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Rare Mutation That Causes Mirror Movements Reflects Nervous System's Complexity

The genetic cause of mirror movements reveals how the nervous system is wired during development



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Andrée Marion, a 47-year-old accountant from St. Sauveur, Quebec, has mirror movements—involuntary motions on one side of her body that mirror voluntary ones on the other. When she does things that require fine movements, like brushing her hair, reaching for change in her pocket or holding her coffee with her right hand, her left hand strokes, dips or grips in synchrony. She can't help it; it just happens. It also happens to her 19-year-old son. In fact, of Marion's 23 blood relatives spanning four generations, about half have mirror movements. It turns out they also have a rare gene defect, giving scientists new insight into how our bodies are wired.

"The right side of the brain controls the left side of the body," says Guy Rouleau, a neurologist and geneticist at the University of Montreal and senior author of a study published April 30 in Science that uncovered a mutation associated with the mirroring condition in Marion and her relatives. That's because the wires of our nervous system cross: axons from motor neurons originating in the brain sweep over the midline of the body before connecting to other motor neurons in the spinal cord, and those spinal motor neurons then connect to the muscles. "In humans, we don't know how or why that happens," Rouleau says.

Mirror movements are extremely rare and are usually only seen in people with disorders of nervous system crossing, such as Klippel-Feil and Kallmann syndrome. So the abnormal wiring of Marion and her relatives in the absence of these disorders gave Rouleau and colleagues a unique opportunity to study how the wiring process can go wrong. Using transcranial magnetic stimulation, the researchers excited neurons in the brain that would normally connect to spinal motor neurons on the opposite side of the body. "The right side of the brain controlled the left hand but also the right hand," says Rouleau. "It's a curious thing—some axons crossed over and some didn't cross. The ones that didn't cross went to the exact same [spinal motor neurons] on the opposite side of the spinal cord. There was a perfect organization that was bilateral as opposed to unilateral."

Because the mirror movements and unusual wiring were hereditary, Rouleau and colleagues looked for gene mutations that might be causing them. It took them a year and a half to collect DNA from all Marion's relatives, but only three months to find the faulty gene: deleted in colorectal cancer (DCC). The mutation interferes with DCC's interaction with netrin—a diffusible extracellular protein that helps guide axons across the body ' s midline during development.

"[DCC] is expressed in the midline of the nervous system, and when the axons sense this protein they move toward it," Rouleau says. But the mutation cuts the level of functional DCC dramatically in Marion and her relatives. "They don't have enough of the protein, and the message isn't strong enough to get all the nerves to cross over," Rouleau says.

Mice with DCC deletions, called Kanga mice, also exhibit mirror movements, which result in a "distinctive hopping gait," the researchers report. But DCC's role in humans was previously unclear. "This basically tells us, not why the [axons] cross, but how," says Rouleau. "It really shows a level of organization that's amazing."

Marion and her relatives had never seen a doctor about the mirror movements. Rather, a neurologist examining one of the family members for another reason happened to observe the involuntary movements, prompting the study. "From when I was a child, I noticed them. But it never really concerned me because I was able to do whatever I wanted to do," says Marion, who can type and even drive without any difficulty. "The only thing I'm really not good at is playing pool," she jokes, "and I have to be careful when I'm cooking and cutting food." Marion's mirror movements are more pronounced than her son's, she says. "His are more in his hands. For me it’s even my biceps and my toes."

"The movements are noticeable but not flagrant," says lead author Myriam Srour, a pediatric neurologist at Montreal Children's Hospital. "It's quite amazing; they function very well. …Several said they are a bit on the clumsy side…but it's more their fine movements that are affected."

The same gene defect was identified in an Iranian family, previously reported to have similar hereditary mirror movements. Knowing that their mirror movements might give doctors more insight into how the nervous system develops and how movements are controlled, Marion and her relatives were happy to participate in the study. "If it could help people with another, more important sickness, that would be great," Marion says.

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