An observational study in Neurodegenerative Disease, Hereditary, Mitochondrial Diseases and Optic Atrophy, sponsored by State University of New York at Buffalo. Completed at 1 site in United States. Open to participants aged 0 Years to 65 Years. Per ClinicalTrials.gov, last updated 2024-03-08.
Sponsored by State University of New York at Buffalo · Observational
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.
21 studies on the registry are indexed under Heredodegenerative Disorders, Nervous System; 5 are open to participants now.
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Primary care clinic
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Exclusion Criteria:
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Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Male and female patients from age 2 to age 65 with clinically confirmed FDXR mutations. Both living and deceased patients will be included, if eligible. For deceased patients, the patient's medical history records will be reviewed, and an interview of the parent(s) or caregiver(s) will be performed.
Genetic: Mutation analysis
The investigators will sequence DNA samples from the patients or their families.
Custom Medical History Questionnaire for Patients with FDXR Mutation-related Mitochondriopathy
In addition to a standard medical history, patients or their legal guardians will be asked to complete a custom medical history questionnaire tailored toward conditions commonly observed in patients with biallelic FDXR mutations. The items that will be asked about in this questionnaire are as follows: 1. Known mutations in FDXR 2. Any family history of illness 3. Complications of pregnancy 4. Premature birth 5. Complications with birth 6. Developmental delay 7. Developmental regression 8. Abnormal size of brain 9. Movement disorders (ataxia, dystonia, etc.) 10. Seizures 11. Optic atrophy in eye exam 12. Vision loss 13. Other vision problems (color, eye movement) 14. Hypotonia (muscle weakness or lack of tone) 15. Electromyogram (EMG) 16. Muscle biopsy 17. Spasticity (muscle stiffness or tightness) 18. Brain MRI performed? 19. Electroencephalogram (EEG)
Time frame: 3 years
Retrospective examination of the medical records of patients with FDXR Mutation-related Mitochondriopathy
With the informed consent of the patients or their parent(s) and/or legal guardian(s), the investigators will perform a retrospective examination of the medical records of both living and deceased patients with confirmed biallelic FDXR mutations.
Time frame: 3 years
Eye assessments to evaluate ocular health
Visual acuity examination will be performed to determine the patient's clarity or sharpness of vision.
Time frame: 3 years
Growth and development (height)
World Health Organization (WHO) growth charts will be used to document height in centimeters (cm) for patients ranging from ages 5 to 19 years old. Routine methods will be used to document height for all other age groups.
Time frame: 3 years
Growth and development (weight)
World Health Organization (WHO) growth charts will be used to document weight in kilograms (kg) for pediatric patients age 5 to 10 years old. Routine methods will be used to document weight for all other age groups.
Time frame: 3 years
Growth and development (BMI)
World Health Organization (WHO) growth charts will be used to document Body Mass Index (BMI) in kilograms per meter square for patients age 5 to 19 years old. Routine methods will be used to document BMI for all other age groups.
Time frame: 3 years
ACTH stimulation testing for adrenal insufficiency
FDXR is known to support the catalytic activities of steroidogenic enzymes involved in aldosterone and cortisol synthesis. However, this deficiency may be partial and therefore only manifest in situations with severe stress, putting these persons at risk for an adrenal crisis. Therefore, we will also be testing patients with pathogenic FDXR variants for their risk of an adrenal crisis using the well-established ACTH stimulation test, assessing their stress-response ability to produce aldosterone and cortisol by comprehensive steroid profiling from blood.
Time frame: 3 years
Plan to share: No
Ran from Nov 2020 to primary completion in Aug 2023, 33 months.
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This study is completed, as verified in Mar 2024. You cannot join it, but the record below documents what was studied.
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Heredodegenerative Disorders, Nervous System →
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