Mysterious children's neurological disease is traced to a single error in one gene

August 3, 2017
A photo of Prof. Orly Elpeleg, head of the Department of Genetics at the Hadassah Medical Center and a professor at the Hebrew University's Faculty of Medicine. Credit: Hebrew University

In a new study published today in The American Journal of Human Genetics, a multinational team of researchers describes, for the first time, the biological basis of a severe neurological disorder in children.

The extremely rare disorder is characterized by developmental regression and neurodegeneration. At first the children lead normal lives and seem identical to their age-matched peers. However, beginning at around 3 to 6 years of age, they present with neurological deterioration, gradually losing motor, cognitive and speech functions. Although the condition progresses slowly, most patients are completely dependent on their caretakers by 15-20 years of age.

Researchers from the Hadassah Medical Center and the Hebrew University of Jerusalem's Faculty of Medicine, working with colleagues from the Pennsylvania State University College of Medicine and a multinational research team, have now identified and studied 7 children—from Canada, France, Israel, Russia and the United States—who suffer from the disorder.

The researchers found in all patients the same spontaneously occurring, non-inherited genetic change in a gene (named "UBTF") responsible for ribosomal RNA formation. Because of this small change, the patients' cells are flooded with ribosomal RNA and are poisoned by it. (Ribosomes are responsible for the translation and production of cell proteins; themselves, they are made up of ribosomal proteins and of ribosomal RNA in a precise ratio).

The researchers found an identical error in the same gene in all the patients tested, representing a difference of one letter among the roughly 3 billion letters that make up human DNA. By finding the identical change in children who suffer from the identical clinical , the researchers determined that the altered gene is indeed the cause of the disease.

Prof. Orly Elpeleg, head of the Department of Genetics at Hadassah Medical Center in Jerusalem and a professor of Pediatrics at the Hebrew University's Faculty of Medicine, led the multinational research. Prof. Elpeleg credits the discovery to deep sequencing technology that Hadassah and the Hebrew University were among the first to introduce into clinical practice in the world, and the first in Israel.

Prof. Elpeleg initially encountered the disease in a young girl who came to Hadassah: "Several years ago, I saw a patient who was healthy until the age of 3, and then experienced a disturbance in her walking and motor function, speech and cognition. Around that time, we had introduced the deep-sequencing technology for clinical use at Hadassah, which enabled us to read all the coding genetic material of a person within a couple of days, in order to identify genetic defects." Since 2010, Hadassah has assembled the largest genetic mapping database in Israel, of about 2400 patients.

"Searching for similar genetic defects in this database, we found a 9-year-old boy who had been treated at Hadassah and now lives in Russia. The boy had been healthy until the age of 5, and then displayed just like the girl I had diagnosed. Dr. Simon Edvardson, a pediatric neurologist at Hadassah, flew to Russia, examined the boy, took genetic samples from him and from his parents and confirmed that his illness was identical to that of the Israeli girl. We then knew we had identified a new disease that was not recognized in the medical literature," said Prof. Elpeleg.

Comparing their data in a program called Gene Matcher, the researchers found several more children around the world who shared an identical genetic defect and the same course of disease.

In order to understand the mechanism of the newly identified disease, the researchers collaborated with Dr. George-Lucian Moldovan at the Pennsylvania State University College of Medicine, in the United States. Dr. Moldovan confirmed the disease mechanism: in the children's cells, there is an excess RNA of the ribosome, which probably causes brain cells to be flooded and poisoned.

"Our study links neuronal degeneration in childhood with altered rDNA chromatin status and rRNA metabolism. It is the first time that an excess of ribosomal RNA has been linked to a genetic disease in humans," said Prof. Elpeleg.

While there is currently no cure for genetic diseases of this kind, the identification of the exact mutation may allow for the planning of therapies designed to silence the mutant gene. "Science may not be able to repair the gene, but now that our findings are published, it may be possible to make early identification of the disease and in the future find ways to prevent such a serious deterioration," said Prof. Elpeleg.

Explore further: Skin disease caused by sperm cell transmission of keratin mutation

More information: American Journal of Human Genetics (2017). DOI: 10.1016/j.ajhg.2017.07.002

Related Stories

Skin disease caused by sperm cell transmission of keratin mutation

June 16, 2017
Nagoya University research identified a patient with the whole-body skin disease epidermolytic ichthyosis that had been inherited as a germline mutation from her father with the milder epidermolytic nevus. Analysis of genomic ...

Researchers reveal developmental mechanisms behind rare bone marrow disorder

April 12, 2017
Myelodysplastic syndrome is an umbrella term used to describe disorders characterized by the bone marrow's inability to produce normal blood cells. Researchers from Charité - Universitätsmedizin Berlin have found that a ...

New insights in genetic defect allow prevention of fatal illnesses in children

January 18, 2017
A team of scientists led by prof. Adrian Liston (VIB–KU Leuven) and prof. Isabelle Meyts (UZ Leuven – KU Leuven) were able to characterize a new genetic immunodeficiency resulting from a mutation in a gene named STAT2. ...

Scientists discover genetic mechanism essential to ovary development

November 5, 2015
Scientists at the Hebrew University of Jerusalem's Faculty of Medicine have announced a discovery that is expected to allow doctors to diagnose a disease causing infertility and lack of puberty in women, with implications ...

Rare feline genetic disorders identified through whole genome sequencing

May 11, 2017
Whole genome sequencing (WGS), which is the process of determining an organism's complete DNA sequence, can be used to identify DNA anomalies that cause disease. Identifying disease-causing DNA abnormalities allows clinicians ...

Researchers discover new genetic brain disorder in humans

April 24, 2014
A newly identified genetic disorder associated with degeneration of the central and peripheral nervous systems in humans, along with the genetic cause, is reported in the April 24, 2014 issue of Cell.

Recommended for you

An architect gene is involved in the assimilation of breast milk

October 17, 2017
A family of "architect" genes called Hox coordinates the formation of organs and limbs during embryonic life. Geneticists from the University of Geneva (UNIGE) and the Swiss Federal Institute of Technology in Lausanne (EPFL), ...

Study identifies genes responsible for diversity of human skin colors

October 12, 2017
Human populations feature a broad palette of skin tones. But until now, few genes have been shown to contribute to normal variation in skin color, and these had primarily been discovered through studies of European populations.

Genes critical for hearing identified

October 12, 2017
Fifty-two previously unidentified genes that are critical for hearing have been found by testing over 3,000 mouse genes. The newly discovered genes will provide insights into the causes of hearing loss in humans, say scientists ...

Team completes atlas of human DNA differences that influence gene expression

October 11, 2017
Researchers funded by the National Institutes of Health (NIH) have completed a detailed atlas documenting the stretches of human DNA that influence gene expression - a key way in which a person's genome gives rise to an observable ...

Genetic advance for male birth control

October 10, 2017
When it comes to birth control, many males turn to two options: condoms or vasectomies. While the two choices are effective, both methods merely focus on blocking the transportation of sperm.

Researchers uncover new congenital heart disease genes

October 9, 2017
Approximately one in every 100 babies is born with congenital heart disease (CHD), and CHD remains the leading cause of mortality from birth defects. Although advancements in surgery and care have improved rates of survival ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.