Discovering the Cause of a Rare Neurological Disease

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April 2024: After 25 years of research, scientists at the University of Utah have uncovered the genetic cause of Spinocerebellar Ataxia 4 (SCA4), a rare and progressive neurological disorder. This discovery gives affected people hope for future therapies.

Spinocerebellar Ataxia 4 (SCA4) is a rare, debilitating condition that disrupts movement. Symptoms often start with difficulty walking and balancing and progress over time. While most people experience symptoms in their forties or fifties, some can develop them as early as their late teens. Until now, there has been no known cause or cure.

Dr. Stefan Pulst and K. Pattie Figueroa at the University of Utah have identified the genetic mutation responsible for SCA4.  Their findings, published in Nature Genetics, mark a significant milestone in understanding the disease.

Unraveling the Genetic Mystery

Long assumed to be inherited, previous studies linked a particular chromosomal region to SCA4.

However, this region was challenging to analyze due to its repetitive and unique structure.

The researchers used advanced DNA sequencing technology to compare genetic samples from affected and unaffected individuals in several Utah families. They discovered that SCA4 patients have an unusually long segment in the ZFHX3 gene containing extra repetitive DNA.

Cells with this extended ZFHX3 gene show signs of malfunction—they struggle to recycle proteins properly, leading to harmful protein clumps. “This mutation disrupts how cells manage misfolded proteins, potentially harming nerve cells,” explains Dr. Pulst.

Looking Forward with Hope

Interestingly, a similar problem occurs in another type of ataxia, SCA2, which also affects protein recycling.  Researchers are testing a potential treatment for SCA2, raising the possibility it could help SCA4 patients as well.

Finding the genetic cause of SCA4 is crucial for developing better treatments. “Knowing the root cause allows us to target the mutation’s effects more effectively,” says Dr. Pulst.

While developing treatments may take time, knowing the cause is invaluable for affected families.  They can test for the mutation, aiding in important life decisions like family planning. “Testing provides clarity, even if the news isn’t always good,” says Figueroa.

The researchers emphasize the critical role of SCA4 patients and their families, whose shared records and samples were essential.  “Families shared not just their homes but their histories with us,” Figueroa notes, tracing the disease’s lineage in Utah back to a pioneer couple from the 1840s.

For Figueroa, this journey is deeply personal.  “Since 2010, when I first met these families, it’s become more than just research.  It’s about people’s lives,” she suggests.

This research involved collaboration with institutions like the University of Tübingen, University of Lübeck and Kiel University, University Hospital Hamburg-Eppendorf, and Veterans Administration Medical Center in Albany, NY.  It was funded by the National Institute of Neurological Disorders and Stroke (NIH) and the DFG-funded INST 37/1049-1.

We thank Science Daily for sharing this educational story with us. 

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