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

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.