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Genetics of familial amyotrophic lateral sclerosis

From the Center for the Study of Brain Diseases, University of Montreal, CHUM Research Center–Notre-Dame Hospital, Montreal, Quebec, Canada.

Address correspondence and reprint requests to Dr. Guy A. Rouleau, Center for the Study of Brain Diseases, University of Montreal, CHUM Research Center–Notre-Dame Hospital, J.A. de Sève Pavilion, Room Y-3633, 1560, Sherbrooke St. East, Montreal, QC, Canada, H2L 4M1 guy.rouleau{at}umontreal.ca

The completion of the Human Genome Project, together with a better understanding of some of the emerging genetic patterns of human disease, has enabled a thorough examination of the most appropriate genetic models for amyotrophic lateral sclerosis (ALS). The pathology and epidemiology of ALS have been intensively studied since Adar, Charcot, and Duchenne first described the disease in the 1860s. Results of genetic studies that have emerged over the past two decades have led to the identification of SOD1 as a well-established causative gene for ALS. However, the identification of SOD1 has not been followed up by the identification of other genes responsible for classic ALS. This leads to the speculation that more complex genetic mechanisms are involved than initially assumed. While mutations in single genes are still likely to constitute a small proportion of ALS cases, the genes responsible for ALS in families with clusters of two or three affected individuals, and more particularly in sporadic cases, are far from being determined. Multigenic, somatic mutation, and gene–environment models may all contribute to the genetic etiology of ALS. The challenge now lies in determining which models are the most appropriate to dissect out the genetic components involved. This research will ultimately aid in identifying the cumulative risk of developing ALS.

GLOSSARY: ALS = amyotrophic lateral sclerosis; FALS = familial ALS; FTD = frontotemporal dementia; HSP = hereditary spastic paraplegia; PDC = Parkinson-dementia complex; PLS = primary lateral sclerosis; PON = paraoxonase; SALS = sporadic ALS; SBMA = spinal and bulbar muscular atrophy; SMA = spinal muscular atrophy; SNP = single nucleotide polymorphism.

This work was supported by grants from the Muscular Dystrophy Association and Amyotrophic Lateral Sclerosis Association. P.N.V. and G.A.R. are supported by funds from the Canadian Institutes of Health Research.

Disclosure: The authors report no conflicts of interest.

Supplemental data at www.neurology.org

Received March 2, 2007. Accepted in final form June 26, 2007.

The complete reference list can be found on the Neurology® Web site at www.neurology.org.

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