NMO or NOT NMO, That Is the Question

A healthy 18-year-old woman presented with sub-acute painless vision loss in the left eye. On annual exam she was found to have a central scotoma in the left eye. Visual acuity was 20/15 in the right eye and 20/400 in the left eye, with an afferent pupillary defect. A visual evoked potential was normal on the right and showed increased latency of P100 on the left. A contrast enhanced MRI showed longitudinal enhancement of the left optic nerve.

“NMO or NOT NMO, that is the question” Carolyne Riehle 1, Emily Spoth 2, Jill Wilson 3, Bradley Katz 4, Meagan Seay 2, Sravanthi Vegunta 1, Judith Warner 5, Kathleen Digre 6 1 Moran Eye Center, 2 University of Utah, Moran Eye Center, 3 University of Utah Health, 4 John A Moran Eye Center; University of Utah Health, 5 University of Utah Health, Moran Eye Center, 6 University of Utah History & Exam: A healthy 18-year-old woman presented with sub-acute painless vision loss in the left eye. On annual exam she was found to have a central scotoma in the left eye. Visual acuity was 20/15 in the right eye and 20/400 in the left eye, with an afferent pupillary defect. A visual evoked potential was normal on the right and showed increased latency of P100 on the left. A contrast enhanced MRI showed longitudinal enhancement of the left optic nerve. Cervical spine MRI, performed for Lhermitte sign, showed extensive, patchy, T2 hyperintensity of the central cervical cord. The brain looked normal. Laboratory studies including AQP4-IgG were negative. She received five days of IV methylprednisolone (1000 mg/day) without improvement in vision. She underwent five sessions of plasmapheresis for presumed seronegative NMO and transitioned to azathioprine and prolonged oral prednisone taper. She presented to our institution two months after symptoms onset with NLP vision and optic atrophy in the left eye. The right eye was normal with 20/15 vision. Over the next four weeks, she experienced worsening vision in her right eye. She was treated with five days of IV methylprednisolone (1000 mg/day). With continued deterioration to light perception only vision in the right eye, she was started on weekly Rituximab for five weeks. Neurological exam showed diffuse hyperreflexia, positive Babinski sign, and reduced sensation in the lower extremities. Repeat AQP4-IgG and MOG-IgG were negative. CSF studies were normal without oligoclonal bands. After completion of Rituximab therapy, she had improvement of vision in right eye to 20/600 with a central island of vision on Goldmann perimetry. Left eye remained NLP. Worsening of vision prompted additional treatments with ACTH injections, plasmapheresis, Rituximab, and IVIG with no improvement. Repeat imaging was unchanged. An unexpected event occurred and a procedure was done. Financial Disclosures: Carolyne Riehle: No; Emily Spoth: No; Jill Wilson: No; Bradley Katz: Dr. Katz is CMO of Axon Optics, an online company that develops, markets and sells eyewear for the treatment of light sensitive conditions. Dr. Katz receives royalties from patents that describe the use of optical filters for the treatment of light sensitive conditions.; Meagan Seay: No; Sravanthi Vegunta: No; Judith Warner: I receive royalties from patents describing the use of optical filters for the treatment of light sensitivity.; Kathleen Digre: Dr. Digre receives royalties from patents describing the use of optical filters for the treatment of light sensitivity. Grant Support: None. 26 | North American Neuro-Ophthalmology Society “NMO or NOT NMO, that is the question” Answer Final Diagnosis: Paternally inherited autosomal dominant missense mutation in AFG3L2 gene resulting in c.1276G>A; p. Glu426Gln variant. Summary of Case: This 18-year-old woman had subacute sequential optic neuropathies. Evaluation was concerning for seronegative NMO, but there was no response to aggressive immunotherapy. Four years after her initial presentation, the patient’s father experienced subacute painless