A team of scientists led by Duke-NUS Medical School has solved a mystery behind a rare and previously undiagnosed disease that affects multiple organs, shedding new light on its cause—and offering fresh hope for treatment.

Published in the Journal of Clinical Investigation, the study pinpointed mutations in a gene called SPNS1 as the underlying cause of the disorder, which impacts how cells recycle fat molecules.

The researchers found that faulty versions of this gene disrupt the function of lysosomes (the body’s cellular recycling system), leading to a harmful build-up of fat and cholesterol, and eventually, progressive liver and muscle damage.

The new condition is part of the lysosomal storage diseases family, a group of more than 70 rare disorders caused by a breakdown in cellular recycling.

The discovery came from studying two unrelated families whose children showed unexplained liver disease, muscle weakness and other symptoms. Genetic analysis revealed mutations in both copies of SPNS1, a transporter crucial for moving fat molecules that have been broken down out of the lysosome and into the rest of the cell to be recycled.

The research builds on a previous Duke-NUS-led study that pinpointed SPNS1’s role in recycling broken-down fats.

Duke-NUS MD-Ph.D. student Ms. He Menglan, the study’s first author, said that the findings are a crucial puzzle piece to understanding a disease that remained a mystery for a long time:

“An important type of fat that our cellular recycling systems process is phospholipids, which are key building blocks of cell membranes. In healthy individuals, SPNS1 moves broken-down phospholipids out of lysosomes to be reused to repair membranes or converted into stored energy for the body.

“When this intricate process fails in patients with SPNS1 mutations, fat recycling is disrupted, leading to tissue damage, particularly in the muscles and liver.”

The researchers discovered that these issues became worse when a key nutrient-sensing system was disrupted, highlighting the importance of SPNS1 in helping cells respond to nutrient stress and maintain energy balance.

Professor David Silver, Deputy Director of Duke-NUS’ Cardiovascular and Metabolic Disorders Program and senior author of the study, said, “SPNS1 is found in every human cell and plays a key role in recycling phospholipids. Our studies revealed that phospholipid recycling by lysosomes plays a crucial role in regulating how cells maintain normal levels of other important lipids such as fat and cholesterol. These findings open up opportunities to explore the importance of SPNS1 in other diseases such as cancer.”

Equipped with these insights, the team is partnering with N = 1 Collaborative, an organization developing personalized therapies for extremely rare diseases, to translate their findings into bedside solutions.

Dr. Marlen Lauffer, a senior researcher at the Dutch Center for RNA Therapeutics, Leiden University Medical Center and a co-author of the study, highlighted the importance of applying these findings in patient care. “Using what we learned from this research, we are working with the N = 1 Collaborative to create a tailored treatment for the children in our study affected by this condition. This work includes exploring ways to correct the faulty fat transport using new genetic therapies.

“Our goal is to transform scientific knowledge into therapies that improve the quality of life and give hope to other families facing similar challenges.”

Dr. Lauffer added that understanding the precise cause of the disease enables researchers to design treatments that directly target the disrupted pathways, offering options for patients who currently have no treatment path.

Ms. Dalila Sabaredzovic, the mother of two of the children in the study, is hopeful that the breakthrough will be the first step towards improving her sons’ quality of life as well as that of others living with the same condition.

“I am so thankful that we now have a foundation to stand on and that work is progressing towards exploring paths of treatments. We feel empowered in many ways we couldn’t before and we really hope that this research will spark not only an understanding of the SPNS1 gene and the condition it’s causing, but also a way towards a cure,” she said.

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, said, “These findings demonstrate the power of precision medicine. By linking unusual patient symptoms to specific genetic mutations, researchers uncover new disease pathways and develop targeted treatments.

“This approach not only provides answers to families affected by rare diseases but also opens doors for broader medical advances. This discovery is a reminder that even the rarest and most puzzling conditions can be solved—when scientists, clinicians and families work together.”