In the first study, two families in Libya and Egypt with Mfsd2a mutations were identified with severely reduced brain size, or microcephaly. Their mutations eliminated Mfsd2a’s ability to transport LPCs, which meant not enough LPCs were absorbed by the brain. In these families, children affected by these mutations died between one and six years of age. The study not only establishes a link between the transport of LPCs by Mfsd2a and human brain growth and function, it is also the first time a genetic disease has been related to LPC transport in humans. The research was co-led by senior author Professor Joseph Gleeson from Rockefeller University.
In a second, separate study, a family in North Pakistan was found to have another type of mutation in the Mfsd2a gene which reduced its transport activity. The individuals with this mutation also had microcephaly, but in this case it was not lethal. However, they did have intellectual disabilities, impaired control of their limbs, and absent speech. Like the first study, findings are proof of the importance of LPCs in brain development and function. The research was co-led by senior author Professor Andrew H. Crosby from Exeter University.
In 2014, Dr. Silver published a landmark study in Nature which served as a basis for these two studies. He and his team discovered that Mfsd2a is the transporter for LPCs. Prior to this breakthrough, LPCs were known to be found at high concentrations in our blood but their function was a mystery. Dr. Silver’s team showed that mice genetically engineered without Mfsd2a failed to transport LPCs into their brains - which resulted in microcephaly. Since DHA deficiency in animals does not result in microcephaly, this meant that LPCs are critical factors in brain growth and function. Also, while it was previously believed the brain made all the fat it needed, Dr. Silver’s research showed that LPCs are transported there from the blood past the blood-brain barrier. His work with Rockefeller and Exeter prove this in humans.
“Our work confirms the essential role of LPCs in brain development and function in humans, and indicates that brain uptake of LPCs during foetal development and in adult life is important,” said Dr. Silver, co-lead on both studies, based in the Cardiovascular and Metabolic Disorders Programme at Duke-NUS. “Now we are studying the functions of LPCs in the brain, and the implications for application are very exciting. We might be able to develop therapeutics in the future that could prevent and treat neurological disorders, and improve brain growth and function. We may even be able to target better brain nutrition for babies, mothers, and the aged.”