SACS gene

About 200 mutations in the SACS gene have been found to cause autosomal recessive spastic ataxia of Charlevoix-Saguenay, commonly called ARSACS. ARSACS is a condition affecting muscle movement that is characterized by abnormal tensing of the muscles (spasticity), problems with balance and coordination (cerebellar ataxia), and reduced sensation and weakness in the arms and legs (peripheral neuropathy).

Two SACS gene mutations have been found frequently in people with ARSACS from the Charlevoix-Saguenay region of Quebec, Canada. One of these mutations deletes a DNA building block (nucleotide) called thymine at position 6594 in the SACS gene (written as 6594delT). This mutation is found in more than 90 percent of people with ARSACS in Quebec. The other mutation replaces the nucleotide cytosine with the nucleotide thymine at position 5254 in the SACS gene (written as C5254T). Both of these mutations lead to production of a sacsin protein that is abnormally short and nonfunctional.

Mutations causing ARSACS in people outside of Quebec are varied and usually unique to that person or family. Most of these mutations either delete one or more nucleotides or replace one nucleotide with another nucleotide in the SACS gene. Mutations in the SACS gene result in the production of an unstable sacsin protein that does not function normally. It is unclear how the abnormal sacsin protein affects the brain and skeletal muscles but it likely impairs normal organization of intermediate filaments in cells, particularly neurofilaments, and disrupts neuron function. This decreased neuronal signaling may result in the signs and symptoms of ARSACS.