FA Severity May Plateau After Certain Number of FXN Gene Repeats
Both clinical severity and frataxin protein levels correlate with the number of disease-causing trinucleotide repeats in the FXN gene of people with Friedreich’s ataxia (FA), with more repeats linked to worse disease.
But FA symptoms appear to plateau with anything greater than 700 repeats — after which both clinical severity and frataxin protein levels showed little variation — according to the results of a new study.
“Our data suggest that there is a ceiling effect on the clinical consequences of [repeat] length in [FA],” the researchers wrote, adding that those patients with more than 700 repeats “represent a subgroup in which the severity of clinical manifestations based on [repeat] length have reached maximal levels.”
The study, “Clinical Evidence for Variegated Silencing in Patients With Friedreich Ataxia,” was published in the journal Neurology Genetics.
FA is most often caused by trinucleotide repeat expansions in both copies of the FXN gene. These expansions consist of excessive repeats of three nucleotides, or DNA building blocks — one guanine (G) and two adenines (A) — in a region of the gene. While usually occurring fewer than 30 times in healthy people, those with FA commonly have hundreds, and sometimes more than 1,000 repeats.
As a result of these mutations, the dysfunctional FXN gene is silenced in the cell, preventing it from producing its protein product, frataxin. This leads to the hallmark FA symptoms, which include loss of muscle control and muscle weakness, skeletal deformities, heart problems, and diabetes.
The number of repeats in FA patients is associated with the age at disease onset and symptom severity, with a greater number of repeats correlating with symptoms that emerge sooner, progress faster, and are more severe.
Studies in cultured patient cells led scientists to develop a model by which this might occur, called the variegated silencing model. Essentially, it was found that in cells from patients with fewer GAA repeats, some cells escaped FXN silencing, allowing a greater frataxin production, which could potentially explain a milder disease.
While the number of cells escaping this silencing decreased with increasing repeat numbers, the effect seemed to plateau with any number of repeats over 500.
But whether a similar plateau in clinical symptom severity with increasing repeat numbers might be observed in FA patients is not known. To answer that question, a research team examined repeat lengths, frataxin levels, and disease severity in FA patients included in the FRDA Clinical Outcome Measures Study database.
Among 1,000 included patients — 50.4% female, and with a median age of 26.5 — the median GAA repeat length was 690 and the median age at disease onset was 11 years.
In 498 participants who had their blood frataxin levels measured, a correlation was observed between GAA length, frataxin levels, and the age at disease onset. Similar correlations have been observed previously, the researchers noted.
But when examining the data more closely, the team found that repeat lengths of up to 700 contributed most significantly to that association. In other words, while frataxin levels and age at onset lowered with increasing GAA lengths, this effect appeared to plateau, or “max out” at 700 repeats, with little variability in age at onset observed with repeats greater than that number.
Similarly, the number of GAA repeats was associated with the severity of clinical outcome measures. More specifically, the overall observed prevalence of cardiomyopathy — a disease of the heart muscle that makes it harder to pump blood — was 59%. Scoliosis, a spine curvature, was seen in 81% of patients, and diabetes in 7%.
The prevalence of cardiomyopathy and scoliosis was higher with increasing repeat lengths, but plateaued at 700 repeats — similar to the observations made with age. An exception was the prevalence of diabetes, which was similar across patients with all repeat lengths but did increase with disease duration.
“Our data further support the variegated silencing model by demonstrating that a ceiling effect exists in GAA-[repeat] length on clinically measured frataxin levels and with severity and prevalence of clinical features of [FA],” the researchers wrote.
The team noted that the data support the notion that it’s the proportion of cells escaping FXN silencing that drives the effects on clinical severity, rather than the direct effects of the frataxin level itself.
This could explain why carriers, who only have one mutated copy of FXN, may show frataxin levels similar to those in FA patients with mild disease, but don’t have any symptoms, the researchers said. Those carriers likely have a higher proportion of cells that escape FXN silencing, which predicts clinical presentation.
Overall, the findings that clinical severity plateaus after 700 repeats may inform clinical trial design and treatment approaches, the team noted. For example, 700 repeats may be a good cutoff point when stratifying groups of data in preclinical or clinical studies for analysis.
Further, the effects of therapies that act to alter gene silencing may produce the greatest effects in patients with fewer than 700 repeats, the team noted.