sequential optic neuropathies. MRI cervical and thoracic spine showed posterior column T2/FLAIR hyperintensity similar to his daughter. Due to the similar vision loss with accompanying myelopathy, targeted genome sequencing including trio testing was pursued. This revealed a novel variant in the ATPase family gene 3-like 2 (AFG3L2) gene (c.1276G>A; p. Glu426Gln) in both patients due to a missense mutation. This variant was determined to be paternally inherited and autosomal dominant. AFG3L2 encodes a protein localized in mitochondria and closely related to paraplegin encoded by the SPG7 gene. AFG3L2 subunits assemble either into homo-oligomeric isoenzymes or with SPG7 subunits into heterooligo proteolytic complexes. AFG3L2 and SPG7 are therefore paralog genes encoding mitochondrial matricial AAA (m-AAA)- proteases that are involved in regulating OPA1 processing. Variants of SPG7 have been identified in hereditary spastic paraplegia as well as dominant optic atrophy (3). Heterozygous pathogenic variants in the AFG3L2 gene have been associated with spinocerebellar ataxia type 28 and optic atrophy. Several studies have linked AFG3L2 variants to dominant optic atrophy (1, 3, 4). At least one individual with an AFG3L2 variant was reported with MRI T2-hyperintensity lesions of the putamen, globus pallidus, and substantia nigra (2). Many of the variants in these studies were in the ATPase domain, as is this novel c.1276G>A, p. Glu426Gln variant. Functional studies of several AFG3L2 pathogenic variants have shown altered OPA1 processing causing mitochondrial dysfunction, indicating a functional explanation for the disease association (1, 2). The AFG3L2 c.1276G>A; p. Glu426Gln variant has not been reported in the medical literature and is not found in population databases. Struggle/Dilemma of the Clinical Presentation Description: The presence of bilateral optic neuropathies and cervical spine lesions was highly suggestive of an autoimmune process (NMO); however, these patients were unresponsive to aggressive immunotherapy. A genetic etiology was not considered, until her father developed optic neuropathy and myelopathy. The underlying etiology, a variant of the AFG3L2 gene, was discovered. This case demonstrates that genetic etiologies should be considered when testing is unrevealing for a specific autoimmune etiology and patients are unresponsive to immunotherapy. Keywords: Optic neuropathy, Neuromyelitis Optica (NMO), Myopathy References: 1. Baderna, V., Schultz, J., Kearns, L.S. et al. A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy. acta neuropathol commun 8, 93 (2020). https://doi.org/10.1186/s40478-020-00975-w 2. Caporali, L., Magri, S., Legati, A., Del Dotto, V., Tagliavini, F., Balistreri, F., Nasca, A., La Morgia, C., Carbonelli, M., Valentino, M.L., Lamantea, E., Baratta, S., Schöls, L., Schüle, R., Barboni, P., Cascavilla, M.L., Maresca, A., Capristo, M., Ardissone, A., Pareyson, D., Cammarata, G., Melzi, L., Zeviani, M., Peverelli, L., Lamperti, C., Marzoli, S.B., Fang, M., Synofzik, M., Ghezzi, D., Carelli, V. and Taroni, F. (2020), ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy. Ann Neurol, 88: 1832. https://doi.org/10.1002/ana.25723 3. Charif M, Chevrollier A, Gueguen N, Bris C, Goudenège D, DesquiretDumas V, Leruez S, Colin E, Meunier A, Vignal C, Smirnov V, Defoort-Dhellemmes S, Drumare Bouvet I, Goizet C, et al. (2020) Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy Neurol, 6 (3) e428; DOI: 10.1212/NXG.0000000000000428 4. Charif M, Roubertie A, Salime S, Mamouni S, Goizet C, Hamel CP, Lenaers G. A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability. Front Genet. 2015 Oct 19;6:311. doi: 10.3389/fgene.2015.00311. PMID: 26539208; PMCID: PMC4609881. 5. Colavito D et al. Non-syndromic isolated dominant optic atrophy caused by the p.R468C mutation in the AFG3 like matrix AAA peptidase subunit 2 gene. Biomed Rep. 2017;7 (5):451-454. Contact Information: Carolyne Riehle, [e-mail] 2023 Annual Meeting Syllabus | 27