The Basics Of ALS Genetics

Humans are made up of cells, which are the building blocks of our organs and body. Inside each cell, we have a DNA sequence. This sequence is the blueprint needed to build and maintain a human being. This DNA sequence is made up of individual DNA pieces called bases. A specific section of DNA bases is known as a gene, which defines our traits and characteristics. A human genome (the entire blueprint) is made up of six billion DNA bases and approximately 20,000 genes.

Genes are passed on from parent to child, resulting in family members having similar features. We have two copies of most genes, with one inherited from a father (sperm) and one from a mother (egg). Genes carry instructions for how to produce things our body needs, such as proteins. Proteins are building blocks for cells, and what our body uses for normal functioning.

Sometimes, due to internal issues while replicating our DNA or external factors, we can have errors in our DNA sequence. These errors happen all the time, in every person. While our bodies have mechanisms to fix these errors, sometimes corrections are not possible, leading to permanent variations in our genes.

A genetic variant is an alteration in the normal sequence of a gene. Normally, a DNA base is altered, missing, or added. Usually these variants are benign, but sometimes they can be pathogenic.

Pathogenic variants can change the instructions for protein production. Proteins produced from these altered genes might not function the way they are supposed to, or the body might not be able to produce them at all. This can alter normal bodily functions, and potentially lead to disease.

Genetic code errors are frequently referred to as “mutations.” This site will use the term “variant” where possible, which means the same thing.

Gene variants that are inherited from your parents are called hereditary. Not every variant the parent has will be passed on to their children, as this depends on the gene and genetic pattern of inheritance.

You can also develop new variants throughout your life, called acquired variants, and there is little to no risk of passing these genes on to your children.

While researchers are still working to understand the exact causes of ALS, it is known that some cases are caused by a genetic variant.

Several genes have been identified that when altered, can contribute to disease. Approximately five to ten percent of people living with ALS will have a family history of the disease. A family history means multiple family members were affected by the disease, due to a hereditary variant in a gene related to ALS.

This is traditionally termed “familial” ALS (FALS), and in some cases, there may be a shared history of frontotemporal dementia (FTD). For some genes, the relation to FTD is stronger.*

*ALS Canada is working to provide better information and understanding on the ALS & FTD spectrum to better support this community. In the meantime, for more information, please check the resources:

For the ninety to ninety-five percent of individuals living with ALS without an obvious family history, traditionally referred to as “sporadic”, it is estimated that between eleven to sixteen percent of cases are caused by known ALS variants.

These individuals, living with seemingly “sporadic” ALS, might have acquired a spontaneous (acquired) variant throughout their lives, their family history information was lacking, or the disease didn’t manifest in other family members. We are still working to better understand the origins of those with variants in known ALS genes and no defined family history.

There is current debate about how the terms “sporadic” and familial ALS are outdated and need to be reevaluated in terms of genetic ALS.

You can find more information on these genes below.

A genetic counsellor is the best person to advise on the risk of an altered ALS gene being passed on to your children. In the majority of cases, the variant has a fifty percent chance of being passed on to a new generation, which is a dominant pattern of inheritance.

The parent has no control over whether the altered gene will be passed on to their children. Whether it is passed on or not is determined by genetic chance, and nothing can be done to change the pattern of inheritance. For those using in vitro fertilization (IVF), many clinics will offer preimplantation genetic testing to screen for specific genetic variants, including ALS. It is important to speak with a genetic counsellor for anyone wishing to explore this option.

If a child does not inherit the gene variant for ALS, they cannot pass it on to their own children.

The proportion of individuals with a genetic variant who will eventually develop the disease is known as penetrance. If a variant has eighty percent penetrance, eighty percent of gene carriers will eventually show symptoms of the disease.

Different variants have different penetrance, hence the importance of genetic counselling to assess your family risk.

A resource from the International Alliance of ALS/MND Associations on the basics of ALS genetics.

These three fact sheets by the International Alliance of ALS/MND Associations provide an overview of genetics.

For additional resources related to specific ALS genes, please visit the Additional ALS Genetic Resources page.

