 1 Patients Characteristics

Shedding the Light on Additional Considerations

Differential diagnoses were considered for all patients, namely, to rule out other conditions, such as demyelinating disease optic neuritis. Additionally, assessment of infectious inflammatory conditions and toxic nutritional deficiencies was performed in select patients with medical insurance. Genetic testing for LHON is expensive and not covered by medical insurance schemes. Cases with high clinical suspicion of LHON presented here benefited from a program sponsored by Biologix FZCO, Pharma, to determine the genetic variants confirming their disease. This sheds the light on the financial burden incurred by this debilitating disease, where the elevated cost of the diagnostic test may delay or impede a definitive diagnosis and, thus, the initiation of vision-sparing treatment. Another consideration lies in the socio-cultural setting, where genetic counselling might be misconstrued to incriminate the mother, given the mitochondrial (maternal) transmission of the genetic variant. Finally, based on clinical experience, and on the seven cases presented herein, another hurdle that is encountered is adherence to medications, given their elevated cost, largely an out-of-pocket expenditure, entailing a financial burden on families.

Discussion

This manuscript presents a compelling case series of patients with LHON of Saudi and Yemeni individuals, highlighting the heterogeneity in disease onset, clinical progression, and visual outcomes following Idebenone treatment.

The variation in age of onset from adolescence to late adulthood underscores the diverse phenotypic expression of LHON. Early-onset cases, though less common, may carry distinct prognostic and psychosocial implications.²⁴ This age variability suggests that environmental and lifestyle-related factors may modulate disease expression, especially in populations with shared cultural or occupational exposures.

Notably, several patients reported modifiable risk factors such as smoking and Khat use, both associated with oxidative stress and mitochondrial dysfunction. Khat, a culturally prevalent stimulant with known euphoric effects and mitochondrial toxicity,²⁵ was reported in multiple cases raising the possibility of a trigger in genetically predisposed individuals. Additionally, the clustering of construction workers among the affected patients points to potential occupational exposures to neurotoxic or oxidative agents.²⁶ All construction workers in this series presented with profound dyschromatopsia and severe visual impairment in both eyes, warranting further investigation into occupation-related risk in larger cohorts.

The coexistence of LHON and psychiatric illness including bipolar disorder and depression, in some patients further supports emerging evidence linking mitochondrial dysfunction with neuropsychiatric conditions.²⁷ One patient, the oldest in this series, presented with late-onset LHON, and coexisting bipolar disorder and depression. These findings highlight the need for holistic evaluation, as neuropsychiatric conditions may not only coexist with LHON but also influence disease trajectory or severity though mitochondrial pathways. Notably, all cases presenting with bipolar disorder in this series were females (2 out of 7 cases). Both receiving valproic acid, which is suggested to trigger vision loss in carriers of LHON mutations.²⁸ This observation underscores the need to raise awareness on the impact of such medications and comorbidities on LHON outcomes.

Genetic analysis revealed both common (m.11778G>A)sand rarer mtDNA variants (m.3395A>G),reinforcing the genetic complexity of LHON. While the majority of cases carried the primary mutation, one patient harbored the heteroplasmic m.3395A>G mutation in the gene coding for MT-ND1,previously reported in LHON but not among the primary pathogenic mutations raising important questions about genotype-phenotypecorrelations in atypical cases.²⁹ These observations emphasize the need for comprehensive genetic testing in clinically suspected cases to guide diagnosis management.

Idebenone, the currently approved therapy for LHON^17,18 demonstrated benefit in recovering lost vision and maintaining good residual vision in a real-world setting.³⁰ Early treatment initiation applied when retinal ganglion cell damage is minimal is associated with greater efficacy and enhanced visual improvement.^30,31 Evidence from RHODOS, RHODOS-OFU, and LEROS trials endorsed early treatment initiation with Idebenone with an exposure for at least 24 months for optimal outcomes.^30,31

In this case series, two of seven cases, one with adolescent-onset disease and the other with adult-onset were treated with Idebenone at least two years after disease onset reflecting delayed treatment initiation and real-world challenges.³⁰ Encouragingly, even in such cases visual improvement was observed, supporting Idebenone potential benefit beyond the acute phase and reinforcing the importance of not withholding therapy based solely on disease duration. Patients were treated for more than one year and both exhibited vision improvement that was sufficient to regain a normal lifestyle. This is consistent with previously published data indicating that prolonged treatment results in considerable vision recovery even in patients with severe vision loss.^19,20 In contrast, patients treated with coenzyme Q10 reported only subjective improvement that was not confirmed by visual metrics, as observed in published cases unlike in other inherited mitochondrial disorders.^32,33 This may be attributed to the limited ability of Coenzyme Q₁₀ to cross the blood–brain barrier when taken orally, a limitation addressed with the pharmacokinetic properties of Idebenone.³⁴

Strengths

This case series provides valuable understanding of LHON manifestations in Saudi and Yemeni individuals, in a region where data remain scarce. It also describes distinct features of disease presentations and heterogeneity in clinical progression and visual outcomes between pediatric and adult onset. The identification of both common and rare mtDNA mutations strengthens understanding of genotype-phenotype correlations in this understudied region. Moreover, this case series sheds the light on financial obstacles to proper and timely diagnosis, to treatment initiation and adherence, as well as to follow up; compromising vision recovery and maintenance.

Limitations

The case series nature of the presented work impedes formal analysis and reduces the ability to assess therapeutic efficacy consistently. Additionally, some data are patient-reported, which may introduce potential bias. Finally, inconsistent or loss to follow up further limit outcomes reported in this case series.

Conclusion

Collectively, these cases reflect the clinical and genetic diversity of LHON and emphasize the need for a comprehensive approach to diagnosis and management, one that integrates genetic screening with careful assessment of risk factors such as smoking, psychiatric comorbidities, stimulant use, and occupational exposures. Our findings show visual improvement after Idebenone treatment; however, due to the small sample size these findings cannot be generalized and should be observed in a larger population. Tailoring LHON management to these broader influences may improve both disease understanding and patient outcomes in genetic variant carriers in the Arabian peninsula. Future research including regional registries or systematic follow-up protocols may provide guidance for optimal management of LHON in the region.