The Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a very rare neurodegenerative genetic disease, largely prevalent in Canada, but present worldwide. There are about fifty cases of the disease in Italy, but this is likely an underestimation.

A mutation in the gene encoding Sacsin, a protein involved in the regulation of cytoskeleton that abounds in cerebellar Purkinje cells, causes the disease. ARSACS manifests with variable symptoms and age of onset, which makes it difficult to predict disease evolution, further complicated by the lack of specific longitudinal biomarkers.

It is necessary to identify pathological hallmarks that characterize ARSACS temporal progression to monitor the efficacy of future clinical treatments that could be thus tailored to the different disease stages and guarantee patients’ wellbeing.

The study

The group coordinated by Doctor Francesca Maltecca, head of the Mitochondrial dysfunctions in neurodegeneration Unit at IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, has recently published a study in Annals of Neurology describing ARSACS progression in a murine model of the disease.

The authors have used Optical Coherence Tomography to evaluate morphological changes in the retinal tissue and Brain Magnetic Resonance to monitor brain alterations in the ARSACS Sacs^-/- mouse model. Visual Evoked Potentials (VEP) as well as photopic Electroretinograms were recorded to evaluate retinal function, while the Beam Walking Test was used to evaluate spastic ataxia in the mouse model.

The researchers have observed that retinal nerve fiber layer thickening, which is peculiar in ARSACS patients and is currently used for differential diagnosis, seems to be an early sign of disease progression in the tested preclinical model.

By contrast, alterations of the corpus callosum, together with slight increases in the VEP N1 latency, phNR and b-wave amplitudes, were detected in later disease stages, implying mild myelin pathology and altered retinal responses to light. These characteristics were accompanied by a general and progressive worsening of the motor response measured over time.

“So far, there haven’t been longitudinal studies in patients based on the use of non-invasive techniques, thus these disease hallmarks that we have identified in the ARSACS preclinical model give important insights to inform the clinics. They represent a starting point to follow ARSACS temporal evolution and evaluate treatment efficacy on the basis of its clinical progression”, says Doctor Maltecca.

IRCCS San Raffaele Hospital, together with the IRCCS Stella Maris in Pisa, is currently leading a study on the natural history of the disease in ARSACS patients, funded by the National Health Ministry, to track more closely disease progression for future clinical studies.