Most people who carry a genetic mutation for a movement disorder called dystonia will never develop symptoms, a phenomenon that has puzzled scientists since the first genetic mutation was identified in the 1990's.
Now, scientists at The Feinstein Institute for Medical Research have figured out why these mutation carriers are protected from symptoms of the disorder - they have an additional lesion that evens the score.
Dystonia is marked by uncontrolled movements, particularly twisting and abnormal postures. Studies have shown that muscles contract abnormally and patients can't stop the involuntary movements. The identification of a specific abnormality in people with the genetic mutation who never develop symptoms could eventually pave the way towards new treatments for dystonia patients. There are half a million people in the United States alone. The brains of people with inherited dystonia are normal at autopsy and the exact cause of their movement abnormality is unknown.
David Eidelberg, MD, the senior author of the study published in the Journal of Neuroscience, said that they used diffusion tensor imaging - a type of magnetic resonance imaging (MRI) that measures changes in the integrity of white matter pathways in the brain - to study those with and without symptoms who carry the disease gene. There were 20 people in the study; 12 with symptoms and eight without. They also had a number of volunteers who agreed to brain scans who had no disease and no mutations in the gene for dystonia.
Dr. Eidelberg and his colleagues identified two discrete areas along the pathway that links the cerebellum to the motor cortex that together determine whether a mutation carrier will display clinical manifestations of the disease.
Their earlier work revealed that patients and non-patients with the disease gene have the same underlying functional brain abnormality, such as overactivity of motor circuits that make it hard to process sequential information. Nonetheless, mutation carriers have a characteristic circuit disorder involving a motor system that is revved up and idling at high speed, making it difficult to integrate the information needed to plan movements and to learn new motor skills. It was not suspected that these otherwise healthy individuals had such difficulties since doctors only saw those who presented with the uncontrollable movements.
While their brains show the same abnormal network, only approximately 30% of people who carry the mutated gene called DYT1 will develop the involuntary movements that can prevent them from living a normal life, according to Dr. Eidelberg.
The puzzle was why.
In the latest study, the new advances in diffusion imaging allowed them to see something for the first time. They saw that there were two places along the motor pathway that seemed to stop the flow of neural signals from one part of the circuit to the other. Those with only one lesion in the circuit developed the debilitating movements and those with two lesions did not. "There is something about this second lesion that is protective," the authors concluded. "We found a consistent cerebellar pathway problem in all DYT1 carriers. When we went back and looked at those without symptoms, we saw that they had an additional lesion downstream in the portion of the pathway connecting directly to the motor cortex." This second area of pathway disruption abrogated the effects of the first lesion.
Normally, the cerebellum (a region that controls movement) puts the breaks on the motor cortex by potentiating inhibition at the cortical level. It is likely that mutation carriers have a developmental problem in the flow of neural signals along this circuit such that the brain can't inhibit an unwanted movement. With the second pathway lesion, Dr. Eidelberg explained, "the flow is shut off and the abnormal activity stops."