Mechanisms, Markers, and Risk Factors in Friedreich s Ataxia Heart Disease (FA-HD)
Abstract
Portfolio: Neuroscience Topic Area: Friedreich s Ataxia Strategic Goal: Identify mechanisms underlying neurological diseases and psychological conditions including potential relationships to environmental/neurotoxic exposures, injury, stress, or infections. Overarching Challenge: The overarching goal of this Program is to distinguish the clinical, genetic, and biological aspects associating with, and contributing to heart disease in Friedreich s Ataxia (FRDA) that are unique and likely separate from the neurological phenotype, thereby providing predictive tools to identify those FRDA families most at risk for cardiomyopathy. Briefly, we will follow a cohort of FRDA patients (and their heterozygous carrier family members) for the duration of the project to characterize the extent of FRDA-Associated Heart Disease (FA-HD) using clinical cardiac testing, imaging, and biomarkers. A broad range of clinical cardiological and neurological surveillance testing will be recorded and correlated with laboratory studies performed on biological samples from the patients to determine which variables are predictive of early FA-HD development. These studies will include expanded patient-specific genetic testing for the presence of hereditary risk variations in the DNA that predispose to heart disease. Patient-specific function studies of nerve and heart cells will help determine specific pathological mechanisms of FRDA leading to FA-HD. Blood samples from each research subject will be used to generate patient-specific induced pluripotent stem cells (iPSCs). These iPSCs will be differentiated into heart cells (cardiomyocytes, termed iCMs) and nerve cells (neurons termed iNs). Patient-specific iCMs and iNs will be investigated for FA-dependent aberrations in gene expression, and metabolism (via mitochondrial studies), and novel biomarkers associating with FA-HD. We will specifically determine how cardiac and neuronal tissue are affected differently in FA. Clinical, genomic, and biological data will be analyzed in a computer-based Machine Learning algorithm to predict which FRDA patients are at highest risk for developing FA-HD who merit heightened surveillance and provide insights into potential therapeutic targets. Rationale: FRDA is an autosomal recessive neurodegenerative disease caused by a defect in the FXN gene that encodes the protein frataxin. Affected individuals inherit the genetic trait from both parents who are generally unaffected since they are carriers with only one copy of the pathological FXN variation. Although overt disease is uncommon, it is the most prevalent hereditary ataxia with an incidence of 1 in 30,000-50,000. Heterozygous carriers are considerably more prevalent with an estimated 1:60 to 1:100 frequency. Although FRDA is characterized as a neurodegenerative condition, it is well recognized as a multisystem disorder that impacts the not only the nervous system, but also the musculoskeletal system, the heart, and the pancreas. Approximately 60% of the patients with FRDA develop progressive cardiac disease that appears similar to primary hypertrophic cardiomyopathy (HCM) but is characterized by more progressive cardiac fibrosis, heart failure, and rhythm disturbances. Twenty percent of FRDA patients present reduced cardiac function that appears in the second to third decade of life, after the neurological disease is well established. Cardiac involvement in FRDA patients is variable however and has been reported in some instances to precede neurological dysfunction, while in other cases, cardiac disease is never manifest. Despite research from many groups, the mechanism(s) of how pathological FA-associated genetic variation of the FXN gene cause disease remain controversial. The protein encoded by the FXN gene, frataxin is severely depressed in FRDA patients and its deficiency appears to have deleterious consequences in energy metabolism of the nerve and in the heart. Howe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310643
Entities
People
- Thomas J. McDonald
Organizations
- United States Army
- University of South Florida