Spinocerebellar Ataxia Type 2: Clinicogenetic Aspects, Mechanistic Insights, and Management Approaches

Abstract

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia that occurs as a consequence of abnormal CAG expansions in the ATXN2 gene. Progressive clinical features result from the neurodegeneration of cerebellum and extra-cerebellar structures including the pons, the basal ganglia, and the cerebral cortex. Clinical, electrophysiological, and imaging approaches have been used to characterize the natural history of the disease, allowing its classification into four distinct stages, with special emphasis on the prodromal stage, which is characterized by a plethora of motor and non-motor features. Neuropathological investigations of brain tissue from SCA2 patients reveal a widespread involvement of multiple brain systems, mainly cerebellar and brainstem systems. Recent findings linking ataxin-2 intermediate expansions to other neurodegenerative diseases such as amyotrophic lateral sclerosis have provided insights into the ataxin-2-related toxicity mechanism in neurodegenerative diseases and have raised new ethical challenges to molecular predictive diagnosis of SCA2. No effective neuroprotective therapies are currently available for SCA2 patients, but some therapeutic options such as neurorehabilitation and some emerging neuroprotective drugs have shown palliative benefits.

Neurorehabilitation therapy in spinocerebellar ataxia type 2: A 24‐week, rater‐blinded, randomized, controlled trial

“…SCA2 is characterized by a progressive cerebellar syndrome accompanied by severe saccadic slowing, peripheral neuropathy, autonomic disturbances, pyramidal signs, cognitive disorders, and sleep disturbances . Similar to other SCAs caused by the polyglutamine domain, the onset of SCA2 cerebellar syndrome is significantly controlled by the mutation size and is preceded by prodromal manifestations up to more than a decade before disease onset …”

Diagnosis of Spinocerebellar Ataxia in the West Indies

“…To our knowledge, ours is only the second report of SCA3 in this region, the first being by Gwinn-Hardy et al,11 who described genetic diagnosis of SCA3 in a family residing in the UK and USA following immigration from Antigua. Apart from a cluster of families with SCA2 documented in the Holguin province of Cuba12–14 and a cluster of families on Martinique,15,16 there have not been any other reports of any of the SCAs in the Caribbean region.…”

Neuroinflammation and Neuromodulation in Neurological Diseases

“…This phase is followed by the prodromal or preclinical stage, characterized by unspecific neurological features such as painful muscle cramps, sensory abnormalities, subtle cerebellar manifestation (increase of the sway during tandem gait), cognitive decline, autonomic disorders, olfactory dysfunction and hyperreflexia. Electrophysiological studies showed the reduction of the maximal saccadic velocity, REM sleep disorders, increased central motor conduction time in transcranial magnetic stimulation and peripheral sensory axonal damage according of the peripheral nerve conduction studies [3,24]. …”

“…This stage also allows identification of the best moment to initiate therapies, and identification of sensitive outcome measures [24]. …”