The Genetic Cause of Spinocerebellar Ataxia 4: A Breakthrough in Diagnosis and Treatment

Thursday - May 2 2024, 00:17 UTC - 6 months ago

After 25 years of uncertainty, researchers at the University of Utah have identified the genetic cause of Spinocerebellar Ataxia 4 (SCA4), a rare and debilitating neurological disorder. The discovery offers hope for potential treatments and improved quality of life for affected families. SCA4 causes difficulty with walking and balancing and typically presents in a person's forties or fifties. The cause was found to be a toxic expanded repeat mutation in the gene ZFHX3, which interferes with the cell's ability to break down non-functional proteins. This discovery also opens the possibility for a potential treatment for another form of ataxia, SCA2.

Families affected by Spinocerebellar Ataxia 4 (SCA4) have often been left with more questions than answers. With no known cure and little understanding of its cause, SCA4 has remained a mystery for the past 25 years. But now, a multinational study led by researchers at the University of Utah has finally uncovered the genetic difference that causes this rare and debilitating neurological disorder. The findings, published in the peer-reviewed journal Nature Genetics, bring hope to families and potential for future treatments.

SCA4 usually first presents as difficulty walking and balancing, progressively getting worse over time. It most commonly affects people in their forties or fifties, but can start as early as the late teens. The impact on patients and their loved ones is profound, with some families viewing it as a test of faith and others as a curse. The lack of a cure has only added to the frustration and sense of hopelessness for those living with SCA4.

The genetic cause of SCA4 has long been known due to its inherited pattern, with previous research pinpointing the responsible gene to a specific region of one chromosome. However, this region has proven to be incredibly challenging to analyze. With repeated segments that resemble parts of other chromosomes and an unusual chemical makeup, most genetic tests have failed to provide a definitive answer.

But now, through the use of advanced sequencing technology, researchers led by Dr. Stefan Pulst and Pattie Figueroa at the University of Utah have overcome this hurdle. By comparing DNA from affected and unaffected individuals from several families, they discovered that in SCA4 patients, a section in the gene ZFHX3 is significantly longer than it should be, containing an extra-long string of repetitive DNA.

Further research showed that isolated human cells with this extra-long version of ZFHX3 exhibited signs of sickness, with a compromised ability to recycle proteins and the presence of clumps of stuck-together protein. According to Dr. Pulst, this mutation is a toxic expanded repeat that interferes with the cell's ability to break down non-functional proteins. This interference could potentially damage nerve cells and explain the symptoms of SCA4.

Interestingly, a similar process appears to be happening in another form of ataxia, SCA2, which also affects protein recycling. This has prompted the researchers to consider the possibility of using a potential therapy currently being tested for SCA2 to also benefit patients with SCA4.

The discovery of the genetic cause of SCA4 is a significant step in developing better treatments for this debilitating disorder. According to Dr. Pulst, understanding the primary cause of inherited diseases is crucial in order to improve the lives of patients. With this knowledge, researchers can now explore multiple approaches to targeting the effects of this mutation and potentially improving the quality of life for those living with SCA4.

But while treatments may still be a long way off, the breakthrough in identifying the genetic cause of SCA4 brings a new sense of hope and potential for future advancements in diagnosis and treatment.