Natural History of Friedreich ataxia in children

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Abstract Friedreich’s ataxia (FRDA) is the most common form of hereditary ataxia, affecting approximately 1 in every 50,000 people in the United States and Europe. Symptoms typically begin between the ages of 5 and 15 years and worsen over time. The pathophysiology of FRDA reflects the deficiency of the protein frataxin. Reduced frataxin levels impair the function of mitochondrial iron-sulfur-cluster-containing enzymes and ability to produce ATP. Recently, amelioration of frataxin deficiency by gene therapy in mouse models of FRDA has produced impressive benefit in reversing the phenotype, providing an evidenced-based approach for treatment of FRDA patients. Mitigation of mitochondrial dysfunction also represents a valid therapeutic approach. However, if attempts at these therapies were made today, they would be limited by the inability to assess the human biology of FRDA in detail, as well as the inability to target therapies to the most biologically responsive individuals, children. To achieve this goal, we will study the natural history of FRDA in children, to understand the course of disease activity in this age group. In the first aim, we will assess potential measures of disease progression in the youngest subjects with FRDA (n=100 at 3 sites) These will include specific revisions and modifications of timed walks (in order to identify a test more suitable for use in young individuals, and an automated measure of upper extremity coordination (the CCFS) that is useful in older FRDA subjects. In aim 2 we will assess biochemical measures of frataxin deficiency and downstream metabolic function, and understand their utility in serial monitoring.in children with FRDA. Peripheral samples (blood, buccal cells, isolated platelets) will be obtained from a large heterogeneous cohort of subjects with FRDA (n=100 at 3 sites). We will then assay the primary biomarker of disease severity, frataxin level, in the samples with a newly devised mass spectrometry-based assay to understand how such levels reflect disease status. In parallel, we will examine mitochondrial-derived alterations in metabolic pathways in platelets to examine events downstream from frataxin deficiency. Finally we will examine physiological tests (motor evoked potentials, Cr-CEST of muscle) that can link clinical parameters with biochemical measurements. Cumulatively these aims will define the utility of such approaches in clinical measurement of FRDA in children, and validate such approaches as the definitive measures needed for design of informative trials in children with FRDA.