Finally, there’s a definitive cause of a rare but potentially debilitating brain disorder, thanks to research teams working on both sides of the globe.
A mutation in the gene that manages the transport from cells of zinc, an essential micronutrient, is responsible for this disorder called myeloid leukodystrophy. The research, which was jointly led by Dr. Kuzar Padiyat at the University of Pittsburgh and Dr. Anju Shukla at the Kasturba Medical School in India, is published in the journal. brain.
This is the first time there has been a mutation in the zinc transporter gene—in this case, TMEM163 It has been definitively linked to the development of any brain disorder, and has the potential to provide insight into zinc’s role in normal brain development, injury and disease.
“Discovering a new gene responsible for causing disease is always exciting; that feeling never gets old,” said Padiath, associate professor of human genetics and neuroscience at Pete. “And the discovery that the zinc transporter is really important for proper myelin development may have many clinical implications and offer new avenues for treating other related neurological conditions.”
Hypoplastic leukodystrophy is a rare and often fatal neurological disorder caused by defects in the genes involved in the growth or maintenance of myelin, the insulating fatty layer surrounding nerves that helps them transmit electrical impulses. As the myelin layer gradually thins and is lost in these patients, nerve signals slow to crawl, leading to a large number of neurological problems, including impaired movement and balance control, muscle wasting, vision problems, hearing and memory loss.
While genes have been linked to leukopenia, the genetic underpinnings of the majority of cases remain unknown. To determine the root cause of a patient’s condition and recommend the most appropriate treatment, clinical neurologists often turn to researchers such as Padiath.
By combing through patients’ genomes, Padiath looks for mutations and analyzes the effect of those mutations in cells and animal models, such as mice. Such an analysis is not easy. To definitively associate a new genetic mutation with disease symptoms, several independent patient cases that share the same genetic defect and clinical presentation must be identified.
For rare diseases, such as hypoplastic leukodystrophy, such cases can only be found by eavesdropping on a network of scientific and clinical collaborators from around the world. In this study, the first patient sample came from Shukla, a professor of medical genetics at Manipal in southwest India. Inquiries made to other cohorts in the United States and the Netherlands identified additional families who also carry mutations in the same gene.
A series of in-depth laboratory studies have shown that TMEM163 Mutations impair the ability of the carrier to effectively convert zinc from within the cell, resulting in decreased production of proteins responsible for myelin synthesis and maintenance and increased cell death.
“Understanding how genes cause rare diseases is the first step in the process of finding treatments,” said Padiath. “It is important to remember that rare diseases in a global context are very important and real to patients and their families. Studying these diseases helps find treatments and gives patients hope and valuable insights into the therapeutic targets that are necessary for cells to function normally.”