Acute Vision Loss Linked to Novel biallelic FDX2 Loss-of-Function Variants: Insights into Biochemical Mechanisms and Therapeutic Implications

Topic:

Translational Research

Poster Number: 396 O

Author(s):

Rotem Or Bach, MD, National Institute of Neurological Disorders and Stroke (NINDS)/NIH, Nunziata Maio, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/NIH, Joshua Todd, NIH/ Neuromuscular and Neurogenetic Disorders of Childhood Section and Neurocrine Biosciences, Laryssa A. Huryn, MD, National Eye Institute (NEI)/NIH, Dimah Saade, MD, University of Iowa/ Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, Sarah Neuhaus, National Institute of Neurological Disorders and Stroke (NINDS)/NIH, Sandra Donkervoort, MS, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Healt, Meghan McAnally, National Institute of Neurological Disorders and Stroke (NINDS)/NIH, Robert Hufnagel, National Eye Institute (NEI)/NIH, Bianca Buchignani, IRCCS Stella Maris Foundation, Pisa, Roberta Battini, IRCCS Stella Maris Foundation, Pisa, Paola Costantini, University of Padova, Juliana Gurgel-Giannetti, MD, Federal University of Minas Gerais, Tracey A. Rouault, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/NIH, Andrea Gropman, Children's National Medical Center, Michael Murphy, University of Cambridge, A. Reghan Foley, MD, MD(Res), Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Health, Carsten G. Bönnemann, MD, habil., Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Health

Ferredoxin 2 (FDX2) encodes a mitochondrial iron-sulfur (Fe-S) protein essential for Fe-S cluster biogenesis. Biallelic pathogenic variants in FDX2 cause two distinct clinical phenotypes: one is predominantly characterized by metabolic myopathy with episodic rhabdomyolysis and lactic acidemia. while the other predominately affects the central nervous system, presenting with optic atrophy, reversible leukoencephalopathy, neuropathy, and/or mild myopathy. We report novel biallelic FDX2 variants (p.H115R; p.L91F) in a patient whose initial clinical manifestation was acute vision loss at 17 months of age, followed by reversible white matter abnormalities on brain MRI, fluctuating ptosis, and hematologic findings including leukopenia and neutropenia.
Using patient-derived fibroblasts, along with a cell line from an additional FDX2 patient harboring a homozygous splice-site variant (c.200+4A>C, CNS phenotype) and fibroblasts from a Friedreich ataxia (FRDA) patient, we demonstrate comparable mitochondrial dysfunction, iron overload, and oxidative stress across FDX2- and FXN-deficient cells relative to controls. Based on these shared biochemical perturbations, we evaluated three redox-modulating compounds with potential to improve mitochondrial function: mitoquinol mesylate (MitoQ, an over-the-counter supplement), omaveloxolone (FDA-approved for FRDA), and vatiquinone. All three agents significantly and dose-dependently reduced lipid peroxidation in FDX2- and FXN-patient derived cells. MitoQ treatment further led to a dose-responsive improvement in mitochondrial respiration in the index patients’ cells.
Our FDX2 patient was enrolled in an NIH single-patient expanded-access protocol (IND: 158370) for MitoQ therapy (up to 1 mg/kg/day) with three years of clinical follow-up. The treatment has been well tolerated with no significant adverse effects; although vision loss remains unchanged, motor function, muscle strength, pyramidal signs, and neuroimaging findings are stable or improved.
In conclusion, we expand the phenotypic spectrum of FDX2-related disease by identifying novel variants and acute vision loss as an early presentation and provide functional evidence linking mitochondrial oxidative stress to pathogenesis, with potential therapeutic benefit from redox-targeted interventions.