Spinocerebellar ataxia 4 is a severe progressive movement disorder that can start in the late teens. A multinational research team, led by University of Utah researchers, has finally pinpointed the genetic variation responsible for the disease. This discovery provides much-needed answers for affected families and paves the way for future treatments.
Future treatments.
Many families see spinocerebellar ataxia 4 (SCA4) as a challenging trial. This rare progressive neurological disease has severe effects on patients and their families. The first sign for most people is difficulty walking and balancing, which worsens over time. Symptoms usually begin in a person’s forties or fifties, but can start as early as the late teens. There is currently no cure and, until recently, the cause was unknown.
After 25 years of uncertainty, a multinational study led by Dr. Stefan Pulst has provided new insights into this condition.
d., professor and chair of neurology, and K. Pattie Figueroa, a project manager in neurology at the Spencer Fox Eccles School of Medicine at University of Utah, have successfully identified the genetic difference that causes SCA4. This discovery provides answers to families affected by the disease and paves the way for potential future treatments. The findings have been published in the peer-reviewed journal Nature Genetics.
Unraveling a genetic mystery
The inheritance pattern of SCA4 has long indicated that the disease is genetic, and previous research had pinpointed the responsible gene to a specific region of one chromosome. However, that region turned out to be more complex than anticipated.It is extremely challenging for scientists to examine due to its abundance of repeated segments resembling parts of other chromosomes, and its unusual chemical composition that causes most genetic tests to fail.
To identify the mutation responsible for SCA4, Figueroa and Pulst, along with their research team, utilized a recently developed advanced sequencing technology. By comparing DNA from affected and unaffected individuals from multiple Utah families, they discovered that SCA4 patients have a abnormally long section in a gene known as ZFHX3, which contains an excessively long string of repetitive DNA.
Human cells with the additional long portion are isolated.The extended version of ZFHX3 indicates that there are indications of illness in the cells, as they appear to have trouble recycling proteins effectively and some of them have clusters of protein stuck together.
“This mutation is a harmful expanded repeat and we believe that it disrupts the process by which a cell manages unfolded or misfolded proteins,” explains Pulst, the senior author of the study. Healthy cells constantly break down dysfunctional proteins. By using cells from SCA4 patients, the team demonstrated that the mutation responsible for SCA4 impedes the functioning of the cells’ protein recycling mechanism in a way that could harm nerve cells.”</p rnrn
Hope for the future
Interestingly, a similar trend appears to be occurring with another type of ataxia, SCA2, which also disrupts the process of protein recycling. Researchers are currently in the process of testing a potential treatment for SCA2 in clinical trials. The similarities between the two conditions suggest that the treatment may also be beneficial for patients with SCA4.
Identifying the genetic mutation that causes SCA4 is crucial for developing improved treatments, according to Pulst. “The key to truly enhancing the lives of patients with inherited diseases is to determine the root cause. We can now target the e..
The potential effects of this mutation could occur at various levels.”
However, although it will take a long time to develop treatments, simply knowing the cause of the disease can be extremely valuable for families impacted by SCA4, according to Figueroa, the study’s first author. Individuals in affected families can determine whether they carry the disease-causing genetic mutation, which can help guide life decisions such as family planning. “They can undergo testing and receive an answer, whether it’s positive or negative,” Figueroa explains.
The researchers stress that their findings would not have been possible without the generosity of SCA4 patients.The researchers were able to compare the DNA of affected and unaffected individuals thanks to the families who shared their family records and biological samples. Figueroa expressed gratitude for the families who not only opened up their homes but also their history to the researchers. The family records were detailed enough for the researchers to trace the origins of the disease in Utah back through history to a pioneer couple who settled in Salt Lake Valley in the 1840s.
Figueroa stated that studying SCA4 has become a personal quest after meeting so many families affected by the disease. Since 2010, Figueroa has been working on SCA4 directly, starting when the first family approached him.When you visit their homes and get to know them, they become more than just a sample in a vial. These are individuals you interact with every day… You can’t just detach yourself. This is more than just scientific research. This is someone’s life.”
This research was conducted in partnership with scholars from the University of Tübingen, University of Lübeck, Kiel University, University Hospital Hamburg-Eppendorf, and Veterans Administration Medical Center in Albany, NY.
The study was funded by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under grant number R35127253 and the DFG-funded INST 37/1049-1.
