In some families, Spinocerebellar Ataxia 4 (SCA4) is seen as a test of faith, while for others, it is viewed as a curse. This progressive neurological condition is scarcescarce but exerts severe effects on patients and their families. Typically, the initial symptoms manifest as difficulties with walking and balance, worsening progressively. Onset usually occurs in one’s forties or fifties, though it can begin as early as the late teens. Currently, there is no known cure, and until recently, its underlying cause remained elusive.
After 25 years of uncertainty, a multinational research effort led by Stefan Pulst, M.D., and K. Pattie Figueroa from the University of Utah’s Spencer Fox Eccles School of Medicine has finally identified the genetic mutation responsible for SCA4. Published in Nature Genetics, their findings provide much-needed answers to affected families and pave the way for potential future treatments. The inheritance pattern of SCA4 strongly suggested a genetic origin, with previous studies pinpointing the responsible gene to a specific region on a chromosome. However, this region posed significant challenges for analysis due to its complex structure, which was filled with repetitive DNA segments that resemble portions of other chromosomes and possessed an unusual chemical composition that thwarted conventional genetic testing methods.
Pulst, Figueroa, and their team used cutting-edge sequencing technology to compare DNA samples from affected individuals within several Utah families to unaffected counterparts. They discovered that SCA4 patients exhibit an abnormally elongated segment within a gene called ZFHX3, containing an extended repeat of repetitive DNA. In laboratory tests using isolated human cells carrying this extended version of ZFHX3, researchers observed impaired protein recycling mechanisms and the accumulation of protein aggregates, indicating cellular dysfunction. Interestingly, similarities in protein recycling dysfunction have been observed in another type of ataxia, SCA2. Current clinical trials testing therapies for SCA2 suggest that treatments targeting this pathway may also benefit SCA4 patients.
Understanding the genetic basis of SCA4 is crucial for developing more effective treatments, notes Pulst, emphasizing that targeting the underlying cause offers the best chance to improve patients’ lives. While the journey towards viable treatments may be lengthy, simply identifying the genetic basis of SCA4 holds immense value for affected families. Figueroa underscores this point, highlighting that genetic testing can now provide definitive answers to families considering their future, including decisions related to family planning. The researchers express deep gratitude to the SCA4 patients and their families whose contributions of biological samples and family histories were essential for this breakthrough.
Through their generosity, researchers traced the disease’s origins in Utah to a pioneer couple who settled in Salt Lake Valley in the 1840s. Figueroa reflects on the personal impact of studying SCA4 since 2010, recalling how interactions with affected families transformed her perspective. “These are not just research subjects; they are individuals whose lives are profoundly affected. This work is more than science; it’s about understanding and supporting real people,” she affirms. In summary, identifying the genetic mutation causing SCA4 represents a significant step forward in scientific understanding and potential treatment development.
By unravelling this genetic mystery, researchers have brought hope to affected families and underscored the importance of community collaboration in advancing medical research and support.
More information: Karla P. Figueroa et al, A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy, Nature Genetics. DOI: 10.1038/s41588-024-01719-5
Journal information: Nature Genetics Provided by University of Utah Health
