Scientists have finally discovered the cause of a rare brain disease

This disease, known as pituitary leukodystrophy, is caused by a mutation in the gene that regulates transport from zinc 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 has an eventual cause.

The disorder, known as hypomyeloid leukodystrophy, results from a mutation in the gene that controls cell transport of zinc, an important nutrient. The study was published in the journal brain It was jointly led by Dr. Kuzar Padiyat of the University of Pittsburgh and Dr. Anju Shukla of Kasturba Medical College in India.

Quasar Badiyat

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

This is the first case of a mutation in the zinc transporter gene, in this case, TMEM163It has been conclusively linked to the development of any brain disorder. It has the ability to highlight zinc’s function in healthy brain development as well as in brain injury and disease.

“The discovery of 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 Pitt. It has many clinical implications and offers new ways to treat other related neurological conditions.”

Hypoplastic leukodystrophy is a rare and often fatal neurological disorder caused by defects in genes involved in the growth or maintenance of myelin, the fatty layer of insulation that surrounds nerve cells and helps transmit electrical impulses. As the myelin layer thins and is lost in these patients, nerve signals creep in, leading to a plethora of neurological problems such as impaired movement and balance control, muscle wasting, vision problems, hearing loss, 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 transporter’s ability to efficiently convert zinc from within the cell, causing 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 essential therapeutic goals for cells to function normally.”

Reference: “Variants in the zinc carrier TMEM163 Caused Hypertrophic Leukodystrophy” by Michelle C. Do Rosario, William Rodriguez Bey, Bruce Nmezi, Fang Liu, Talia Oranberg, Anna S.A. Cohen, Keith A. Kauffman, Maya R. Brown, Kirill Kislev, Quentin Weisfish, Merth Flohill, Shahyan Siddiqui, Jill Rosenfeld, Alexander Church, Kata Mohan Gerisha, Nicole I. Wolf, Quasar Salim Badiyat and Anju Shukla, August 12, brain.
DOI: 10.1093/brain/awac295

The study was funded by the National Institutes of Health.

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