Abstract
Introduction: This presentation introduces a cohort of patients with Friedreich's ataxia (FA) in the Czech Republic, longitudinally monitored according to an international harmonized protocol, in preparation for administering omaveloxolone (Skyclarys), the first drug for this disease. The drug was already approved in the USA, its EU approval is underway.
FA, the most common autosomal recessive hereditary ataxia, is caused by FXN gene mutations, leading to decreased frataxin levels and mitochondrial dysfunction, characterized by ataxia, posterior column injury, sensory disorders, scoliosis, cardiomyopathy, and other symptoms. Omaveloxolone, a new Nrf2 modulator class drug, slows FA progression.
We present original research on prospective FA biomarkers. Methodology: At the Center of Hereditary Ataxias in Motol University Hospital, the only Czech center focused on hereditary ataxias and registered in the European Reference Network for Rare Neurological Diseases (ERN-RND), we have been examining a cohort of genetically confirmed FA patients since 8/2021 using the European Consortium for Translational Studies on Friedreich's Ataxia (EFACTS) clinical protocol, with results entered into the EFACTS registry.
From 8/2021 to 8/2023, 42 patients were examined at T0, 40 at T1, and 23 at T2. Blood samples for genetic tests were taken at T0, and GAA expansion lengths were analyzed in 39 patients at the EFACTS laboratory in Milan.
NFL levels (Elisa method) were measured, a promising biomarker for neurodegenerative processes, along with mitochondrial enzyme functions (activities of respiratory chain complexes within the OXPHOS system in isolated thrombocytes - complex I NQR, complex II SQR, complex IV COX, spectrophotometry method) in 28 patients and 17 healthy controls. Results and Conclusions: Between August 2021 and 2023, we registered 42 patients (including 6 under 18 at T0; 1 deceased; 1 from Slovakia) in the EFACTS registry.
The average age of FA patients at T0 was 34 years (7-72; N=42), with a male-to-female ratio of 23/19 (N=42). One patient, a compound heterozygote with a point mutation and GAA expansion, exhibited a slightly different phenotype, while others had average GAA1/GAA2 lengths of 638/886 (90-1160/150-1330, N=39).
The average age of onset was 12.8 years (1-50 years), with instability and falls detected in 28 patients, scoliosis in 19, cardiomyopathy in 4, and other issues like tremor and fine motor skills in 3 at disease onset. The presentation includes video documentation of typical and atypical patients.
Data show NFL level differences between FA patients and healthy controls (t-stat=2.6, p=0.01), with higher levels in early disease stages, decreasing with FA progression measured by a seven-point severity index (R2=0.13, p=0.001) and disease duration (R2=0.17; p<0.001). An inverse correlation was observed between NFL levels and age at sampling between patients and controls - levels decrease with age in patients (R2=0.25, p<0.001) and increase in controls (R2=0.16; p<0.05).
Lower activities of complex I, II, and IV within the OXPHOS system were detected compared to healthy controls (NQR t-stat=-2.37, p<0.01; SQR t-stat=-5.06, p<0.001; COX t-stat=-4.8, p<0.001). Summary: As expected, we confirmed NFL and mitochondrial enzyme alterations in FA patients.
Plans include verifying enzyme activity changes after initiating innovative therapies. Until now, FA treatment has been only symptomatic, but targeted therapy onset necessitates increased attention to patients with progressive ataxia, as about 200 FA patients are estimated in the Czech Republic based on reported incidence and heterozygote frequency, indicating significant underdiagnosis.
With new treatment options, specialized center care access is crucial for long-term disease and complication management.