Spinocerebellar ataxia 4 (SCA4) is a progressive movement disease that can begin in the late teens, affecting a person’s ability to walk and balance. The disease is rare but has severe effects on patients and their families, with no known cure or cause until recently. A multinational research team, led by University of Utah researchers Stefan Pulst and K. Pattie Figueroa, has identified the genetic difference that causes SCA4 after 25 years of uncertainty, offering answers to families and potential future treatments. Their findings, published in the journal Nature Genetics, pinpoint a mutation in the ZFHX3 gene that leads to the disease.
By using advanced sequencing technology to compare DNA from affected and unaffected individuals from Utah families, the researchers discovered an extra-long sequence of repetitive DNA in the ZFHX3 gene of SCA4 patients. This mutation impairs the cell’s ability to recycle proteins, potentially causing nerve cells to become toxic and lead to the disease. The researchers also noted similarities with another form of ataxia, SCA2, which also affects protein recycling, suggesting that a potential therapy for SCA2 being tested in clinical trials could benefit SCA4 patients as well.
Identifying the genetic change that causes SCA4 is crucial for developing effective treatments, allowing researchers to target the effects of the mutation at multiple levels. While treatments will take time to develop, the knowledge of the disease’s cause can already provide valuable information for affected families. People in these families can now be tested for the disease-causing genetic change, helping them make informed decisions about family planning and their future. The researchers credit the generosity of SCA4 patients and their families for sharing family records and biological samples, which enabled them to compare DNA and trace the disease back through history in Utah.
The personal connection with families affected by SCA4 has made studying the disease a significant quest for the researchers involved. Figueroa, who has been working on SCA4 since 2010, emphasizes the importance of seeing these individuals beyond DNA vials and recognizing them as people who are directly impacted by the disease. The collaboration with other research institutions in Germany and the United States has been essential in conducting this groundbreaking study, which was supported by grants from the National Institutes of Health and the German Research Foundation. The hope is that this discovery will not only offer insights into SCA4 but also lead to improved treatments and outcomes for patients with this devastating disease.
