Risk Factors for Sporadic Amyotrophic Lateral Sclerosis

Scientists using whole-genome analysis are beginning to uncover susceptibility factors underlying sporadic ALS.

About 10 percent of all cases of amyotrophic lateral sclerosis (ALS) are inherited. The others are sporadic and are attributed to a combination of genetic susceptibility and environmental agents. To understand age-related neurodegenerative diseases, scientists at the nonprofit Translational Genomics Research Institute in Arizona have used methods derived from the U.S. Human Genome Project. In a study involving three different cohorts from ALS Centers throughout the country (total, 1287 white patients with sporadic ALS and 1567 healthy controls), Dunckley and colleagues used gene chips to map 766,955 single nucleotide polymorphisms (SNPs).

The researchers found 10 genetic foci that were significantly associated with the disease in all three groups. The tightest association was with a SNP near a gene called FLJ10986; this protein was found in spinal cord and cerebrospinal fluid of both ALS patients and controls. The normal function of this protein is not certain, but it seems to be involved in maintaining the cytoskeletal integrity of neurons and other cells. The authors concluded that numerous low-risk susceptibility factors are at work.

In another approach to identifying genetic risk factors for sporadic ALS, Cronin and colleagues used more focused SNPs associated with genes encoding enzymes that hydrolyze organophosphate insecticides, among other toxins. These three paraoxonase genes are located on chromosome 7q21.3. PON1 is most centromeric, followed by PON3 and then PON2. In an Irish population (221 patients and 202 controls), PON1 and PON3 were associated with sporadic ALS.

Comment

These results must be replicated in other populations, and the normal function of FLJ10986 requires study. If we could identify people at risk for sporadic ALS, it might be possible to prevent or to treat the disease. These two studies do not make either possibility a reality, but they do indicate that both goals might be reasonable.

Reviewing Author

Lewis P. Rowland, MD

Citation(s):

Dunckley T et al. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med 2007 Aug 23; 357:775.

Cronin S et al. Paraoxonase promoter and intronic variants modify risk of sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2007 Sep; 78:984.