Genotype-Phenotype Relationships in Patients Carrying Biallelic FDXR Pathogenic Variants-New Cases and Systematic Review.

Antoine Paul, Ghizlene Lahlou, Sophie Achard, Jérôme Nevoux, Isabelle Mosnier, Isabelle Rouillon, Yann Nguyen, Maya Benali, Jean-François Papon, Agnes Rotig, Margaux Serey-Gaut, Celine Labeyrie, Guillemette Beaudonnet, Laurence Jonard, Ralyath Balogoun, Sandrine Marlin

Journal: Human mutation 2026;2026():5928629

PMID: 42829511

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Abstract

Biallelic pathogenic FDXR variations were identified in 2017 as being responsible for sensorial neuropathies. The first reported patients suffered from auditory and optic sensorineural impairments (ANOA, MIM #617717). Since then, many publications have described various phenotypes including peripheral and central nervous systems impairments (MMDS9B, MIM #620887). This is consistent with the role of the encoded protein ferredoxin reductase (FDXR) as one of the actors of iron-sulfur proteins synthesis in mitochondria. Ophthalmologic and neurologic symptoms have often been reported, but little is known about the associated inner ear disabilities, although hearing loss was described in the early clinical reports. Firstly, we would like to characterize inner ear abnormalities, sharing our observations of five new patients' hearing and the outcome after rehabilitation. Thereafter, considering the increasing numbers of publications about FDXR, it appeared useful to provide an overview of literature, analyzing how molecular data may correlate with clinical symptoms. We analyzed the clinical and molecular findings in patients reported from 2017 until March 2025. Data included 89 cases from 79 unrelated families. Protein changes were mostly located in the FAD binding domain, whereas those in NADPH binding domains seem to be less prevalent but more related to severe cases with earlier onset symptoms. These data, combined with current knowledge about FDXR catalytic function and its interaction with FDX and/or cytochrome P450 proteins, could help to understand potential phenotype-genotype correlations.

Address: Department of Otolaryngology Bicetre Hospital APHP Le Kremlin-Bicêtre France.; Department of Otolaryngology and Auditory Implants Pitie-Salpetriere Hospital AP-HP Sorbonne University Paris France sorbonne-universites.fr.; Audiology Research Center Pitie-Salpetriere Hospital APHP Paris Cite University Pasteur Institute Inserm CNRS Fondation pour l'audition IHU reConnect Paris France cnrs.fr.; CRMR surdites genetiques Pitie-Salpetriere Hospital APHP Paris France.; Department of Pediatric Otolaryngology Necker-Enfants Malades Hospital APHP Paris France.; Department of Otolaryngology and Auditory Implants Pitie-Salpetriere Hospital AP-HP Sorbonne University Paris France sorbonne-universites.fr.; Audiology Research Center Pitie-Salpetriere Hospital APHP Paris Cite University Pasteur Institute Inserm CNRS Fondation pour l'audition IHU reConnect Paris France cnrs.fr.; Department of Otolaryngology and Auditory Implants Pitie-Salpetriere Hospital AP-HP Sorbonne University Paris France sorbonne-universites.fr.; Department of Ophthalmology Bicetre Hospital APHP CRMR OPHTARA Paris-Saclay University Paris France universite-paris-saclay.fr.; Genetics of Rare Ophthalmological Auditory and Mitochondrial Disorders Inserm UMR S1163 Imagine Institute Paris France.; Reference Center for Genetic Hearing Loss Department of Genomic Medicine for Rare Diseases Necker-Enfants Malades Hospital APHP Paris France.; Department of Neurology French National Reference Center for Rare Neuropathies Bicetre Hospital APHP Le Kremlin-Bicêtre France.; Genetics of Rare Ophthalmological Auditory and Mitochondrial Disorders Inserm UMR S1163 Imagine Institute Paris France.; Reference Center for Genetic Hearing Loss Department of Genomic Medicine for Rare Diseases Necker-Enfants Malades Hospital APHP Paris France.

DOI: 10.1155/humu/5928629

MeSH Terms: Humans, Ferredoxin-NADP Reductase, Genetic Association Studies, Female, Phenotype, Mutation, Alleles, Male, Child, Child, Preschool, Adolescent, Adult