Genetics:

• A type of variant, called a repeat expansion, in a gene called C9orf72, is attributed to causing ALS, as well as frontotemporal dementia (FTD).
• A repeat expansion is when a section of the genetic code is repeated multiple times, impacting how the genetic code is read. The segment of the gene expanded in ALS/FTD is GGGGCC (each letter is a DNA base).
• Research is ongoing to identify how variants in C9orf72 contribute to ALS/FTD. Multiple theories exist and are currently being studied worldwide, with researchers investigating whether it is the loss of the normal protein function that contributes to disease, if the altered RNA and/or protein gains a toxic function, or if it is a combination of both.
• Since the discovery of C9orf72’s connection to ALS and FTD in 2011, it has become one of the most studied topics in the field.

Prevalence and clinical presentation:

• C9orf72 variants are the most common genetic cause of ALS, believed to be responsible for approximately twenty-five to forty per cent of familial ALS cases and around five to ten per cent of individuals with no obvious family history*[1], [2]. The understanding of the likelihood that someone with a repeat expansion will develop disease, a term known as penetrance, is still evolving. A study published in 2023 suggests it might be lower than previously thought, but families can have unique experiences with the disease prevalence and onset. Results from this study should stimulate a much more focused examination and yield better answers about C9orf72 penetrance in the future.
• It is not clear yet what contributes to the development of ALS or FTD in an individual. The ALS and FTD clinical and research communities are working together to better understand the connection between the two diseases and what that might mean for future education, care and treatment. Talking to a genetic counsellor is important for more information available on clinical presentation and family history where applicable.

Clinical trials and therapies:

• There are currently no approved therapies targeting the C9orf72 genetic variant that contributes to ALS/FTD.
• A few clinical trials aimed at individuals with C9orf72-ALS have been conducted in recent years, including:
  • Phase 2a study of TPN-101 by Transposon Therapeutics;
  • Phase 2a of LAM-002A by OrphAI Therapeutics
  • Phase 1 clinical trials of antisense oligonucleotides (ASO) BIIB078 by Biogen and WVE-004 by Wave Life Sciences.
  • The Biogen (press release) and Wave (press release) clinical trials, investigating ASOs, were terminated due to a lack of efficacy. In other words, the clinical trials did not meet the intended end results. The field has learned a lot from these trials in how to move forward with targeting C9orf72.
• Preliminary results from LAM-002A have been presented and it is anticipated it will lead to additional studies to evaluate its potential to affect ALS.
• It is expected that more clinical trials targeting C9orf72-ALS/FTD will be available soon as a large proportion of work done in the field is focused on understanding and targeting mechanisms that lead to disease development.

Genetics:

• The SOD1 gene encodes the information to make a protein called superoxide dismutase 1. This protein helps cells to function properly by clearing toxic byproducts called reactive oxygen species. These byproducts are created naturally in the cell after normal cellular processes and must be broken down regularly to prevent cell damage.
• Many variants in this gene can lead to a defective version of this protein, which becomes toxic and disrupts normal biology in cells, causing ALS.
• Since 1993, when the SOD1 gene was discovered to be connected to ALS, over 200 different variants have been found in it.

Prevalence and clinical presentation:

• Variants in the SOD1 gene are believed to cause ten to thirty percent of familial ALS cases and approximately one to four percent of individuals with no obvious family history*[1][2][3].
• Different variants in this gene may be associated with a slower or faster progression of the disease. Talking to a genetic counsellor is important to gain more information on specific variants, the role of family history, and associated clinical presentation.
• While the majority of individuals with SOD1 genetic variants are linked to known family history, several examples have been documented where variants are identified in individuals with no obvious hereditary link (these individuals will often be classified as having “sporadic ALS”) as mentioned above.

Clinical trials and therapies:

You can find current clinical trials targeting the SOD1 gene on our Research Opportunities page.

• Tofersen (Qalsody) Tofersen is an investigational therapy for the treatment of SOD1-ALS, developed by Biogen. See drug page.

• Canadian status and how to access it:
  • Qalsody (tofersen) is available to Canadians through Biogen’s Early Access Program.
  • In March 2024, Biogen Canada announced that Health Canada has accepted its New Drug Submission (NDS) for tofersen for the treatment of ALS in adults living with SOD1-ALS. This step triggers a thorough regulatory review of the therapy, which will result in the decision as to whether tofersen will be approved for use in Canada. Learn more here.

