Scientists have finally discovered the cause of a rare brain disease

Scientists have finally discovered the cause of a rare brain disease

Artificial intelligence illustration of the human brain

The disease, known as hypomyelinating leukodystrophy, is caused by a mutation in a gene that regulates the transport of zinc from cells.

Researchers discover a new mechanism behind a rare brain disease.

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

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

Quasar Padiath

Quasar Padiath, Ph.D. Credit: Joshua Franzos, University of Pittsburgh

This is the first case where a mutation in a zinc transporter gene, in this case, TMEM163, is definitely associated with the development of any brain disorder. It has the potential to shed light on the function of zinc in healthy brain development, as well as in brain injury and disease.

“Discovering a new gene responsible for causing a disease is always exciting; that feeling never gets old,” said Padijat, an associate professor of human genetics and neurobiology at Pitt. “And the discovery that the zinc transporter is really important for proper myelin development could have many clinical implications and offer new ways to treat other related neurological conditions.”

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 helps transmit electrical impulses. As the myelin sheath thins and is lost in these patients, nerve signals come to a crawl, resulting in a host of neurological problems such as impaired movement and balance control, muscle wasting, vision problems, hearing loss, and memory loss.

While genes are associated with leukodystrophies, the genetic basis for most cases is still unknown. To identify the root cause of a patient’s condition and recommend the most appropriate therapy, clinical neurologists often turn to researchers like Padiath.

By combing 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 no small feat. To definitively link a new gene mutation with disease symptoms, it is necessary to identify multiple independent cases of patients sharing the same gene defect and clinical presentation.

For rare diseases, such as hypomyelinating leukodystrophies, finding such cases is possible only by tapping into a network of scientific and clinical collaborators from around the world. In this study, the first sample of patients came from Shukla, a professor of medical genetics in Manipal in southwest India. Research by other groups in the USA and the Netherlands identified additional families that also carried mutations in the same gene.

A series of in-depth laboratory studies showed that mutations in TMEM163 impair the transporter’s ability to efficiently divert zinc from the interior of the cell, causing reduced 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,” Padiath said. “It is important to remember that diseases that are rare in a global context are very important and real for patients and their families. Studying these diseases helps find cures and provides hope for patients and valuable insight into therapeutic targets that are essential for normal cell function.”

Reference: “Variants in the zinc transporter TMEM163 cause hypomyelinating leukodystrophy” 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 Sill A Rosenfeld, Alexander Church, Katta Mohan Girisha, Nicole I Wolf, Quasar Saleem Padiath and Anju Shukla, August 12, The brain.
DOI: 10.1093/brain/awac295

The study was funded by the National Institutes of Health.

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