October 10, 1996
|Geneticist Dr. Guy Rouleau||Neurologists Drs. Frederick and Eva Andermann|
by Sylvain Comeau
The pattern was there for a long time, but it took McGill neurology professors Frederick and Eva Andermann to put the pieces together and discover a new disease.
On frequent visits to the Saguenay and Charlevoix regions in the 1970s, the married couple, both affiliated with the Montreal Neurological Institute, started to identify a common disorder among many different, and misdiagnosed, patients.
"There were a great number of young people with this disorder, who were considered to have muscular dystrophy or cerebral palsy," explains Dr. Frederick Andermann, currently director of the MNI's Epilepsy Clinic, "but they were too similar to each other, and they did not fit the classic picture of these diseases. Also, because the disorder we were looking at runs in families, we knew we were dealing with a genetic disorder; cerebral palsy is not genetic. Our understanding of the disorder started to crystallize."
Initially, in 1972, the Andermanns studied ill children from three families. The following summer, they found another eight affected families, for a total of 45 symptomatic individuals. It quickly became clear that the misdiagnoses were having serious consequences.
"There were up to six affected individuals in one family," says Dr. Eva Andermann, who is director of neurogenetics at the MNI. "Yet the families were told that this was not hereditary; that it was cerebral palsy, and just bad luck. So they went on and had more children."
A pattern which had not previously been recognized became unmistakable to the Andermanns. "The appearance of children with the disorder is very typical," Eva explains. "They almost resemble each other, as if they were brother and sister. It became obvious that this disorder was common to the Saguenay Lac St. Jean region, because we kept coming across patients in that area with those physical similarities, and with similar symptoms and neurological signs."
Brain imaging techniques then became available which enabled them to identify common nervous system abnormalities, such as absence of the corpus callosum, a structure which connects the right and left hemispheres of the brain.
The Andermanns published the first paper on the disorder in 1972, based on their study of three affected families, in the Transactions of the American Neurological Association. The disease got its name when a neurologist at Hôpital Ste. Justine who knew of the couple's research published a paper referring to the disorder as "Andermann Syndrome."
"We've worked on a lot of diseases," notes Frederick, who last year received the Distinguished Clinical Investigator Award of the American Epilepsy Society and the Milken Foundation. "It's interesting, because you never know what you're going to be identified with, and remembered for."
Andermann Syndrome is characterized by degeneration of both the central and peripheral nervous system. Two-thirds of victims are born without a corpus callosum. Symptoms include a decrease in mental ability, generalized weakness, loss of muscle bulk and scoliosis (lateral curvature of the spine). In their early teens, patients have difficulty walking and are eventually confined to a wheelchair. In their twenties, they often develop psychosis or a hallucinatory disorder.
The Andermanns have examined many victims of the syndrome, but Frederick admits that few therapies are available to help them.
"All we can offer is some physiotherapy, and later straightening of the spine for the scoliosis. The best hope is molecular genetic research."
That's where Dr. Guy Rouleau comes in. In 1989, Rouleau opened a new front in the battle against the disease. Rouleau, who teaches neurology at McGill, is the founder and head of the neurogenetics laboratory at the Montreal General Hospital. In recent years, his lab has helped identify the gene that causes the hereditary form of Lou Gehrig's disease, as well as the gene which causes neurofibromatosis type 2, a hereditary disease which predisposes sufferers to develop brain tumors. If he could do the same for Andermann Syndrome, it may be the first real hope for sufferers.
"My primary research interest is genetic diseases of the nervous system. After I set up my lab, I was contacted by a neurologist in Chicoutimi, Jean Mathieu, who told me that they had a lot of families affected by Andermann Syndrome. He started to systematically collect blood samples for my study."
Last January, Rouleau announced the first genetic breakthrough on the syndrome; working with graduate students, he "mapped" the gene.
"We narrowed the area where the gene is located down to about one-thousandth of the human genome. That size area, on average, should contain about 100 genes. When we have it narrowed down to an area containing about 20 genes or less, we'll start a process of elimination, testing them all for defects."
Rouleau agrees with Andermann that work on the molecular or genetic level offers the best hope for attacking the disease. "The only way we'll ever figure out how to treat this is by finding out the genetic cause."
Once the defective gene is found, prenatal diagnosis will be the most likely immediate application, says Rouleau. "For parents who have someone in the family with the disease, or who already have an affected child and don't want another one, amniocentesis could be done as a form of screening."
Another preventive measure would be for couples to be tested to see if they are both carriers of the defective gene, or the testing of newborns.
Rouleau says that future therapeutic applications of his work will depend largely on what is learned about how the disease develops. "Since the gene is recessive, that means something is absent, therefore something could be replaced, using gene therapy. Or maybe that absence leads to the buildup of a toxin, which would call for an altered diet, or some kind of medication which would eliminate or prevent the formation of the toxin."
A recessive gene only causes a certain condition when both copies are defective (there are two copies of every gene in the human genome). Only people born with two abnormal copies of the Andermann Syndrome gene, whichever gene that turns out to be, acquire the disease.
"The absence of both copies of the normal gene is what causes problems. Normally, if one copy is lost--meaning that it's defective--the remaining normal copy will compensate. But if both copies are abnormal, there is nothing left to compensate for that."
In the case of Andermann Syndrome, the "lost" gene pair is likely responsible for the production of a particular protein.
"We don't know what role that protein has, but it would most likely have to do with the normal development or maintenance of the nervous system. Children with Andermann Syndrome may appear normal at first, but then start to show evidence of delay in development and degeneration of the nervous system.
Any treatments or therapies that emerge will have their greatest impact in Quebec, where the disease is far more concentrated than anywhere else in the world. Most Quebec cases, in turn, are concentrated in the Saguenay Lac St. Jean region, and Charlevoix. Eva Andermann and Rouleau believe that the reason is a phenomenon known as "the founder effect".
"The Quebec population was founded by a small number of people," Rouleau explains, "and the Saguenay Lac St. Jean region was founded by a subgroup of this founder population. That means that the people of the region are distantly related--not cousins or anything like that--but related 100, 150 years back. That kind of relatedness leads to high frequencies of certain genetic diseases, while some other diseases are very rare, depending on what the founders of the population carried."
Since 1993, a private non-profit group, La Fondation des jumelles Coudé, has contributed $90,000 to Rouleau's Andermann Syndrome research. The foundation was formed by parents of twin girls afflicted with the syndrome.
"Funding from the foundation has made it possible to move ahead rapidly. Without their help, our progress would be nearly zero. It's too bad that private funding is the only kind available, but I'm glad that local people are getting together to do something about this devastating disease."