Novel Mutations in the ND5 Gene Associated With Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a mitochondrial optic neuropathy caused by pathogenic mutation(s) to mitochondrial DNA (mtDNA). Mitochondrial dysfunction leads to progressive loss of retinal ganglion cells (RGCs) that typically reside within the papillomacular bundle, leading to painless loss of central vision. Young men are at higher risk for developing LHON; however, females and individuals of all ages may be affected. Missense point mutations in mtDNA at positions 11,778, 14,484, and 3,460 account for 90% of LHON cases. These mutations cause dysfunction of vital genes that encode protein subunits of mitochondrial Complex I, leading to perturbations in adenosine triphosphate (ATP) synthesis (1). Although the aforementioned mutations cause the majority of cases, novel mutations that cause LHON continue to be discovered. In this article, we present 2 LHON patients who tested positive for novel mtDNA mutations (m.12814G>T p.(Ala160Ser) and m.13615A>G p.(Ile427Val)) affecting ND5, a gene that encodes for a Complex I subunit. Patient 1 is a 71-year-old woman who was referred for bilateral progressive vision loss. She had a medical history of Type 2 diabetes and associated peripheral neuropathy, hypertension, dyslipidemia, and gastroesophageal reflux disease. Her medications included perindopril, rosuvastatin, metformin, gabapentin, and aspirin. The initial examination revealed a visual acuity of 20/100 in the right eye and 20/150 in the left eye. Automated 24-2 Swedish Interactive Thresholding Algorithm (SITA)-Fast visual field testing showed bilateral cecocentral scotomas, and her optic nerves appeared normal. An extensive workup including MRI of the brain and orbits with contrast, complete blood count (CBC), B12, folate, aquaporin-4-IgG, myelin oligodendrocyte glycoprotein (MOG)-IgG, and temporal artery biopsy were all normal. A 5-day course of methylprednisolone 1 g daily was prescribed but did not result in any vision improvement. Whole mitochondrial genome sequencing revealed a homoplasmic mutation in MT-ND5:m.12814G>T, p.(Ala160Ser). Mild spontaneous improvement was observed 1 year after onset, and 3 years after onset, her visual acuity was 20/100 in the right eye and 20/80 in the left eye. There was modest improvement in the visual field with less dense cecocentral scotomas (Fig. 1).FIG. 1.: Automated 24-2 SITA-Fast visual fields and optical coherence tomography of the retinal nerve fiber layer at presentation (A) and follow-up (B) 3 years later. The mean deviation at presentation was −12.79 dB in the right eye and −17.01 dB in the left eye, and it was −8.50 dB in the right eye and −12.28 dB in the left eye at the final follow-up.Patient 2 is a 31-year-old woman who was presented to medical attention after she developed bilateral progressive vision loss over 2 weeks. She had a history of sensorineural hearing loss that started 6 months before her visual symptoms and did not take any medications. A referral to neuro-ophthalmology was made and she was seen 1 month after onset of visual symptoms. At that time, she was found to have a visual acuity of counting fingers (CF) at 2 feet in both eyes. Additionally, she had bilateral cecocentral scotomas on automated 24-2 SITA-Fast visual fields and normal-appearing optic nerves. MRI of the orbits and brain with contrast was performed and was normal. Furthermore, CBC, B12 levels, and folate levels were all normal. Mitochondrial genome analysis revealed a homoplasmic mutation at MT-ND5:m.13615A>G, p.(Ile427Val). The patient was started on idebenone 900 mg daily, but her vision did not improve. At the final follow-up 1 year after onset, her visual acuity remained CF at 2 feet in both eyes, with temporal pallor of the optic nerves. Oxidative phosphorylation is central to ATP production and is dependent on a number of enzyme complexes. Complex I of the electron transport chain consists of 14 core subunits that are evolutionarily conserved, 7 of which are encoded by mitochondrial genes (e.g., ND5) (2). The ND5 gene is particularly important in the context of mitochondrial disease and has been identified as a hotspot for pathogenic mutations (3). The presence of such pathogenic mutations can result in Complex I dysfunction, leading to disruption of the processes that underpin ATP synthesis. In LHON, this results in progressive RGC loss and eventual atrophy of the optic nerve. Pathogenic mutations in ND5 causing LHON continue to be characterized in the literature and are rare (e.g., m.12848C>T (4), m.13259G>A (5), m.13345G>A (1)). We identified 2 putatively pathogenic mutations (m.12814G>T and m.13615A>G) in the ND5 gene in 2 patients with phenotypic LHON. Additionally, the m.12814G>T and m.13615A>G mutations were observed at 95.3% and 99.9% homoplasmy, respectively. The m.12814G>T p.(Ala160Ser) mutation involves substitution of a nonpolar amino acid (i.e., alanine) to a polar amino acid characterized by a hydroxyl functional group (i.e., serine). The addition of a polar hydroxyl functional group at the hydrophilic surface of the ND5 protein creates an additional hydrogen bond donor that may influence interactions with proteins adjacent to ND5, thereby perturbing Complex I structure and/or function. The m.13615A>G p.(Ile427Val) mutation leads to the substitution of isoleucine to valine. Because isoleucine is bulkier and slightly more hydrophobic than valine, this substitution could have structural and functional implications due to alterations in these physical properties. Overall, from a mechanistic perspective, it is reasonable to suggest that both mutations may be deleterious. However, to confirm the pathogenicity of these novel mutations and elucidate the specific mechanism(s) contributing toward their pathogenicity, further biochemical studies are required. The lack of biochemical evidence to support the pathogenicity of both mutations serves as a key limitation in this case report. However, it is crucially important to correlate the patients' clinical features with the mutational data. An association between pathogenic ND5 mutations and LHON has already been established in the literature; therefore, the possibility that both mutations described in this article confer phenotypic LHON by causing Complex I dysfunction must be strongly considered. Additionally, both mutations described are highly homoplasmic, which further reinforces their putative pathogenicity. It is also worth reiterating that the described patients did not test positive for any of the primary LHON mutations or any other mutations associated with LHON (e.g., nuclear DNA mutations). Aside from hereditary causes, symmetric optic neuropathy may be caused by toxic, nutritional, and metabolic derangements. However, extensive workup for toxic and nutritional causes (which included heavy metal analysis and measurement of B12 and folate levels) was normal, and none of the patients' medications have been associated with optic neuropathies. Both patients underwent MRI of the orbits and brain with contrast to rule out compressive lesions of the optic chiasm. Therefore, no other etiologies could explain the phenotypic features present in both patients. Taken together, there is strong reason to suspect that both mutations may be associated with LHON. In summary, we report 2 novel mutations in the ND5 gene that likely contributed to the LHON phenotype described in both patients. The discovery of either mutation in other LHON patients would further reinforce their putative pathogenicity. STATEMENT OF AUTHORSHIP Conception and design: B. U. Pandya, J. A. Micieli, E. A. Margolin; Acquisition of data: B. U. Pandya, N. A. Takyi, A. R. Vosoughi, J. A. Micieli, E. A. Margolin; Analysis and interpretation of data: B. U. Pandya, N. A. Takyi, A. R. Vosoughi, J. A. Micieli, E. A. Margolin. Drafting the manuscript: B. U. Pandya, E. A. Margolin, J. A. Micieli; Revising the manuscript for intellectual content: B. U. Pandya, N. A. Takyi, A. R. Vosoughi, E. A. Margolin, J. A. Micieli. Final approval of the completed manuscript: B. U. Pandya, N. A. Takyi, A. R. Vosoughi, E. A. Margolin, J. A. Micieli.

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