The finding was published online ahead of print in this week’s issue of the journal em>Neuron)00797-5.
Michael G. Benatar, M.D., Ph.D., associate professor of neurology, chief of the Neuromuscular Division and the Walter Bradley Chair in ALS Research, and Joanne Wuu, Sc.M., research assistant professor of neurology in the Clinical Translational Research Division, are co-authors of the Miller School arm of this landmark study.
Investigators have identified on chromosome 9 a genetic abnormality that is probably the most common cause of familial ALS discovered to date. More importantly, this genetic mutation may also be the cause of disease in a significant minority of individuals with apparently sporadic (non-familial) ALS. “This finding considerably pries open the door to new avenues of discovery in both familial and sporadic ALS,” says Benatar.
Amyotrophic lateral sclerosis, like Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease, is a neurodegenerative disease. ALS attacks the motor nerves and leads to progressive muscle weakness. Currently, there is no effective therapy for ALS and the lifespan of those affected by this devastating disease is typically only three to five years.
Although the cause of sporadic ALS remains a mystery, scientists have made some progress in identifying the genes responsible for familial ALS. Mutations in the SOD1 gene, for example, are responsible for about 20 percent of familial ALS, and mutations in several other genes are responsible for another five to ten percent of cases. However, since only about eight percent of ALS is familial, these genes collectively only explain about two to three percent of all cases of ALS. That is, until now.
Scientists have known for some time that a gene on chromosome 9 was associated with ALS and a form of dementia known as frontotemporal dementia (FTD). In the study published this week, which examined a large number of patients from Finland, as well as smaller numbers from Italy, the United Kingdom and the United States, scientists have discovered a mutation in the C9ORF72 gene on chromosome 9. This mutation is known as a “hexanucleotide repeat” (i.e. six “letters” of the genetic code – GGGGCC – are repeated over and over). Under normal circumstances, this sequence of letters may be repeated up to 20 times. In ALS patients with this mutation, however, this sequence of letters is repeated many more times – at least 30, but sometimes as high as 250 or more. A team from the Mayo Clinic Jacksonville has independently identified the same repeat expansion as the genetic cause of FTD/ALS, and their study is reported in the same issue of Neuron.
Benatar, who leads a large ALS research program at the Miller School, explains that these findings represent a “very substantive breakthrough.” Benatar studies patients with sporadic ALS as well as more than 400 families across the U.S. with the familial form of this disease. With the genetic cause now identified in a much larger number of familial (and perhaps also some sporadic) ALS cases, he expects to be able to expand an ongoing study of people at genetic risk for ALS, but who have not yet shown any symptoms of the disease.
“Studying the genetics of ALS offers a unique opportunity to better understand the biology of both the familial and sporadic forms of the disease,” says Benatar. “The discovery of mutations in C9ORF72 in both familial and sporadic ALS exemplifies this point. Such insights should greatly facilitate our efforts to develop effective therapies for patients with ALS.”