Abstract
Friedreich ataxia (FRDA) is an autosomal recessive inherited multisystem disease, characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate. In the current era of expanding therapeutic discovery in FRDA, including progress toward novel gene therapies, a deeper and more specific consideration of potential treatment targets in the nervous system is necessary. In this work, we have re-examined the neuropathology of FRDA, recognizing new issues superimposed on classical findings, and dissected the peripheral nervous system (PNS) and central nervous system (CNS) aspects of the disease and the affected cell types. Understanding the temporal course of neuropathological changes is needed to identify areas of modifiable disease progression and the CNS and PNS locations that can be targeted at different time points. As most major targets of long-term therapy are in the CNS, this review uses multiple tools for evaluation of the importance of specific CNS locations as targets. In addition to clinical observations, the conceptualizations in this study include physiological, pathological, and imaging approaches, and animal models. We believe that this review, through analysis of a more complete set of data derived from multiple techniques, provides a comprehensive summary of therapeutic targets in FRDA.
Highlights
First described in 1863 by Nikolaus Friedreich, a German physician, the genetic cause of Friedreich’s ataxia was discovered in 19963: a homozygous expansion of a guanine-adenine-adenine (GAA) trinucleotide repeat in intron 1 of the frataxin gene (FXN), or rarely, a point mutation or large deletion in one FXN allele and GAA expansion in the other
Fe/S clusters are cofactors for proteins with a variety of functions that are located in all cellular compartments. These include Krebs cycle enzymes, subunits of respiratory chain complexes I, II, and III, ferrochelatase, lipoic acid synthase, and several others. The function of these proteins is impaired by frataxin deficiency, leading to lower energy production and oxidative stress due to respiratory chain dysfunction
While the early loss of proprioceptive afferents remains a characteristic aspect of the pathology of FRIEDREICH ATAXIA (FRDA), other areas such as the dentate nucleus (DN), the corticospinal system, and other nuclei do atrophy and play important roles in the neurological features of the disorder
Summary
Friedreich ataxia (FRDA) is an autosomal recessive inherited multisystem disease, characterized by marked differences in the vulnerability of neuronal systems. In the current era of expanding therapeutic discovery in FRDA, including progress toward novel gene therapies, a deeper and more specific consideration of potential treatment targets in the nervous system is necessary. We have reexamined the neuropathology of FRDA, recognizing new issues superimposed on classical findings, and dissected the peripheral nervous system (PNS) and central nervous system (CNS) aspects of the disease and the affected cell types. Understanding the temporal course of neuropathological changes is needed to identify areas of modifiable disease progression and the CNS and PNS locations that can be targeted at different time points. As most major targets of longterm therapy are in the CNS, this review uses multiple tools for evaluation of the importance of specific CNS locations as targets.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
