Researchers Find Source of Rare Movement Disorder

by Staff Writer
May 1, 2024 at 11:40 AM UTC

A research team identified the mutation responsible for Spinocerebellar ataxia 4 (SCA4), offering insights into treatment and genetic testing.

Clinical relevance: SCA4, a rare progressive neurological disease, presents with symptoms like trouble walking, and reduced touch sensation, and typically manifests in one’s 40s or 50s.

  • A research team led by Stefan Pulst at the University of Utah isolated the genetic difference causing SCA4, unveiling a toxic mutation in the ZFHX3 gene affecting protein recycling in nerve cells.
  • This discovery facilitates genetic testing for affected families, aiding in family planning decisions.
  • Similarities between SCA2 and SCA4 suggest a potential therapy, emphasizing the importance of understanding genetic causes to address inherited diseases effectively.

Spinocerebellar ataxia 4 (SCA4), a rare progressive neurological disease remains a rare movement disorder, but its repercussions can be devasting.

Typically, early warning signs include trouble walking and balancing, a reduced sense of touch, and vibration detection. Symptoms generally emerge in one’s 40s or 50s. But they can also crop up as soon as a patient’s early teens.

Now, after more than two decades of questions, an international team of researchers might have found an answer. The group, led by Stefan Pulst, M.D., professor and chair of neurology, and K. Pattie Figueroa, a project manager in neurology, at the Spencer Fox Eccles School of Medicine at the University of Utah, has isolated the genetic difference that causes SCA4.

The peer-reviewed journal Nature Genetics published the research in its latest publication.

Solving a Genetic Puzzle

Scientists have long suspected that the movement disorder’s origins lie in the patient’s DNA. And earlier research traced it back to a specific region of one chromosome. But investigators struggled because of what appeared to be duplicate sections and “an unusual chemical makeup that makes most genetic tests fail.”

To identify the SCA4 catalyst, the research team relied on a new advanced sequencing technology. With that, they compared DNA from affected and unaffected people from several Utah families. Subsequently, they found that in SCA4 patients, a part of the ZFHX3 gene appeared to be longer than it should be. They also noticed that it included an elongated string of repetitive DNA.

The researchers found that isolated human cells with that protracted ZFHX3 “show signs of being sick – they don’t seem able to recycle proteins as well as they should, and some of them contain clumps of stuck-together protein.”

“This mutation is a toxic expanded repeat, and we think that it actually jams up how a cell deals with unfolded or misfolded proteins,” Pulst said.

Working with SCA4 patients’ cells, the team demonstrated that “the SCA4-causing mutation gums up the works of cells’ protein-recycling machinery in a way that could poison nerve cells.”

This discovery can help families find out whether they possess the disease-causing genetic change, which can help with family planning.

“They can come and get tested and they can have an answer, for better or for worse,” Figueroa pointed out.

Histories Offer Hope

The study also revealed a similar interaction – a disruption in protein reclamation –  in SCA2 patients. As such, the researchers are looking at a potential SCA2 therapy for clinical trials, since the similarities between the two disorders sparked hope that it could help SCA4 patients, too.

“The only step to really improve the life of patients with inherited disease is to find out what the primary cause is,” Pulst explained. “We now can attack the effects of this mutation potentially at multiple levels.”

The researchers added that their success hinged on the generosity of SCA4 patients and their families. They shared family histories and biological samples so the researchers could compare the various DNAs.

The team even traced its regional origin back “to a pioneer couple who moved to Salt Lake Valley in the 1840s.”

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