Natural History Study of FDXR Mutation-related Mitochondriopathy

NCT04580979 | Completed DMC

• 1 other identifier: STUDY00004513-FDXR
• Study Type: observational
• Target: 33
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Neurodegenerative Disease, Hereditary; Mitochondrial Diseases; Optic Atrophy

Keywords

Neurodegeneration; Mitochondrial disease; Optic atrophy; Ferredoxin reductase; Iron-sulfur cluster biogenesis; Iron overload; Iron homeostasis

Outcome Measures

Primary Outcomes (7)

• 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)

  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.

  3 years

• Eye assessments to evaluate ocular health

  Visual acuity examination will be performed to determine the patient's clarity or sharpness of vision.

  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.

  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.

  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.

  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.

  3 years

Study Arms (1)

Patients with ferredoxin reductase deficiency

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

Interventions

Mutation analysis GENETIC

The investigators will sequence DNA samples from the patients or their families.

Patients with ferredoxin reductase deficiency

Eligibility Criteria

• Age: 0 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Primary care clinic

You may qualify if:

• Patients who are clinically diagnosed with biallelic mutations in the ferredoxin reductase gene
• Male and female patients from 2 to 65 years of age
• Patients who have consented to the study
• In the case of a deceased patient whose parent(s) and/or legal guardian(s) have provided informed consent for study participation, the investigators will review the patient's medical records to determine study eligibility.

You may not qualify if:

• Significant postnatal complications or congenital anomalies that are not known to be associated with ferredoxin reductase deficiency
• Patient has received any experimental treatment for ferredoxin reductase deficiency within the 6 months prior to enrollment, or is expected to receive any such therapy during the study period

Sponsors & Collaborators

• State University of New York at Buffalo: lead
• The Callum McKeefery and Nikki Albano McKeefery Pediatric Division of Genetics Fund: collaborator

Study Sites (1)

UBMD Pediatrics

Buffalo, New York, 14203, United States

Location

Related Publications (5)

• Slone J, Peng Y, Chamberlin A, Harris B, Kaylor J, McDonald MT, Lemmon M, El-Dairi MA, Tchapyjnikov D, Gonzalez-Krellwitz LA, Sellars EA, McConkie-Rosell A, Reinholdt LG, Huang T. Biallelic mutations in FDXR cause neurodegeneration associated with inflammation. J Hum Genet. 2018 Dec;63(12):1211-1222. doi: 10.1038/s10038-018-0515-y. Epub 2018 Sep 25.

  PMID: 30250212 BACKGROUND

• Slone JD, Yang L, Peng Y, Queme LF, Harris B, Rizzo SJS, Green T, Ryan JL, Jankowski MP, Reinholdt LG, Huang T. Integrated analysis of the molecular pathogenesis of FDXR-associated disease. Cell Death Dis. 2020 Jun 4;11(6):423. doi: 10.1038/s41419-020-2637-3.

  PMID: 32499495 BACKGROUND

• Peng Y, Shinde DN, Valencia CA, Mo JS, Rosenfeld J, Truitt Cho M, Chamberlin A, Li Z, Liu J, Gui B, Brockhage R, Basinger A, Alvarez-Leon B, Heydemann P, Magoulas PL, Lewis AM, Scaglia F, Gril S, Chong SC, Bower M, Monaghan KG, Willaert R, Plona MR, Dineen R, Milan F, Hoganson G, Powis Z, Helbig KL, Keller-Ramey J, Harris B, Anderson LC, Green T, Sukoff Rizzo SJ, Kaylor J, Chen J, Guan MX, Sellars E, Sparagana SP, Gibson JB, Reinholdt LG, Tang S, Huang T. Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy. Hum Mol Genet. 2017 Dec 15;26(24):4937-4950. doi: 10.1093/hmg/ddx377.

  PMID: 29040572 BACKGROUND

• Yang L, Slone J, Zou W, Queme LF, Jankowski MP, Yin F, Huang T. Systemic Delivery of AAV-Fdxr Mitigates the Phenotypes of Mitochondrial Disorders in Fdxr Mutant Mice. Mol Ther Methods Clin Dev. 2020 May 22;18:84-97. doi: 10.1016/j.omtm.2020.05.021. eCollection 2020 Sep 11.

  PMID: 32995353 BACKGROUND

• Campbell T, Slone J, Metzger H, Liu W, Sacharow S, Yang A, Moosajee M, La Morgia C, Carelli V, Palombo F, Lines MA, Innes AM, Levy RJ, Neilson D, Longo N, Huang T. Clinical study of ferredoxin-reductase-related mitochondriopathy: Genotype-phenotype correlation and proposal of ancestry-based carrier screening in the Mexican population. Genet Med Open. 2023 Nov 11;2:100841. doi: 10.1016/j.gimo.2023.100841. eCollection 2024.

  PMID: 39669623 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

The medical records will be retained for all patients. For select patients, blood, DNA, skin punch biopsies will also be obtained for the purpose of genetic and biochemical analysis

MeSH Terms

Conditions

Heredodegenerative Disorders, Nervous System; Mitochondrial Diseases; Optic Atrophy; Nerve Degeneration; Iron Overload

Condition Hierarchy (Ancestors)

Neurodegenerative Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Optic Nerve Diseases; Cranial Nerve Diseases; Eye Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Iron Metabolism Disorders

Study Officials

• Taosheng Huang

  State University of New York at Buffalo

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: OTHER
• Target Duration: 3 Years
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 2, 2020
• First Posted: October 9, 2020
• Study Start: November 3, 2020
• Primary Completion: August 17, 2023
• Study Completion: August 17, 2023
• Last Updated: March 8, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)