• International status and additional information:
  • On April 25, 2023, the U.S. Food and Drug Administration (FDA) approved Qalsody (tofersen) for the treatment of SOD1-ALS under the Accelerated Approval pathway, and On May 30, 2024, the European Commission (EC) has granted marketing authorization for Qalsody (tofersen) under exceptional circumstances. Learn more here.
  • Tofersen – ALS Association Reference
  • FDA Grants Accelerated Approval for QALSODY™ (tofersen) for SOD1-ALS, a Major Scientific Advancement as the First Treatment to Target a Genetic Cause of ALS.

Genetics:

• The TARDBP gene encodes the information to make an important protein called TAR DNA binding protein 43 (TDP-43). TDP-43 plays many roles in gene regulation, RNA and protein biology, and normal cell functioning. TDP-43 is typically found in the nucleus of the cell, which houses DNA, but in most cases of ALS, the protein ends up in the cytoplasm (the portion of the cell outside of the nucleus) and can form clumps called aggregates. Researchers are working to understand if the vulnerability of motor neurons to abnormal TDP-43 biology is due to a loss of its normal function in the nucleus, an extra toxic function in the nucleus or cytoplasm, or a combination of these.
• The connection of ALS and frontotemporal dementia (FTD) to TARDBP genetic variants didn’t happen until 2008. Since then, over 50 different variants have also been found related to the TARDBP gene.
• Since then, it has also been discovered that the majority of ALS cases have abnormal TDP-43 biology, regardless of a genetic variant. Currently, it is believed that more than ninety percent of ALS cases have abnormal TDP-43 biology, making restoration of its proper functioning an important target to explore in ALS research.

Prevalence and clinical presentation:

• Mutations in the TARDBP gene cause about four to five per cent of familial ALS cases and are found in about one per cent of individuals with no obvious family history.*[1]
• TARDBP variants can also cause FTD or ALS/FTD. Talking to a genetic counsellor is important for more information available about clinical presentation.

Clinical trials and therapies:

• There are currently no clinical trials or therapies directly targeting the TARDBP genetic form of ALS.
• However, given that TDP-43 biology is abnormal in most cases of ALS, most other trials not aimed specifically at SOD1 or FUS may be viable for someone with a TDP-43 variant. Additionally, certain clinical trials are targeting biology believed to be disrupted by abnormal TDP-43, such as restoration of stathmin-2 (STMN2).
• UNC13A, a target also believed to play a role in TDP-43 pathology, is being targeted by pharmaceutical companies such as AcuraStem and QurAlis, and clinical trials are expected soon.
• One of the first clinical trials to target TDP-43 biology involved the use of an antisense oligonucleotide (ASO – BIIB105) to reduce the levels of a protein called ataxin-2 (ATXN2), that has demonstrated benefit in multiple TDP-43 animal model studies. Lowering levels of ATXN2 was believed to reduce TDP-43 toxicity. Preliminary results were negative for a significant effect on disease and the sponsors, Biogen and Ionis have halted BIIB105’s further development.

Genetics:

• The FUS gene contains the instructions to make a protein called fused in sarcoma (FUS). This protein is primarily located in the nucleus of the cell, and it is believed to contribute to normal cell function by playing a role in the complex biology between RNA and proteins. In ALS, researchers have discovered that variants in the FUS gene lead to creation of a defective FUS protein, causing toxicity to motor neurons.
• Specific types of FUS variants have also been identified to contribute to juvenile onset ALS (occurring in individuals under 25 years old). Clinicians diagnosing an individual with younger onset of disease are encouraged to consider advising genetic counselling and testing, while informing them about the ongoing clinical trial by Ionis Pharmaceuticals, specifically targeting FUS.
• Since the discovery of its connection to ALS and frontotemporal dementia (FTD) in 2009, 50 different variants have been found related to the FUS gene.

Prevalence and clinical presentation:

• FUS genetic variants cause about three to six per cent of familial ALS cases and are found in about one per cent of individuals with no obvious family history*[1][2][3]. FUS variants can also lead to frontotemporal dementia and ALS/FTD. In clinical presentation, FUS-ALS often presents itself with an early-onset and faster rate of disease progression. Talking to a genetic counsellor is important for more information available about clinical presentation.

Clinical trials and therapies:

• There are currently no approved therapies targeting FUS-ALS.
• You can find current clinical trials targeting the SOD1 gene on our Research Opportunities page.
  • Ionis Pharmaceuticals is currently recruiting for a clinical trial of an antisense oligonucleotide (ASO) called ulefnersen, designed to target the reduction of FUS protein levels.