A large, European registry study shows that Friedreich’s ataxia patients have a considerable spectrum of clinical symptoms that go beyond the typical neurological ataxia.
Common non-neurologic clinical symptoms identified by researchers included abnormal eye movements and skeletal deformities, as well as urinary problems and heart disease.
The first symptoms of Friedreich ataxia (FRDA) usually include poor balance and coordination — a condition collectively known as ataxia — that typically can be detected around puberty.
However, the disease is characterized by broader features. Recognition of this variability is not only a key factor for clinical trials evaluating potential therapies for FRDA, the study noted, but are invaluable to practicing clinicians as well.
A group of researchers investigated the nonataxia symptoms in patients with genetically confirmed Friedreich’s ataxia, ages 6 to 76 (53.1% women) from the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) registry.
The EFACTS patient registry integrates clinical research data, coupled with biological specimens (e.g. blood, urine) from individuals with genetically confirmed disease and unrelated control research participants.
The researchers performed a prospective, observational analysis (NCT02069509) of patients’ medical history, as well of questionnaires and reports on their clinical features.
They gave special attention to symptom differences between typical-onset (age at onset less than 24 years) and late-onset (25 years or older) patients. Moreover, they tried to identify predictors for the most common clinical features of the patients analyzed. The study included 540 people with typical FRDA and 108 with late FRDA.
The most common non-neurologic clinical symptoms included abnormal eye movements (90.5%) and skeletal abnormalities — scoliosis (73.5%) or a twist and curve of the spine, and feet deformities (58.8%), mainly bilateral pes cavus, a deformity that causes the foot to have a very high arch and be relatively stiff.
“The 74% prevalence figure in our cohort is close to the average of the older studies, confirming that scoliosis is highly increased in FRDA compared to the normal population,” the researchers wrote.
Large numbers of these patients were also found to have urinary dysfunction (42.8%), heart muscle disease and an abnormal enlargement of the heart (40.3%), and lower-than-normal visual acuity (36.8%).
All of these symptoms were more prevalent in patients with typical-onset than those with late-onset disease. Less frequent symptoms included depression (14.1%) and diabetes (7.1%).
Major predictors for the presence of nonataxia features were earlier age at onset, more severe ataxia (measured using the Scale for the Assessment and Rating of Ataxia, SARA), and longer GAA repeats.
A segment of the FXN gene contains a DNA stretch called the GAA trinucleotide, which is repeated multiples times in a row. In Friedreich’s ataxia patients, the GAA segment is repeated from 66 to more than 1,000 times. The length of the trinucleotide repeat seems to correlate with disease progression, including heart defects.
This study “provides a comprehensive characterization of the FRDA phenotype, with distinct differences between typical- onset and late-onset patients, and identifies predictors for highly relevant clinical symptoms,” the researchers wrote.
“This knowledge is critical for clinical practice as well as for trial design, where the multisystem nature of FRDA challenges the use of merely one-dimensional outcome measures,” they concluded.