Understanding the Pathophysiology of Spinocerebellar Ataxias through genetics, neurophysiology, structural and functional neuroimaging

Pramod Kumar Pal

Abstract


Over the past 10 years a large cohort of 656 index patients with clinically suspected degenerative ataxias were clinically evaluated under various research projects. Of these, 625 index patients underwent genetic tests for the clinically suspected most probable diagnosis. A diagnosis could be achieved in 218 patients (34.9%). Among these 218 index patients, 82 each were SCA1 and SCA2, 32 were SCA3, 4 were SCA12, and 18 were Friedreich's Ataxia. Thus among the Autosomal Dominant Ataxias (SCAs) there was equal prevalence of SCA1 and SCA2 (41% each) followed by SCA3 (16%) and SCA12 (2%). This high prevalence of SCA1 is in contrast to the available National and International literature. The rate of clinical disease progression, especially in SCA2, was dependent on the CAG repeat size, and may commence linearly from birth.

Apart from cerebellar involvement, a comprehensive evaluation of the neuroaxis in various subsets of this genetically proved cohort showedsubclinicalinvolvement of the cerebral cortex, central motor and sensory pathways, peripheral nervous system and autonomic nervous system. Important findings include: (a)Amixedsensorimotor and pure sensory neuropathy was seen in all the three subtypes of SCAs, while pure motor neuropathy was uncommon; (b) There was reduced cortical excitability and prolonged central motor conduction time, most evident in SCA1 and least in SCA2; (c) Cardiac autonomic dysfunction, predominantly parasympathetic, was seen in SCA, and the severity correlated with the duration of illness in SCA1; (d) In SCA1 there was a global impairment of balance, with greater instability in anterior–posterior than medio–lateral directions; (e) In all the three SCAs there was a significant loss of gray matter in both cerebellar hemispheres and vermis. Vermian atrophy was more pronounced in SCA3, while SCA1 and SCA2 had significant white matter atrophy. Pontine white matter atrophy was more pronounced in SCA2; (f) Cerebellar activity was largely absent with additional activity in contralateral cortices and in thalami in patients with SCA1; increased thalamic function could be one of the causes for disinhibition of the motor cortex contributing to uncoordinated movements.

Studies on larger cohort of each subtype of SCAs to validate the above findings, follow-up studies to determine the rate and nature of progression of neurodegeneration and evaluation of pre-symptomatic genetically confirmed SCAs will help understand the pathophysiology of the SCAs.


Keywords


SCAs, spinocerebellar ataxias, genetics of ataxias

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References


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