A new model developed at TAU following a family’s request is helping researchers study a rare brain disorder known to affect only 40 people worldwide.

When the parents of an 8-year-old Israeli boy reached out to Tel Aviv University, a research team at the Gray Faculty of Medical and Health Sciences stepped up. Their mission: to find answers for a devastating genetic condition with no known cure. The result is a breakthrough mouse model that mimics the disease with striking accuracy — and may pave the way for life-saving treatments.

The study was led by Prof. Moran Rubinstein and Prof. Karen Avraham, Dean of the Faculty. Other participants included students Mor Yam, Julan Nasir, Daniel Gelber, Shir Kavin, Roni Gal, Mor Ovadia, Mor Bordinik-Cohen, and Eden Peled — all from the Gray Faculty of Medical and Health Sciences at Tel Aviv University or the Sagol School of Neuroscience — as well as Dr. Moran Heusman-Kedem and Prof. Aviva Fattal-Valevski from the Pediatric Neurology Institute at Dana-Dwek Children’s Hospital, Tel Aviv Medical Center, and Prof. Christopher McKinnon and Prof. Wayne Frankel from Columbia University in the United States.

Prof. Avraham explains: “We were approached by the parents of an Israeli child named Adam, now 8 years old, who is one of approximately 40 people worldwide suffering from an extremely rare genetic disease. It’s a mutation in a gene called GRIN2D, which causes developmental epilepsy, severe delays in motor and cognitive development, and sometimes even premature death.”

Eden Maimon Benet, Adam’s mother, adds: “At Tel Aviv University, we met a remarkable all-women team that took on the mission: to find a cure for our son. I believe the fact that they got to know Adam and our family personally only deepened their dedication and commitment. When Adam was two years old, we embarked on this long journey together — and today, we can already see real light at the end of the tunnel.”

How Do You Study a Disease No One Understands?

In the first stage, the researchers aimed to better understand the disease’s characteristics. To do so, they created a mouse model with a mutation similar to that found in human patients. However, due to the severity of the disease, most of the mice did not survive their first weeks of life — before any meaningful research observations could be made. This led the team to conclude that while the model mimics the human disease, it poses a major challenge: too few mice could be generated for scientific study.

To overcome this, they used genetic engineering tools to create a strain of mice that carry the mutation but do not develop symptoms. These serve as carriers, with half of the offspring born healthy and the other half born with the disease. The affected mice exhibited symptoms similar to those seen in children with the disease. Most lived only a few weeks, and only a few survived up to three months. The researchers observed their behaviour and development at four key stages: at two weeks old (infancy), three weeks (when mice transition to solid food — roughly equivalent to a one-year-old child), four weeks (roughly age six in children), and five weeks (the onset of sexual maturity).

“Because the disease is so rare, we don’t yet fully understand how it progresses with age,” Prof. Rubinstein says. “The mouse model helped us characterize symptoms at various stages. The tests we conducted revealed interesting findings: neurological symptoms — including epilepsy, hyperactivity, and severe motor impairments — appeared as early as infancy. Cognitive impairments, on the other hand, showed up later and worsened gradually. In addition, their lifespan was short — most of the affected mice did not survive to sexual maturity.”

What Happens in the Brain?

In a follow-up experiment, the researchers monitored communication between neurons in the brains of the model mice, focusing on the cerebellum — the brain region responsible for motor control. The tests showed that by just two weeks of age, pathological changes were already present, expressed as reduced neuronal activity. Later in life, activity levels returned to normal; however, the communication between neurons became impaired. Finally, the researchers identified structural changes in the neurons themselves. All these findings help shed light on the mechanism driving the disease.

EEG recordings conducted on the affected mice revealed a unique brain activity pattern that also characterizes the disease in humans. “In most types of epilepsy, seizures are caused by disruptions in brain activity, but between seizures, brain activity is relatively normal,” explains Prof. Rubinstein. “In this disease — in both children and mice — brain activity is consistently disrupted. Moreover, using specific markers we developed, we identified the same abnormal parameters in both mice and humans — a finding that most clearly demonstrates the validity of the model.”

From Testing to Treatment

After confirming that the mouse model accurately mimics the human disease, the researchers began testing the effects of various drugs on the progression of symptoms. They found that ketamine — a drug previously proposed for treating this condition — actually worsened the seizures. In contrast, memantine, another drug currently used for this disease, led to partial improvement in brain function. The same was true for phenytoin, an anti-seizure medication, which also improved some markers of brain activity.

New Hope for Rare Disease Patients

“Modeling the disease using a mouse model is a key tool in making clinical decisions for treating rare diseases,” explains Dr. Heusman-Kedem, who adds: “The model allows us to test the efficacy of known drugs, as well as the safety and effectiveness of innovative treatments — before administering them to patients. For example, the results found in the mouse model helped clarify that memantine may help prevent seizures. Using a mouse model provides critical insights for developing new treatment strategies for rare diseases, where the number of patients is too small to establish broad statistical conclusions. In such cases, animal studies can offer major breakthroughs and support the development of personalized medicine.”

“In this study, we created a mouse model of a rare genetic disease caused by a mutation in the GRIN2D gene,” concludes Prof. Rubinstein. “The model allowed us to better understand how the disease progresses and to test the effectiveness of several existing drugs. We’re now continuing the research and exploring additional therapies — both pharmaceutical and genetic — and we’ve reached promising results, including improvements in cognition and motor function and increased lifespan in the affected mice. We sincerely hope our work brings hope and real progress to families and children battling this rare and devastating disease — and to those affected by other brain conditions with similar mechanisms.”