October 13, 2000

Dementia, ALS may be linked

Dementia, ALS may be linked

A multi-center team, including Vanderbilt’s Program in Human Genetics, has linked a new spot in the genome to an inherited form of amyotrophic lateral sclerosis (ALS) combined with dementia.

The finding, reported Oct. 4 in The Journal of the American Medical Association, focuses the search for genes that may cause ALS and dementia to a small region of chromosome nine. It also represents the first evidence that some cases of ALS and fronto-temporal dementia–the type of dementia associated with Alzheimer’s disease–may share a common cause.

ALS, commonly called “Lou Gehrig’s disease,” is a progressive disease characterized by the degeneration and death of motor neurons. As the motor neurons die, the ability of the brain to initiate and control muscle movement is lost, eventually leaving patients totally paralyzed.

ALS usually affects only motor neurons. In rare cases patients show signs of other neurodegenerative disease, including fronto-temporal dementia.

The causes of ALS are not understood. Searching for the genes that underlie inherited ALS–about 10 percent of all ALS cases–may point to the culprits involved in the more common, sporadic form of the disease.

The multi-center team of researchers selected 16 families with autosomal dominant inheritance of ALS (the disease develops if one of the two copies of a culprit gene is defective). The set of families included a total of 549 people, of which 93 were affected with ALS. The researchers conducted a genome-wide search for chromosome areas linked to ALS in these families.

The search uncovered a spot on chromosome nine that was linked to the disease in two of the families. When the researchers examined the clinical records of these two families, they were surprised to find that patients in both families developed motor neuron disease concurrently with progressive dementia. There was no evidence of ALS dementia in the other 14 families.

“This was not something we were looking for–it was a bit of a surprise,” said Jonathan L. Haines, Ph.D., professor of Molecular Physiology and Biophysics and director of the Program in Human Genetics. “A connection between ALS and fronto-temporal dementia had only been hypothesized before and this really solidifies that the two are genetically linked to each other.”

To further confirm the finding, the research team selected four more families–three with members who have ALS concurrent with dementia. The investigators found that in these three families, the same spot in the genome linked to the disease. In the other family, where ALS was not accompanied by dementia, there was no linkage to the chromosome nine site.

Investigators will now “zoom-in” on the defined area of chromosome nine to search for a gene that can cause ALS and dementia.

“If we can figure out what the gene is, it will give us another clue about what’s going on with the pathophysiology of these diseases, and enough clues will eventually lead us to potential therapies or preventions,” Haines said.

The completion of the human genome sequence–announced this summer–will simplify the task of finding the culprit gene on chromosome nine.

“It should be fairly easy now to enumerate and test each gene within the region we defined,” Haines said.

Other centers involved in the study are located at Massachusetts General Hospital, Northwestern University, Massachusetts Institute of Technology, Mayo Clinic, University of Minnesota, and Duke University Medical Center. The research was supported by the Muscular Dystrophy Association, the Amyotrophic Lateral Sclerosis Association, the Howard Hughes Medical Institute, and the National Institutes of Health.