Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia

Cells. 2022 Mar 12;11(6):981. doi: 10.3390/cells11060981.


Hereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal recessive (AR) inheritance, to identify the causal genes. A phenotypic classification was performed, considering the main clinical syndromes: spastic ataxia, ataxia and neuropathy, ataxia and oculomotor apraxia (AOA), ataxia and dystonia, and ataxia with cognitive impairment. The most frequent causal genes were associated with spastic ataxia (SACS and KIF1C) and with ataxia and neuropathy or AOA (PNKP). We also identified three families with autosomal dominant (AD) forms arising from de novo variants in KIF1A, CACNA1A, or ATP1A3, reinforcing the importance of differential diagnosis (AR vs. AD forms) in families with only one affected member. Moreover, 10 novel causal-variants were identified, and the detrimental effect of two splice-site variants confirmed through functional assays. Finally, by reviewing the molecular mechanisms, we speculated that regulation of cytoskeleton function might be impaired in spastic ataxia, whereas DNA repair is clearly associated with AOA. In conclusion, our study provided a genetic diagnosis for HCA families and proposed common molecular pathways underlying cerebellar neurodegeneration.

Keywords: cerebellar ataxia; de novo variant; exome sequencing; molecular mechanisms; recessive ataxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cerebellar Ataxia* / genetics
  • DNA Repair Enzymes / genetics
  • Humans
  • Intellectual Disability
  • Kinesins
  • Muscle Spasticity
  • Optic Atrophy*
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Portugal
  • Sodium-Potassium-Exchanging ATPase
  • Spinocerebellar Ataxias* / genetics
  • Spinocerebellar Degenerations* / genetics


  • ATP1A3 protein, human
  • KIF1A protein, human
  • PNKP protein, human
  • Phosphotransferases (Alcohol Group Acceptor)
  • Kinesins
  • DNA Repair Enzymes
  • Sodium-Potassium-Exchanging ATPase

Supplementary concepts

  • Spastic Ataxia