Scientists finally discover the cause of a rare brain disease

Researchers discover a new mechanism behind a rare brain disease.

Thanks to research teams on both sides of the world, a rare but potentially debilitating brain disorder now has a definitive cause.

The condition, known as hypomyelinating leukodystrophy, is caused by a mutation in the gene that controls the transport from cells of zinc, an important dietary micronutrient. The study was published in the journal Brain and was jointly led by Dr. Quasar Padiath of the University of Pittsburgh and Dr. Anju Shukla of Kasturba Medical College in India.

This is the first time a mutation in a zinc transporter gene, in this case TMEM163, has been definitively linked to the development of brain disease. It has the potential to shed light on zinc’s function in healthy brain development, as well as brain injury and disease.

“It’s always exciting to discover a new gene responsible for causing disease; that feeling never gets old,” said Padiath, an associate professor of human genetics and neurobiology at Pitt. “And discovering that a zinc transporter is really important for proper myelin development could have many clinical implications and provide new ways to treat other related neurological disorders.”

Hypomyelinating leukodystrophies are rare and often fatal neurological disorders caused by defects in genes involved in the growth or maintenance of myelin, the fatty insulating layer that surrounds neurons and aids in the transmission of electrical impulses. As the myelin layer thins and is lost in these patients, nerve signals come to a crawl, resulting in a plethora of neurological problems, such as impaired movement and balance control, muscle wasting, vision problems, hearing loss and memory loss.

Although genes have been linked to leukodystrophies, the genetic underpinnings for most cases are still unknown. To identify the cause of a patient’s condition and recommend the most appropriate therapy, clinical neurologists often turn to researchers such as Padiath.

By combing through the genome of patients, Padiath looks for mutations and analyzes the effect of these mutations in cells and animal models, such as mice. Such an analysis is no mean feat. To definitively link a new gene mutation to disease symptoms, multiple independent patient cases with the same gene defect and clinical presentation must be identified.

For rare diseases, such as hypomyelinating leukodystrophies, finding such cases is only possible by leveraging 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 southwestern India. Inquiries with other groups in the US and the Netherlands identified additional families that also carried mutations in the same gene.

A series of in-depth lab studies showed that the TMEM163 mutations reduce the transporter’s ability to effectively shunt zinc from the cell, reducing production of proteins responsible for myelin synthesis and maintenance and increasing cell death.

“Understanding how genes cause rare diseases is the first step in the process of finding treatments,” Padiath says. “It is important to remember that diseases that are rare in the global context are very important and real to patients and their families. Studying these diseases helps to find cures and give patients hope and valuable insights into therapeutic targets essential for normal cell function.”

Reference: “Zinc Conveyor Variants” TMEM163 cause hypomyelinating leukodystrophy” by Michelle C do Rosario, William Rodriguez Bey, Bruce Nmezi, Fang Liu, Talia Oranburg, Ana SA Cohen, Keith A Coffman, Maya R Brown, Kirill Kiselyov, Quinten Waisfisz, Myrthe T Flohil, Shahyan Siddiqui, Jill A Rosenfeld, Alexander Church, Katta Mohan Girisha, Nicole I Wolf, Quasar Saleem Padiath and Anju Shukla, August 12, Brain.
DOI: 10.1093/brain/awac295

The study was funded by the National Institutes of Health.