Have questions? Visit https://www.reddit.com/r/SNPedia

Amyotrophic Lateral Sclerosis

From SNPedia
(Redirected from ALS)

Often first diagnosed in adults based on asymmetric muscle issues, ALS is a neurodegenerative disorder that can lead to fatal paralysis.

ALS, formally known as amyotrophic lateral sclerosis and informally as Lou Gehrig's disease, occurs in both a less common familial form (i.e. an inherited form, known as ALS1), and perhaps independently, in a sporadic form. Only 5 - 10% of ALS cases are thought to be inherited.

So far (Sept. 2011), a large hexanucleotide (GGGGCC) repeat expansion in the C9ORF72 locus appears to be the most common genetic abnormality in both frontotemporal dementia (11.7%) and familial ALS (23.5%) cases.10.1016/j.neuron.2011.09.01010.1016/j.neuron.2011.09.011

A mutation (rs80265967)]in the SOD1 (superoxide dismutase) gene appears to be the cause of 1/5th of the inherited cases of ALS. Accounting for less cases of familial ALS than SOD1 mutations, variations in several other genes may bring about familial ALS, including:

The sporadic (and more common) form of ALS is now somewhat associated with pathological changes in a protein known as TDP-43, and these changes are not often seen in the SOD1 associated (inherited) forms of ALS. [PMID 17469116] This implies that the inherited and sporadic forms may arise by different mechanisms. However, more recently, several mutations in exon 6 of the corresponding gene, TARDBP, have been found in at least some cases of both familial and sporadic ALS. These (rare) mutations are known as G294A, Q331K, and M337V.[PMID 18309045]

A January 2008 article in SCIENCE suggests that if the SNPs being found in whole genome association studies associated with (slightly) increased risk for ALS aren't statistical flukes, then either any one its own has only minor impact, or ALS might be a spectrum of conditions lumped together clinically while being genetically composed of many different subtypes.[PMID 18174402]

Another January 2008 article presents a model combining ~50 SNPs from genes in axon guidance pathways said to predict susceptibility to ALS, survival free of ALS, and age of onset of ALS.[PMID 18197259]; Medpage news article

In August 2010, researchers found that expansions of a polyglutamine repeat in the ATXN2 gene, a modifier of TDP-43 toxicity, were associated with increased risk for ALS. This type of change to the ATXN2 gene may account for ~5% of all sporadic ALS cases, making it the most common susceptibilty gene known so far.[PMID 20740007]

SNPs that have been (individually) associated with the sporadic form of ALS include:

Also, a variation known as D148E (G allele) in the APEX gene is associated with slighly increased (~1.5 fold) risk for ALS in both Scottish and Irish populations. [PMID 10371543, PMID 15557516]

[PMID 19193627] A study of 553 individuals with ALS and 2,338 controls found 0 SNPs to survive replication, just like "all previously reported loci for ALS, which have also failed to replicate successfully".