A Novel Metric for Predicting Severity of Disease Features in Friedreich's Ataxia

Abstract

A BS TRACT: Background: Friedreich's ataxia (FRDA), most commonly caused by a GAA triplet repeat (GAA-TR) expansion in intron 1 of the FXN gene, is characterized by deficiency of frataxin protein and clinical features such as progressive ataxia, dysarthria, impaired proprioception and vibration, abolished deep tendon reflexes, Babinski sign, and vision loss in association with nonneurological features such as skeletal anomalies, hearing loss, cardiomyopathy, and diabetes. Pathogenic GAA-TRs range in size from 60 to 1500 triplets and negatively correlate with age of onset. Clinical severity is predicted by a combination of GAA-TR length and disease duration (DD) via multivariable regressions, which cannot typically be used for the small sample sizes in most studies on this rare disease. Objective: We aimed to develop a single metric, which we call "disease burden" (DB), that encompasses both GAA-TR length and DD for predicting disease features of FRDA in small sample sizes.Methods: Linear regression and multivariable regression analysis was used to determine correlation coefficients between different disease features of FRDA. Results: Using large datasets for validation, we found that DB predicts measures of neurological dysfunction in FRDA better than GAA-TR length or DD. Analogous results were found using small datasets. Conclusions: FRDA DB is a novel metric of disease severity that has utility in small datasets to demonstrate correlations that would not otherwise be evident with either GAA-TR or DD alone. This is important for discovering new biomarkers, as well as improving the prediction of severity of disease features in FRDA.

Retinal hypoplasia and degeneration result in vision loss in Friedreich ataxia

“…FACOMS contains data on GAA‐TR length, age at data collection, age of onset, mFARS scores, FA Functional Disease Stage scores, high‐contrast and low‐contrast letter acuity testing via Sloan letter charts. Disease burden was calculated as length of the shorter GAA allele (GAA1) multiplied by disease duration attachment 22 …”

“…The modified Friedreich Ataxia Rating Scale (mFARS) and FA Functional Disease Stage score provide two validated metrics of neurological severity and can detect temporal progression of the disease. mFARS correlates with both GAA1 length and disease duration but is best predicted by the product of the two, called disease burden 16–22 . This measure predicts many features of FRDA better than its two components alone 22 .…”

“…mFARS correlates with both GAA1 length and disease duration but is best predicted by the product of the two, called disease burden 16–22 . This measure predicts many features of FRDA better than its two components alone 22 . Similarly, in linear regression models, outcome measures that capture progression are predicted by both disease duration and GAA repeat length, such that those with longer GAA1 lengths and longer disease duration have more severe disease including visual acuity deficits in some cases.…”

Preparing for Disease‐Modification Trials in Degenerative Cerebellar Ataxias: Which Endpoints to Choose?

“…The last paper by Rodden and colleagues differs somewhat from the other three as its primary objective was not to characterize the course of a particular type of degenerative ataxia with existing rating scales, imaging measures, or biofluid markers. Instead, the authors present a novel observer‐independent metric called “disease burden” and demonstrate its utility as a predictor of disease severity in FRDA 7 . Resembling the recently published S‐factor, which integrates genetic severity and time since ataxia onset into a single measure for the most common polyglutamine SCAs, disease burden in FRDA is the product of GAA1 repeat length and disease duration 13 .…”

“…Delineating and predicting natural disease evolution with clinical rating scales, patient‐reported outcomes, observer‐independent metrics, (infratentorial) MRI measures, and biofluid markers constitutes an essential prerequisite for conducting meaningful disease‐modification trials. This issue of Movement Disorders features a series of articles on dominantly inherited SCAs, MSA‐C, SAOA, and Friedreich ataxia (FRDA) that share this important outcome theme 5‐8 …”