A multinational team of researchers in their new study described the biological basis of a severe neurodegenerative disorder in children for the first time, which has been published in The American Journal of Human Genetics.
Developmental regression and neurodegeneration were the characteristics associated with the extremely rare disorder observed in the children. These children initially lead a normal life, but completely relied on caretakers as the condition progressed. Around 3 to 6 years of age neurodegeneration becomes apparent. This is followed by a gradual loss of motor, cognitive and speech functions finally leading to dependency on caretakers by 15-20 years of age.
A team of researchers have identified and studied 7 children who suffered from this neurodegeneration. The change in the gene named ‘UBTF’ (upstream binding transcription factor) was found to be responsible for the ribosomal RNA formation. The spontaneously occurring, non-inherited genetic change in the gene resulted in the patient’s brain cells to be flooded with ribosomal RNA resulting in the disorder. An identical error was found in the same gene in all the patients tested with the same identical clinical disease, concluding it to be the cause of the disorder.
Prof. Orly Elpeleg, head of the Department of Genetics and professor of Pediatrics who led the multinational research, acclaims the discovery to a deep sequencing technology that Hadassah and the Hebrew University were first to introduce into clinical practice in the world.
Prof. Elpeleg initially encountered the neurodegeneration in a young girl who came to Hadassah. He observed that the girl was healthy until the age of 3, but later developed problems with walking and motor function, speech and cognition. During this interval, deep-sequencing technology for clinical use was introduced which enabled the detection of any genetic defects. Genetic mapping of about 2400 patients has been carried out in Hadassah since 2010.
A 9-year-old boy had similar genetic defects. Until the age of 5 he was healthy, but later developed neurodegeneration similar to the girl. Dr. Simon Edvardson, a pediatric neurologist, examined genetic samples from the boy confirmed the disorder to be identical in both cases. Comparing their data in a program called Gene Matcher, an identical genetic defect and the same course of disease was found in several children around the world.
The researchers collaborated with Dr. George-Lucian Moldovan in order to understand the mechanism of the newly identified disease and confirmed that in these children, there is an excess ribosomal RNA, which affected the brain cells.
Prof. Elpeleg reported that "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."
"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," he concluded.