Human genetics study identifies the most common cause of ALS and dementia

ALS, also known as Lou Gehrig's disease, causes destruction of neurons that control voluntary movement. ALS is characterized by a progressive paralysis that often leads to death from respiratory failure within a few years of diagnosis. FTD, the second most common cause of early-onset dementia, is associated with degeneration of the frontal and temporal lobes of the brain and leads to a dramatic deterioration in personality, language and behavior. There have been suggestions that these two disorders share some underlying genetic features.

About 10% of ALS cases and about 50% of FTD cases are thought to be inherited, and, although multiple genes have been linked with the disorders, much of the genetic risk has remained unexplained. "Each new gene implicated in the etiology of ALS or FTD provides fundamental insights into the cellular mechanisms underlying neuron degeneration, as well as facilitating disease modeling and the design and testing of targeted therapeutics," explains Dr. Bryan J. Traynor from the National Institutes of Health who is an author of one of the studies. "Identification of new genes that cause ALS or FTD is of great significance."

Recent research has linked a region on chromosome 9, called 9p21, with both ALS and FTD. Dr. Traynor's group performed an exhaustive next generation genetic analysis of this region in patients with 9p21-associated ALS or FTD, including the group of Finnish ALS patients that had previously been used to identify the association with 9p21. A second research group, led by Dr. Rosa Rademakers from the Mayo Clinic Jacksonville, performed a similar analysis using a large family with ALS and FTD linked to chromosome 9p21.

Both groups discovered a "repeat expansion" within the non-coding region of C9ORF72, a gene whose function is not known. This mutation argues that both ALS and FTD are diseases caused by defects in RNA metabolism. This idea is in line with other recent work in ALS, FTD and neurodegenerative diseases more broadly stressing RNA-driven disease pathology.

The researchers searched for clinical and pathological characteristics associated with the mutation. "Our findings suggest multiple potential disease mechanisms associated with this repeat expansion," says Dr. Rademakers. "For example, we found evidence of a previously described process where the expansion region accumulates inside the neurons as abnormal structures called RNA foci that are likely to promote disease pathogenesis. Further molecular studies are needed to explore how these mechanisms contribute to neurodegeneration."

Taken together, the findings of both studies suggest that the repeat expansion in C9ORF72 is a major cause of an unprecedented proportion of both sporadic and familial FTD and ALS cases. The mutation explains nearly half of all cases in Finland alone and at least a third of all familial FTD and ALS cases in Europeans. Importantly, the mutation was also associated with a number of non-inherited cases of ALS and FTD. "With this discovery we can now explain nearly all of familial ALS disease in Finland, which has the highest incidence of ALS in the world. In the longer term, the identification of the genetic lesion underlying chromosome 9p21-linked ALS and FTD, together with the observed high frequency in these patient populations, makes it an ideal target for drug development aimed at amelioration of the disease process," concludes Dr. Traynor.