Vanishing white matter (VWM) disease is a devastating condition that destroys the brain's white matter. This white matter protects the axons of neurons, and leads to seizures and the progressive loss of motor function, eyesight, and speech. Also known as Childhood Ataxia with Central Nervous System Hypomyelination (CACH), the disease has no cure, and victims do not typically live longer than the early teens.
It's a heartbreaking diagnosis that the O'Brien family of Boston, Massachusetts, knows well. Their daughter Marisol — "a very energetic, funny, beautiful girl who could light up a room," says her father Tom O'Brien — was diagnosed with the disease at the age of three in 2003, sparking a long journey that led to the finest doctors in Boston, Lourdes, Bethesda's National Institutes of Health and finally Tel Aviv Univ.
For Prof. Orna Elroy-Stein, whose lab at TAU's Department of Cell Research and Immunology is focused on research surrounding VWM disease, Marisol is a daily source of inspiration. She was first alerted to Marisol's condition through Rafi Schiffman of the National Institutes of Health, one of her research collaborators. Schiffman took some hair, skin and blood samples from Marisol at his Maryland clinic and asked Marisol's father for permission to send them along to Elroy-Stein's lab; he agreed.
Developing "Marisol's mice"
Marisol passed away from the disease in 2008, but her DNA pattern and specific genetic mutation were the basis for Elroy-Stein's breakthrough development of the first population of laboratory mice — called "Marisol's mice" — with a VWM disease mutation. With this invaluable biological tool in place, researchers have been able to make important progress into understanding how the disease functions.
Through these mice, the researchers were able to discover that VWM disease was in essence a developmental disorder — the mutation causes delayed development of the myelin that forms after birth, they reported in the journal Brain. The researchers' most recent findings, published in the journal PLoS One, add to this understanding.
"Because of these mutations, the brain's response to physiological stress, such as fever or blunt trauma, is not normal. Following damage, the proteins can't be synthesized quickly enough to make a repair," explains Elroy-Stein, who keeps a photograph of Marisol on her desk to motivate her in this challenging research. "Every morning, she smiles at me and it keeps me going," she says.
What Marisol's mice revealed
In VWM disease, the systematic loss of the brain's myelin is due to a mutation in the translation factor eIF2B, which translates genetic information from our DNA for the use of proteins, explains Prof. Elroy-Stein. But with this mutation, the protein responsible for the production of white matter is faulty.
That's why patients with VWM disease have an impaired ability to cope with physiological stresses that damage the brain. The brain usually responds to such injuries by triggering elevated protein synthesis to make the proteins necessary for repair, says Elroy-Stein. But the mutated version of elF2B cannot keep up with such acute demand.
"As long as there is no stress, protein production rate is slower but still sufficient," Elroy-Stein says. The crisis begins when protein production is needed critically and on a large-scale. Because the developmental delay renders immediate response impossible, it leads to more severe and permanent brain damage, findings suggest.
The personal touch
Four years after Marisol's death, Tom O'Brien visited Elroy-Stein's lab, and what he found had a powerful effect. "I felt Marisol's strong presence in the lab," he says. "And then Orna took me down to where the mice were — there were thousands and thousands of them! It was amazing! Prof. Elroy-Stein is a very kind, wonderful person and a beautiful human being," O'Brien recalls. "There were a lot of researchers we met who were specialists and very smart. But she also understands how this research is very personal for us."
In the future, Elroy-Stein hopes that she and her team will be able to unravel one of the mysteries connected to VWM disease. Unlike patients of other genetic diseases, the severity of a VWM patient's mutation is not necessarily correlated to disease onset and deterioration. The researchers hypothesize that this could be a simple matter of timing. Myelin forms at a specific stage of development, when the brain is the most sensitive. Early trauma may impact the trajectory of the disease.
These discoveries — and the promise of future findings — are only a part of Marisol's legacy, says Elroy-Stein. "Though they weren't able to save their daughter, the O'Brien family continues to help others through their Foundation for Marisol's Journey. Their courage and unbelievable effort inspires me to continue on in this challenging research, hoping to help patients in the future. Marisol is the spirit that drives us all forward," she says.