Neurological Manifestations and Genetic Characterization in Autosomal Recessive Spastic Ataxia

Autosomal recessive spastic ataxia encompasses a spectrum of early-onset neurodegenerative disorders most notably exemplified by ARSACS, in which biallelic mutations in the SACS gene lead to loss or dysfunction of sacsin. Clinically, patients present with cerebellar ataxia, pyramidal tract signs such as lower limb spasticity and extensor plantar responses, and variable peripheral neuropathy. Ocular findings include retinal nerve hypermyelination and optic atrophy. Magnetic resonance imaging typically reveals pontine linear hypointensities and thickening of the middle cerebellar peduncles, often accompanied by cerebellar and cerebral atrophy. At the cellular level, degeneration of cerebellar Purkinje cells is a hallmark, linked to disrupted calcium homeostasis, cytoskeletal disorganisation and mitochondrial dysfunction. Recent genetic surveys have uncovered over 200 distinct pathogenic SACS variants worldwide, extending the original founder effect in Quebec to diverse populations. Sacsin, a large multi-domain chaperone-like protein, is implicated in protein quality control, intermediate filament organisation and autophagic processes. Mounting evidence points to impaired autophagic flux, aberrant organellar trafficking and secondary neuroinflammation as convergent mechanisms driving neuronal loss. Efforts to translate these insights into therapeutic strategies include repurposing of neuroprotective agents and development of minimally invasive diagnostic assays to validate variants of uncertain significance.

Research from Nature Portfolio

Recent transcriptomic profiling in a sacsin knockout cellular model has defined a defective autophagy signature as central to pathogenesis. Loss of sacsin led to accumulation of autophagic substrates, diminished LC3-mediated autophagosome formation and impaired fusion with lysosomes, resulting in failed clearance of damaged mitochondria. Pharmacological up-regulation of autophagy restored autophagic flux in vitro, suggesting that targeted modulation of autophagy could ameliorate neurodegenerative processes in patients with recessive spastic ataxia.

Neurological Manifestations and Genetic Characterization in Autosomal Recessive Spastic Ataxia publication trend

The graph below shows the total number of articles in neurological manifestations and genetic characterization in autosomal recessive spastic ataxia across all publications each year (not limited to Nature Index journals).

Technical terms

Ataxia: Impaired coordination of voluntary movements due to cerebellar dysfunction.

Spasticity: Increased muscle tone and exaggerated tendon reflexes from upper motor neuron lesions.

Sacsin: A large, multi-domain protein encoded by SACS, involved in chaperone activities and proteostasis.

Purkinje cell: A type of large inhibitory neuron in the cerebellar cortex critical for motor coordination.

Autophagy: A cellular degradation pathway that removes damaged organelles and protein aggregates via lysosomal fusion.

References

1. Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum. Orphanet Journal of Rare Diseases (2013).
2. Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay: A Report of MR Imaging in 5 Patients. American Journal of Neuroradiology (2007).
3. Altered organization of the intermediate filament cytoskeleton and relocalization of proteostasis modulators in cells lacking the ataxia protein sacsin. Human Molecular Genetics (2017).
4. A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay. Human Molecular Genetics (2016).
5. Functional Transcriptome Analysis in ARSACS KO Cell Model Reveals a Role of Sacsin in Autophagy. Scientific Reports (2019).
6. Restoring calcium homeostasis in Purkinje cells arrests neurodegeneration and neuroinflammation in the ARSACS mouse model. JCI Insight (2023).
7. Compound Heterozygous Mutations of SACS in a Korean Cohort Study of Charcot-Marie-Tooth Disease Concurrent Cerebellar Ataxia and Spasticity. International Journal of Molecular Sciences (2024).
8. Reduction of sacsin levels in peripheral blood mononuclear cells as a diagnostic tool for spastic ataxia of Charlevoix–Saguenay. Brain Communications (2024).
9. Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration. International Journal of Molecular Sciences (2022).
10. Efficient Neuroprotective Rescue of Sacsin-Related Disease Phenotypes in Zebrafish. International Journal of Molecular Sciences (2021).