Cerebellar and non-cerebellar symptoms in hereditary ataxias

Joana Damásio
Neurologist

Cerebellar and non-cerebellar symptoms in hereditary ataxias

Hereditary cerebellar ataxias (HCA) are a group of neurological disorders characterized by imbalance and hindered coordination of voluntary movements. It may stem from pathology of the cerebellum, cerebellar pathways, or the proprioceptive input.

This work, conducted across five years, provided a comprehensive characterization of over 250 patients with HCA, and established a prospective cohort with ongoing annual evaluations. We identified over 50 genetic causes, some for the first time, reinforcing the high genetic diversity of HCA. The most common forms were due to repeat expansions (Machado Joseph disease in autosomal dominant (AD), Friedreich ataxia and ATX-RFC1 in autosomal recessive (AR)), still not easily detected by next generation sequencing techniques, emphasizing the need for diagnostic protocols that prioritize the study of expansions at first.

While cerebellar presentation was predominant, we identified some instances of non-cerebellar onset, particularly in AR-HCA. Our research contributed also to expanding the classical perspective of age at onset in HCA; despite AR-HCA typically manifesting at an early age, over a third had late onset; in AD-HCA, traditionally linked to late onset, approximately 40% presented with early onset. A pure cerebellar phenotype was rare, with additional neurological symptoms emerging as disease progressed. This reinforced the involvement of extra-cerebellar structures in HCA. The presence of additional symptoms associated with increased severity and disability.

We expect this cohort to help constituting homogenous groups for future clinical trials, and raise awareness on the diverse manifestations of all its forms, providing valuable insight for clinical practice of neurologists, paediatric neurologists, and geneticists.

Read the full version at: https://repositorio-aberto.up.pt/handle/10216/163200

Joana Damásio, a senior hospital assistant in Neurology at ULS de Santo António and manager of the Neurology outpatient clinic, is dedicated to movement disorders, particularly hereditary cerebellar ataxias. She is the president-elect of the Portuguese Society of Movement Disorders, a member of the scientific panel in neurogenetics of the European Academy of Neurology, as well as the Statutes Committee and the Editorial Board of the Movement Disorders Society website. She is part of the Genetic Epidemiology and Epigenetics research group at the Multidisciplinary Research Unit in Biomedicine of ICBAS-UP, where she collaborates on various research projects in cerebellar ataxias. She obtained her PhD in Medical Sciences at ICBAS-UP in October 2024 under the supervision of Professor Jorge Sequeiros and Professor José Barros.