Natural History Study of FDXR Mutation-related Mitochondriopathy

Overview

The purpose of the study is to systematically characterize the clinical course of the progressive neuropathy and optic atrophy observe in pediatric and adult patients with biallelic mutations in the ferredoxin reductase gene.

The mitochondrial membrane-associated ferredoxin reductase (FDXR) is a flavoprotein that initiates the mitochondrial electron transport chain by transferring electrons from NADPH to the mitochondrial cytochrome P450 system via the ferredoxins FDX1 or FDX2. In addition to essential roles in Fe-S cluster biogenesis, this pathway is also central to the biosynthesis of steroid hormones. Previously, Dr. Taosheng Huang's research group has identified mutations in the FDXR gene in many individuals who share clinical presentations consistent with a mitochondrial disorder-including ataxia, hypotonia and optic atrophy-and obtained a naturally-occurring Fdxr mutant mouse model from Jackson Lab that corroborated these results (PMID: 29040572 and PMID: 30250212). In particular, FDXR enzyme activity, mitochondrial complex activities and ATP production were all significantly reduced in their patient samples. Their studies further indicated that Fdxr mutation leads to neurodegeneration that is associated with both inflammation as well as the abnormal accumulation of iron in the mitochondria, likely as a result of disrupted Fe-S cluster synthesis. More recently, his group has used the CRISPR-Cas9 system to generate a mouse line with a p.R389W amino acid change, which more precisely matches the most common human variant observed in their patients and shows a much more severe phenotype than their previous, naturally occurring Fdxr mouse model. They have also show that AAV-based gene therapy can significantly improve the condition of Fdxr mutant mice (DOI:https://doi.org/10.1016/j.omtm.2020.05.021), providing valuable preclinical data that may open the door for adapting such gene therapy treatments for use in human clinical trials. Given the recent regulatory approval granted to gene therapy treatments for LCA2, SMA1, and β-thalassemia, there is strong possibility that such an approach will ultimately produce a viable clinical treatment for FDXR patients as well. FDXR is required for Iron-sulfur (Fe-S) clusters synthesis which is essential for multiple important biological processes, including electron transfer, cofactor synthesis, and gene regulation. Fe-S cluster biosynthesis is a tightly regulated process that requires coordinated delivery of both iron and sulfur and is a cofactor of many proteins. A variety of human disorders have been associated with impaired Fe-S cluster synthesis, including neurodegenerative disorders (e.g. Friedreich's ataxia) and myopathy with lactic acidosis. Iron homeostasis, which requires precise synthesis and localization of Fe-S clusters in mitochondria, is critical to ensure that there is sufficient iron for cellular functions, without reaching toxic levels of iron. Excessive levels of iron favor the formation of excess oxygen free radicals and consequent mitochondrial dysfunction. The Rare Disease Act and Rare Disease Orphan Product Development Act highlight the importance of rare disease research and the obstacles to developing effective treatments for these diseases. However, the study of rare diseases may open a window to studying other human conditions. For example, Iron-sulfur biosynthesis abnormalities have been observed in more common human diseases such as Friedreich's ataxia. This relationship highlights the importance of human disease research by multiple approaches to understand biological mechanisms and for general application to human health. For these reasons, a better understanding of the pathogenesis of FDXR deficiency may help facilitate our knowledge of disease biology, neurodevelopment, brain function, and other organ abnormalities. Thus, in order to better understand the function of FDXR and to help lay the groundwork for eventual clinical trials of gene therapy or drug-based treatments for FDXR-related disease, the investigators propose this natural history study of both pediatric as well as adult patients with biallelic mutations in the ferredoxin reductase gene.

Conditions

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Eligibility

Locations (1)

Outcomes