Identification of GGC Expansion as a Basis for SCA4 Movement Disorder

Spinocerebellar ataxia type 4 (SCA4) is a rare movement disorder whose symptoms begin in adolescence or adulthood, usually with difficulty walking and balancing. Affected individuals may go on to experience muscle weakness, lose sensation in their hands and feet, and lose their reflexes. The condition is inherited, but until recently, its specific genetic cause was unknown, because the mutation associated with SCA4 falls within a region of DNA that is particularly difficult to analyze. With the latest DNA sequencing technology, U of U Health scientists led by neurologist Stefan Pulst, MD, were finally able to pinpoint the genetic cause of SCA4: a stretch of repetitive DNA in a gene called ZFHX3 that is longer than it should be. Knowing the genetic cause of SCA4 provides relief for patients and their families, who can now be tested for the mutation. The discovery has also enabled Pulst and his team to dig into why expansion of the ZFHX3 gene harms neurons, which they hope will open a path toward an effective treatment. The team's experiments suggest the abnormal ZFHX3 protein encoded by the mutated gene interferes with neurons' ability to recycle unwanted proteins and other cellular debris. A drug designed to overcome defects in this type of cellular recycling is already being tested in clinical trials for another movement disorder, SCA2. Given the similarities they have uncovered, the researchers say it's possible that treatment might benefit patients with SCA4, too.