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Review
. 2022 Oct;12(5):267-283.
doi: 10.2217/nmt-2022-0011. Epub 2022 Jun 29.

Friedreich ataxia: clinical features and new developments

Medina Keita  1 , Kellie McIntyre  1 , Layne N Rodden  1 , Kim Schadt  1 , David R Lynch  1
Affiliations
Review

Friedreich ataxia: clinical features and new developments

Medina Keita et al. Neurodegener Dis Manag. 2022 Oct.

Abstract

Friedreich's ataxia (FRDA), a neurodegenerative disease characterized by ataxia and other neurological features, affects 1 in 50,000-100,000 individuals in the USA. However, FRDA also includes cardiac, orthopedic and endocrine dysfunction, giving rise to many secondary disease characteristics. The multifaceted approach for clinical care has necessitated the development of disease-specific clinical care guidelines. New developments in FRDA include the advancement of clinical drug trials targeting the NRF2 pathway and frataxin restoration. Additionally, a novel understanding of gene silencing in FRDA, reflecting a variegated silencing pattern, will have applications to current and future therapeutic interventions. Finally, new perspectives on the neuroanatomy of FRDA and its developmental features will refine the time course and anatomical targeting of novel approaches.

Keywords: Frataxin; NRF2; antioxidant; clinical care guideline; clinical trial; multisystem.

Plain language summary

Friedreich's ataxia (FRDA), mainly referred to as a disorder of balance, is characterized by loss of coordination (ataxia) in the arms and legs and other neurological features, affecting about 1 in 50,000 people in the USA. FRDA also includes serious heart disease, aggressive scoliosis, diabetes and many other disease characteristics. Due to various clinical care needs, disease-specific clinical care guidelines have been created. New developments in FRDA include the advancement of clinical drug trials targeting cell signaling pathways and restoration of the deficient protein found in individuals with FRDA. Additionally, a new understanding of the role of the various genetic factors that contribute to the development of FRDA could affect current and future therapies. Finally, new perspectives on the early developmental features of FRDA will help refine the time course and accelerate new treatments.

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Figures

Figure 1.
Figure 1.. Retinal nerve fiber layer pathology in Friedreich's ataxia.
Optical coherence tomography scans of the retina in (A) a healthy control subject (age and sex matched) and (B) a subject with FRDA. The RNFL (white arrows) is outlined in red. Overlay of RNFL thickness deviation map on fundus images of the optic disk in (C) the same healthy control and (D) the same subject with FRDA. Red and yellow regions reveal areas of the retina that deviate in thickness compared with the normal distribution. Yellow: <5th percentile, red: <1st percentile. FRDA: Friedreich's ataxia; RNFL: Retinal nerve fiber layer.
Figure 2.
Figure 2.. A model of variegated silencing in Friedreich's ataxia.
Each cluster of 10 cells represents a theoretical person who does not have FRDA (non-FRDA), is a carrier of one GAA repeat expansion (carrier) or is one of three people who have FRDA with various GAA repeat lengths. Parentheses indicate the GAA repeat lengths: N = normal length GAA; >700 = more than 700 triplets; <700 = fewer than 700 triplets. The relative color saturation of cells represents the relative amount of frataxin (darker color = more frataxin). Homogenous silencing (top set of FRDA subjects) shows the same amount of frataxin in every cell, and less frataxin in each cell as the GAA repeat length increases. Variegated silencing (bottom set of FRDA subjects) shows how most cells in people with FRDA have very little frataxin (gray/no color), and few cells have escaped silencing, a proportion that increases with decreasing GAA repeat length. Protein/RNA assays would give the same result in either silencing model for a given repeat length i.e. shorter repeat patients would have ∼30% residual frataxin. Recent studies however support the variegated silencing model in FRDA. FRDA: Friedreich's ataxia.
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