The Mystery of the Rare Mutation

A collaboration between researchers from Israel and Japan solved a medical mystery that has puzzled doctors and researchers for years. At its heart: a rare genetic disease caused by a defect in the DNA that prevents the body from producing myelin, the fatty molecule coating nerve cells and enabling them to function.

A baby born in Haifa’s Rambam hospital in 2011 began suffering from seizures a few hours after birth. As the standard tests were not helpful in diagnosis, a specialized team was appointed, led by Hanna Mandel and Ayelet Eran. MRI scans revealed that the myelin layer surrounding the nerve cells in the baby’s brain was very thin.

Myelin works similarly to the plastic coating covering electric cables – it insulates nerve cells’ "tails" – or axons – enabling them to conduct electric signals rapidly and efficiently. Myelin plays a central role in brain function and development. Its absence leads to severe symptoms, such as impaired speech and cognitive function, impaired vision and hearing, as well as a decline in motor skills.

The child's development was extremely slow and his function was very low. When he was four years old, doctors and researchers from Hadassah Medical Center and The Hebrew University examined his DNA sequence. The team, led by Orly Elpeleg, an expert on rare genetic disorders, compared the child's DNA sequence to that of healthy people from the general population and from his immediate family. The test revealed a rare mutation – a change in the DNA sequence – in a gene called EPT1.

At this point, the Israeli researchers approached a Japanese team that discovered that the gene governs the production of a protein called EPT1 a decade ago. The protein plays a role in the production of an important fatty molecule called phosphatidylethanolamine (PE), a component of the membranes surrounding all cells in the body.

The Japanese researchers compared cell samples taken from the child to samples from healthy individuals and found that the mutation results in the production of a shorter, inactive form of the protein. The researchers were surprised to find that despite the low protein amount, PE levels were only slightly lower than the levels found in healthy individuals. A possible explanation for this is that there are other proteins in the cell that compensate for the mutation and produce PE.

At the same time, they also found that the child's cells contain very low levels of another fatty molecule called plasmalogen, which was not previously known to be related to EPT1 in any way. Plasmalogen is an important component of nerve cell membranes and of the myelin coating. As an antioxidant, it plays a key role in protecting myelin from oxidative damage by free radicals. The researchers concluded that EPT1 has a unique function in plasmalogen production, and that it is essential for the proper production of myelin required for the normal development of the brain and nervous system.  

Early diagnosis

To date, only one other patient with this disease has been reported: a British teenager who also suffers from the rare disorder stemming from an EPT1 mutation. Currently, no treatment is available for the disease itself and the developmental damage it causes cannot be reversed; the Israeli child is paralyzed, blind, deaf, and still suffers from seizures.

The discovery of the genetic cause and the disease's mechanism are a necessary step for future diagnosis and detection of the disease, and perhaps even a treatment. The identification of the gene itself will allow the child's parents to receive genetic consultation, to rule out that in future pregnancies, the fetus carries the mutation. And importantly, the study demonstrates how an international scientific collaboration can lead to new discoveries.

Translated by Elee Shimshoni