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Old 08-01-2007, 05:56 PM #1
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Thumbs Up Understanding the Causes of Amyotrophic Lateral Sclerosis

Understanding the Causes of Amyotrophic Lateral Sclerosis

Richard W. Orrell, M.D.


Amyotrophic lateral sclerosis (ALS) is a human disease resulting from the degeneration of motor neurons in the brain, spinal cord, and peripheral nervous system. The resultant clinical features include weakness of the arms, legs, and face and difficulties with speech, swallowing, and breathing. ALS affects women and men, regardless of ancestry, and the risk of disease increases with age. Its clinical progression is one of the fastest of the neurodegenerative diseases, with death (often from respiratory failure) typically occurring within 3 to 5 years after onset. The incidence is approximately 2 per 100,000 persons per year, and the prevalence is approximately 6 per 100,000 persons.1

Generally speaking, the cause of ALS remains unknown. The most important advance in understanding the cause was provided through the identification of mutations in the SOD1 gene (encoding copper–zinc superoxide dismutase) in about 2% of all patients and in 20% of those with an autosomal dominant form of ALS. The SOD1 gene was found after many years of study; linkage studies of large families with autosomal dominant ALS ultimately proved pivotal in the discovery. Since then, mutations in five additional genes (encoding alsin, angiogenin, dynactin 1, senataxin, and vesicle-associated protein B) have been associated with a motor neuron disease (although often not a typical ALS phenotype) in a few families. There remain regions in the genome — genetic loci — that have been associated with disease but in which a specific gene has yet to be identified.2

Our understanding of the pathogenesis of ALS is also scant. A great deal of research has been done with the use of cellular and animal models, in particular with mice transgenic for the human SOD1 mutations. These mice have some features that are similar to those of patients with ALS, although a unifying understanding of any ALS mechanism remains elusive. Also disappointing is the lack of therapeutic advances built on findings from research in animals. Many therapeutic agents have been tested on mouse models of ALS, but they have so far failed to translate into clinical practice. The only disease-modifying medication for patients with ALS is riluzole, which was licensed more than 10 years ago. It was developed as an inhibitor of glutamate release with antiexcitotoxic effects, and in clinical trials its use has resulted in the extension of survival by approximately 2 to 3 months.3 A recent disappointment has been the trial of minocycline (a second-generation tetracycline with antiinflammatory properties); a preliminary report suggests that it may accelerate disease progression in humans,4 although it had promising effects on a mouse model transgenic for mutated SOD1.5

Although classic studies of linkage and mutation detection continue in the rare families in which the mutated gene has not been identified, clinical genetic studies have moved on from the "simple" genetics of clearly heritable mendelian disorders to the "complex" genetics of diseases that may have multiple genetic influences. This shift has been enabled by high-throughput methods, the cost of which — although considerable — is rapidly falling. At the center of many ongoing studies is the microarray (or "DNA chip") designed to genotype hundreds of thousands of single-nucleotide polymorphisms (SNPs) simultaneously in a single experiment.6 SNPs are single-nucleotide variations in the DNA sequence that can be used as markers for neighboring genetic variation. By comparing the prevalence of a specific SNP in case patients and controls, one can determine whether the chromosomal region represented by the SNP is associated with disease. This approach, known as a high-density genomewide association study, has been used to examine sporadic late-onset Alzheimer's disease.7 Disappointingly, only the well-established risk factor apolipoprotein E (encoded by the APOE gene) was identified with the use of this approach, by Coon et al.7 The study by Coon et al. underscores a limitation of the current tests of "high-density" SNPs: only a single SNP was truly associated with APOE. Chips that genotype larger numbers of SNPs will result in a lower rate of false negative results.

In this issue of the Journal, Dunckley et al.8 describe a genomewide association study of patients with ALS. The associations found in the first-pass analysis were confirmed in two additional series; 10 genetic loci were significantly associated with ALS in all three populations. The most significant association was for a SNP near an uncharacterized gene on chromosome 1. Since the function and relevance of this gene in ALS is not known, the authors showed that the protein it encodes was expressed in spinal cord and non–neural tissue specimens from unaffected persons, as well as in spinal-cord specimens from patients with ALS. Perhaps this pathway, if validated in other studies, could lead to a new approach to treatment of ALS.

One limitation of whole-genome SNP association studies is the need for a large number of patients and controls, because the associations of SNPs with disease typically have low odds ratios. At the same time, hundreds of thousands of tests are carried out, so a high level of significance, together with replication in separate studies, is required for credibility. The most significant association in the present study was found for a SNP near the uncharacterized gene FLJ10986.

Schymick et al.9 also performed a genomewide association study in patients with ALS. They found a number of potential associations, but none implicated a single locus with certainty. The authors did, however, make the results — that is, the P value for each SNP — publicly available, so Dunckley et al. were able to use these data as their second replication series. Kasperaviciute et al.10 recently described a large-scale, pathways-based association study in patients with ALS, involving technology similar to that used by Schymick et al. and Dunckley et al. as well as replication, but they did not find a strong association of any of the tested genes with disease.

So far, these genomic studies raise more questions than they answer. As techniques improve, the specificity and speed of the analyses should also improve. The clinical phenotyping of patients and controls and the clinical interpretation and application of the results should be pursued with the same rigor, enthusiasm, and support as have been applied to the genomic technologies.

Dr. Orrell reports receiving consulting fees from Teva Pharmaceuticals for serving on a data and safety monitoring board. No other potential conflict of interest relevant to this article was reported.


Source Information

From the University Department of Clinical Neurosciences, Institute of Neurology, University College London, London.

This article (10.1056/NEJMe078146) was published at www.nejm.org on August 1, 2007. It will appear in the August 23 issue of the Journal.

References


Mitchell JD, Borasio GD. Amyotrophic lateral sclerosis. Lancet 2007;369:2031-2041. [CrossRef][ISI][Medline]
Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci 2006;7:710-723. [CrossRef][ISI][Medline]
Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 2007;1:CD001447-CD001447. [Medline]
Gordon PH, Moore DH, Florence JM, et al. Results of the phase III randomised controlled trial of minocycline in ALS. Neurology 2007;68:Suppl 1:A90-A90. [CrossRef]
Van Den Bosch L, Tilkin P, Lemmens G, Robberecht W. Minocycline delays disease onset and mortality in a transgenic model of ALS. Neuroreport 2002;13:1067-1070. [CrossRef][ISI][Medline]
Amos CI. Successful design and conduct of genome-wide association studies. Hum Mol Genet (in press).
Coon KE, Myers AJ, Craig DW, et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. J Clin Psychiatry 2007;68:613-618. [ISI][Medline]
Dunckley T, Huentelman MJ, Craig DW, et al. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med 2007;357. DOI: 10.1056/NEJMoa070174.
Schymick JC, Scholz SW, Fung HC, et al. Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 2007;6:322-328. [CrossRef][ISI][Medline]
Kasperaviciute D, Weale ME, Shianna KV, et al. Large-scale pathways-based association study in amyotrophic lateral sclerosis. Brain (in press).
http://content.nejm.org/cgi/content/full/NEJMe078146
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