Disease Progression May Differ Even in Groups With Similar FA Severity
Changes in symptom worsening smaller for older patients, study finds
Disease progression can vary significantly among people with Friedreich’s ataxia (FA) — even when patients are grouped by disease severity — a multicenter natural history study reported.
Further, changes in symptom worsening may be smaller in older patients with the inherited, progressive disease.
These findings, and others from the study, will help to inform future clinical trials in FA, according to researchers.
“Understanding of the diversity within Friedreich’s ataxia populations and their patterns of functional decline provides an essential foundation for future clinical trial design including patient selection and facilitates the interpretation of the clinical relevance of progression detected in Friedreich’s ataxia,” the scientists wrote.
The study, “Natural History of Friedreich’s Ataxia: Heterogeneity of Neurological Progression and Consequences for Clinical Trial Design,” was published in the journal Neurology.
The main genetic cause of FA is excessive repeats of the GAA sequence of nucleotides — the building blocks of DNA — in the FXN gene. Longer GAA repeats are associated with a younger age at disease onset and more severe, rapidly progressing symptoms.
Given the small number of people in the world with FA — the disorder affects about 1 in every 50,000 people — researchers in clinical trials need to group patients together, based on their characteristics, to better predict their disease progression patterns.
Evaluating disease progression in FA
Identification of factors associated with disease progression in FA have been investigated in two large natural history studies. One, the European Friedreich’s Ataxia Consortium for Translational Studies, is known as EFACTS (NCT02069509). The other is FA-COMS (NCT03090789), or the Friedreich’s Ataxia – Clinical Outcome Measures Study.
Findings from these studies revealed that patients with earlier FA onset have faster disease progression.
Researchers have previously noted that shorter repeats of GAA can differentiate well between patients with severe, early onset disease, and those with milder, later onset FA. However, repeat length is not as efficient at predicting differences within groups of patients with similar ages of onset.
To further identify the genetic and clinical features of FA, an international team of scientists studied the progressive loss of physical abilities in patients enrolled in the FA-COMS trial, which is ongoing.
“The goal of this work was to acknowledge the broad genetic diversity of the [FA] population, especially with respect to younger individuals and to provide analyses stratified by age to guide population selection in future studies,” the researchers wrote.
The FA-COMS study is still recruiting participants at 14 sites, nine of which are located in the U.S.
Here, the main goal was to evaluate the worsening of specific functions over time using the modified Friedreich Ataxia Rating Scale (mFARS) — a standardized measure of FA progression. Data were collected before April 28, 2020, to exclude any influence of the COVID-19 pandemic.
mFARS measures physical abilities through several subsections, such as the ability to stand and walk, called the USS score. The FARS A score assesses speaking and swallowing, while the use of arms, hands, and legs are scored as upper and lower limb coordination.
Two different methods were used to analyze disease progression over time. In their first analysis, the researchers grouped patients based on age of onset: 0 to 7 years as early onset; 8 to 14 years as typical onset; 15 to 24 years for intermediate onset; and older than 24 years as late onset.
In the second analysis, changes in symptoms were examined in one- or two-year intervals, stratified by the patients’ current ages. Patients were grouped into six age brackets, specifically younger than 8, 8–11, 12–15, 16–24, 25–40, and older than 40.
A total of 1,115 patients were included in the study. Among them, 324 (29%) were early onset, 438 (39%) were typical onset, 234 (21%) were intermediate onset, and 119 (11%) were late onset. The median follow-up time was five years.
Typically, FA patients will require a wheelchair within 10 years after the onset of symptoms. At enrollment, most patients — 70% — were able to walk. By the most recent visit, just less than half of the patients (49% ) could walk.
Patients carrying point mutations or gene deletions as a disease cause were excluded from the analysis as their genetic alterations may lead to atypical clinical features.
Study findings confirmed that early onset patients had a faster-progressing form of the disease, as reflected by the mFARS scores. In the ambulatory phase, early onset patients worsened almost 50% faster than typical onset patients, and about twice as fast as intermediate onset patients. The late and intermediate onset groups had similar mFARS scores.
Additionally, patients in the intermediate and late onset groups showed slower declines in USS scores. FARS A declined mostly in the early and typical onset groups, with greater changes showing in the non-ambulatory phase.
Further analysis showed no differences in the Activities of Daily Living (ADL) score between ambulatory early onset and typical onset patients. However, worsening in ADL was slower in the intermediate and late onset patients compared with the typical onset group.
Next, the researchers analyzed yearly changes by age group. The youngest age group showed the highest mean yearly changes in mFARS score, which decreased with age. In younger patients, upper limb scores contributed markedly to the overall decline
“In conclusion, we demonstrate the large diversity of clinical presentation and disease progression in [FA],” the researchers wrote.
“Individual severity was contextualized with age-based population analyses, providing selection criteria and stratification schemes for clinical trials. Most importantly, the relevant drivers of decline by disease phase were identified and quantified, informing the discussion of clinical relevance of rating scale changes in [FA],” they wrote.