Israeli team finds biological basis for rare neurological kids' disease

The breakthrough in Jerusalem may help doctors around the globe detect genetic abnormalities early.

The secret to healing what ails you lies within your own DNA (photo credit: DREAMSTIME)
The secret to healing what ails you lies within your own DNA
(photo credit: DREAMSTIME)
The biological basis of a severe and mysterious neurological disorder in children that is caused by a single error in one gene has been described for the first time by a multinational team led by researchers from Jerusalem.
Just published in the American Journal of Human Genetics, the study was headed by Prof. Orly Elpeleg of the pediatrics department at the Hebrew University of Jerusalem’s Faculty of Medicine and director of the genetics department at Hadassah- University Medical Center.
Elpeleg credits the discovery to deep sequencing technology that Hadassah and Hebrew U. were among the first to introduce into clinical practice in Israel and in the world.
The team found that affected children’s cells are flooded with ribosomal RNA and are poisoned by it. It was the first time an excess of ribosomal RNA has been linked to a disease in human regression and neurodegeneration.
The disease does not yet have a name.
At first, affected children lead normal lives and seem identical to their age-matched peers.
However, beginning at age three to six, they show neurological deterioration – gradually losing motor, cognitive and speech functions. Although the condition progresses slowly, most patients are completely dependent sometime between 15 to 20 years of age.
Working with colleagues from the Pennsylvania State University College of Medicine and a multinational research team, the Israeli-led team have now identified and studied seven children from Canada, France, Israel, Russia and the US 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.
It is because of this small change that patients’ cells are flooded with ribosomal RNA.
Ribosomes are responsible for the translation and production of cell proteins. 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 three billion that make up human DNA.
By finding the identical change in children with the identical clinical disease, the researchers determined the altered gene was indeed the cause of the disease.
Elpeleg initially encountered the disease in a young girl who came to Hadassah.
“Five years ago, I saw a patient who was healthy until the age of three 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 with around 2,400 patients.
“Searching for similar genetic defects in this database, we found a nine-year-old boy who had been treated at Hadassah and now lives in Russia. The boy had been healthy until the age of five and then displayed neurological deterioration just like the girl I had diagnosed,” said Elpeleg.
Dr. Simon Edvardson, a pediatric neurologist at Hadassah, flew to Russia, examined the boy, took genetic samples from him and 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 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.
To understand the mechanism of the newly identified disease, the researchers collaborated with Dr. George-Lucian Moldovan at Pennsylvania State University College of Medicine who 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.
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,” Elpeleg said.