Discovery of a Novel Ultra-Rare Hereditary Ataxia Syndrome Caused by Changes in the POU4F1 Gene

Researchers are continuing to discover new genetic causes of hereditary ataxia, conditions that affect balance and coordination, many of which are extremely rare. One such discovery involves the POU4F1 gene. 

In 2021, Dr. Bryn Webb, Associate Professor at the University of Wisconsin School of Medicine and Public Health, and her colleagues used whole-exome sequencing (a form of advanced genetic testing) to study individuals with unexplained neurological symptoms. They identified POU4F1 gene changes in four unrelated people, all of whom shared strikingly similar clinical features (Webb et al., 2021).  

Using whole-exome sequencing, Dr. Bryn Webb, Associate Professor at the University of Wisconsin School of Medicine and Public Health, and colleagues identified heterozygous (single-copy) loss-of-function variants in the POU4F1 gene in four unrelated individuals presenting with similar neurological symptoms in 2021. So far, these are the only known reported cases worldwide. Dr. Webb’s team, working closely with the newly formed POU4F1 Patient Foundation, is now connecting with more families and learning from their experiences. 

The POU4F1 gene provides instructions for making a protein called a transcription factor. This protein helps control the activity of other genes during brain development, especially in regions responsible for balance and coordination.  

When there are changes (mutations) in this gene, it can lead to symptoms such as: 

• Problems with balance and coordination (ataxia)  
  
• Shaking of the hands when reaching for objects (intention tremor)  
• Low muscle tone (hypotonia)  
• Occasional brief episodes of the eyes rolling upwards (paroxysmal tonic upgaze) 

In addition, brain scans show that persons with this disorder may have a smaller cerebellum than typical. The cerebellum is the part of the brain that helps controls balance and movement. Some also experience developmental delays, meaning milestones like walking, talking, or speaking may occur later than typical.