Amyotrophic Lateral Sclerosis

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:

• Variations in the angiogenin ANG gene may predispose individuals to developing ALS, at least in individuals of Scottish or Irish descent [PMID 16501576];
• TXNRD1 SNPs, including rs6539137, rs4630362 and rs10861192 may also play a role in familial ALS [PMID 18996185];
• Mutations in the FUS gene have also been linked to familial ALS [PMID 19251628][PMID 19251627]
• Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. [PMID 21857683]
• A dominant mutation in the ANXA11 gene led to ALS, and functional studies concluded it impairs intracellular protein trafficking 10.1126/scitranslmed.aad9157
• NEK1 mutations may account for up to 3% of familial ALS, according to [PMID 27455347]
• TUBA4A mutations lead to ALS apparently through destabilizing the microtubule network [PMID 25374358]
• Other ALS mutations found via exome sequencing include: TBK1, CCNF, GLE1, MATR3, and CHCHD10 [PMID 27538057]
• Variants located in the low-complexity domains of the protein encoded by the TIA1 gene, such as rs757332023
• Variants in the GLT8D1 gene [PMID 30811981]

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:

• rs12608932, in ch 19p13.3;
• rs2814707 and rs3849942, in ch 9p21.2;
• rs10260404, in the DPP6 gene;
• rs10239794, a neighbor of rs10260404 SNP and forming a risk haplotype with it;
• rs3825776, a SNP on ch 15 in the LIPC gene
• rs12704795, originally known as rs17876088; this variation occurs in the PON2 gene, which encodes a protein involved in the detoxification of certain environmental toxins. [PMID 16822964]
• 3 SNPs in the progranulin GRN gene: rs9897526, rs34424835, rs850713

• Several SNPs near the uncharacterized FLJ10986 gene, from a 1,152 patient study [PMID 17671248]:
  • rs6700125
  • rs6690993
  • rs10493256
  • rs6587852
  • rs1470407
  • rs333662
• Additional SNPs also found in the 1,152 ALS patient study [PMID 17671248]:
• rs13036957, in the PTPRT gene
• rs3771150, in the IL18RAP gene
• rs757863, in the MAGI2 gene
• rs988213, in the LOXHD1 gene
• rs1027615, in ch 12q12
• rs12473579, in ch 2q33.1
• rs17027230, in ch 2q12.1
• rs2836061, in ch 21q22.13
• rs905080, in ch 12q12

• A SNP in the ITPR2 gene [PMID 17827064]

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".