Retinal hypoplasia and degeneration result in vision loss in Friedreich ataxia

Abstract

Objective: Friedreich ataxia (FRDA) is an inherited condition caused by a GAA triplet repeat (GAA-TR) expansion in the FXN gene. Clinical features of FRDA include ataxia, cardiomyopathy, and in some, vision loss. In this study, we characterize features of vision loss in a large cohort of adults and children with FRDA.

Methods: Using optical coherence tomography (OCT), we measured peripapillary retinal nerve fiber layer (RNFL) thickness in 198 people with FRDA, and 77 controls. Sloan letter charts were used to determine visual acuity. RNFL thickness and visual acuity were compared to measures of disease severity obtained from the Friedreich Ataxia Clinical Outcomes Measures Study (FACOMS).

Results: The majority of patients, including children, had pathologically thin RNFLs (mean = 73 ± 13 μm in FRDA; 98 ± 9 μm in controls) and low-contrast vision deficits early in the disease course. Variability in RNFL thickness in FRDA (range: 36 to 107 μm) was best predicted by disease burden (GAA-TR length X disease duration). Significant deficits in high-contrast visual acuity were apparent in patients with an RNFL thickness of ≤68 μm. RNFL thickness decreased at a rate of -1.2 ± 1.4 μm/year and reached 68 μm at a disease burden of approximately 12,000 GAA years, equivalent to disease duration of 17 years for participants with 700 GAAs.

Interpretation: These data suggest that both hypoplasia and subsequent degeneration of the RNFL may be responsible for the optic nerve dysfunction in FRDA and support the development of a vision-directed treatment for selected patients early in the disease to prevent RNFL loss from reaching the critical threshold.

Figure 1

RNFL thickness is reduced in FRDA. RNFL thickness in the 4 quadrants of (A) the right eye (OD) and (B) the left eye (OS) in 77 controls and 198 participants with FRDA. (C) Average RNFL thickness of all quadrants in the right eye (OD), left eye (OS), and the average of OD and OD (ODOS) in 77 controls and 198 participants with FRDA. (D) Frequency distributions of RNFL thickness controls (black curve) and participants with FRDA (red curve). Sup. = superior, Inf. = inferior, Temp. = temporal. Stats: t‐test, ****p < 0.0001.

Figure 2

Children with FRDA have thin RNFLs early in disease. (A) Frequency distributions of RNFL thickness in kids (<18 years n = 35 CNTR, n = 61 FRDA) and adults (≥18 years n = 42 CNTR, n = 172 FRDA). Black and gray curves = non‐FRDA controls, pink and red curves = FRDA. (B) RNFL thickness plotted by age and FRDA status. Stats: one‐way ANOVA with Tukey's post hoc, ****p < 0.0001, ***p < 0.001.

Figure 3

RNFL thickness measured with two different OCT devices give similar outcomes. (A) RNFL thickness for non‐FRDA controls, carriers, and participants with FRDA. (B) comparison of RNFL thickness values for five participants that were assessed by both machines. Stats: one‐way ANOVA with Tukey's post hoc analysis. n.s. = not significant, ****p < 0.0001.

Figure 4

Disease burden predicts RNFL thickness. RNFL thickness plotted against (A) age, (B) GAA1 length, (C) disease duration [age minus age of onset], and (D) disease burden [GAA1 multiplied by disease duration].

Figure 5

RNFL thickness correlates with neurological severity in FRDA. RNFL thickness plotted against (A) mFARS score and (B) FA Functional Disease Stage (FA stage).

Figure 6

RNFL thickness predicts vision loss in FRDA. RNFL thickness plotted against (A) full‐contrast vision, (B) low‐contrast visual acuity (LCVA) at 2.5% contrast, and (C) LCVA at 1.25% contrast. Dotted line in (A) at X = 60 represents 20/20 vision. Dotted line in (B) and (C) represents values obtained from 4 non‐FRDA controls. The equation of linear regression curve in (A) is Y = 0.5107*X + 42.50, when X = 59 letters (vision below 20/20), Y = 73 μm. When X = 50 letters (2 lines lost compared to 20/20 vision), Y = 68 μm.

Figure 7

RNFL loss is −1.2 ± 1.4 um/year in FRDA. (A) RNFL thickness plotted over time in n = 17 people with FRDA. (B) Change in RNFL thickness (μm/year). Horizontal solid line depicts the mean (−1.2 ± 1.4 um/year).