Channelopathy-related SCN10A gene variants predict cerebellar dysfunction in multiple sclerosis

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Multiple sclerosis (MS) is a chronic neurological disease affecting motor function.
• The sodium channel NaV1.8, encoded by SCN10A, plays a role in neuronal excitability.
• Functional variants in SCN10A may influence MS pathophysiology and clinical presentation.

Purpose of the Study:

• To investigate the in vivo motor-behavioral and neural correlates of SCN10A gene variants in patients with MS.
• To determine if specific SCN10A polymorphisms are associated with functional status and brain imaging findings in MS.

Main Methods:

• Recruited 161 MS patients and 94 healthy controls.
• Assessed clinical status using Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC).
• Performed structural MRI, voxel-wise analysis, cerebellar volumetry, and resting-state fMRI to evaluate brain structure and function. Genotyped participants for SCN10A polymorphisms.

Main Results:

• Two SCN10A polymorphisms (rs6795970 and rs6801957) were significantly associated with MSFC performance in MS patients.
• The rs6795970(AA) genotype correlated with worse MSFC scores, independent of EDSS and cerebellar atrophy.
• MS patients with the rs6795970(AA) genotype showed reduced cerebellar functional connectivity with the thalami and midbrain.

Conclusions:

• SCN10A gene variation significantly affects functional status and motor coordination in MS patients.
• The observed effects on cerebello-thalamic circuitry support the role of SCN10A in motor control.
• NaV1.8 may represent a potential therapeutic target for managing cerebellar dysfunction in MS.