Cause of acute liver failure in young children discovered

According to the European Union, a disease such as acute liver failure is classified as rare if it affects less than five in 10,000 people. Yet despite low patient numbers, research into rare diseases has been on the rise in recent years. The reason for this is that many of these illnesses have a genetic cause that researchers can pinpoint. The findings could also provide important insights into metabolic processes in healthy people or serve as a model for other diseases.

Using sequence analyses to identify genetic defects

Professor Georg Hoffmann at the pediatric hospital in Heidelberg has spent 20 years caring for several patients who have suffered from recurrent acute liver failure since childhood. The similarities in the progression of the disease led him to suspect that there might be a common cause. Dr. Tobias Haack and Dr. Holger Prokisch at the Institute for Human Genetics at TUM and the Helmholtz Zentrum Munich have been examining four children suffering from recurrent, fever-dependent liver failure in a bid to identify a genetic cause. "In our study, we initially focused on the genetic similarities in these children to determine a possible cause for their disease," explains Haack.

The researchers used exome sequencing to do this, a process that involves sequencing all subsets of a patient's DNA that contain information on creating protein. They also examined the DNA of close family members. In multiple instances, they discovered mutations in one specific gene. "We identified mutations in the NBAS gene in a total of 11 patients. This is the first time that we have been able to establish a link between this gene and liver disease. This discovery could also be interesting for other illnesses," summarizes Prokisch.

Mutations disrupt transport processes

However, the researchers were keen to find out exactly how these mutations affect cellular processes. To do this, they carried out a number of molecular biology experiments. These revealed that when the mutations were present in the NBAS gene, only small amounts of the NBAS protein were created. NBAS is involved in cell transport processes that pack proteins in vesicles and transport them from one cell compartment to another. "We were able to show that the faulty protein is more susceptible to heat. This means that when an individual has a fever, there are fewer proteins available for coordinating the transport processes. This, in turn, can have a negative impact on metabolic processes in the liver in an acute situation," elaborates Prokisch.

The researchers' primary aim is to improve the diagnosis of rare diseases such as acute liver failure in childhood and pave the way for targeted treatment. Haack believes that the results give them an important starting point: "When a child suffers from liver failure triggered by fever, we can now specifically investigate the NBAS gene."

"Diagnosis already triggers a specific therapeutic path," adds Hoffmann. "Over the years, we have been able to empirically develop a therapy that uses specific drugs as well as sugar and fat infusions. These can be immediately administered once a patient is diagnosed. We can now use the latest findings to further improve our therapeutic approach."