insideALS for HCPs is…

A place for US healthcare professionals interested in learning more about the rapidly changing science of genetic ALS, featuring content co-created with key medical experts in the field.

Learn more about the science of genetic ALS.

Patient portrayal

Not all ALS is the same.

ALS is a rare, fatal, neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord.1 Onset of ALS is usually between the ages of 40 to 70, with the average age at diagnosis being 55 years. Unfortunately, typical life expectancy following diagnosis is only 3 to 5 years.1,2 ALS is a complex disease likely underpinned by the presence of different pathogenic mechanisms, including multiple genetic factors.2

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Understanding “genetic ALS” and the role it plays.

ALS has historically been divided into 2 categories: familial ALS (fALS) and sporadic ALS (sALS). Familial ALS is defined by a known family history of more than one relation with a confirmed diagnosis of ALS, while sporadic ALS includes everyone else.1 Many ALS patients may not be aware of a family history of disease.

Recent scientific discoveries have identified more than 25 ALS-associated genes that may play a role in disease pathology, a number of which have been discovered in both fALS and sALS patients.2 Currently, fALS is estimated to be 5% to 10% of the total ALS population2—of these approximately 70% have a known genetic component.3 sALS is 90% to 95% of the total ALS population and of these  approximately 10% have a known genetic component.4–7

Genetic ALS makes up more than 10% of all ALS cases.8 Although it makes up a significant percentage of familial ALS cases, there are also sporadic ALS cases that can be linked to genetic causation. By definition, sporadic ALS patients do not have a known family history of ALS.1,6

A closer look at the 2 most common gene mutations in ALS

The discovery and investigation of these genes hold great promise for a better understanding of genetic ALS and disease management in the future.


SOD1 (superoxide dismutase 1) was the first gene discovered to be associated with ALS, identified in 1993.9 SOD1 accounts for approximately 15% of fALS patients and has been found in ~1% of sALS patients.10 C9orf72 (chromosome 9 open reading frame 72), discovered in 2011,7 accounts for approximately 33% of identified  fALS patients and has been found to account for ~5% of sALS patients.10 These 2 genes are the most common gene mutations in genetic ALS, but there are many others, including TARDBP (~3.3% for fALS and ~0.5% for sALS), and FUS (~3.0% for fALS and ~0.4% for sALS).*10,11


*based on global population data.

FAMILIAL ALS

Whole-genome or exome sequencing technology has assisted researchers in identifying more than 25 genes associated with familial ALS cases.2


Genetic mutations

  • C9orf72 ~33%

  • SOD1 ~15%

  • TARDBP ~4%

  • FUS ~3%

  • OTHER ~7%

  • UNKNOWN ~37%

Estimates of percentages are from European sources.

SPORADIC ALS

Although genetic testing is often limited to patients with a family history of ALS, research shows ~10% of sporadic ALS may have a genetic cause.6,12


 

  • C9orf72 ~5%

  • SOD1 ~1%

  • TARDBP ~1%

  • FUS ~1%

  • OTHER ~1%

  • UNKNOWN ~88%

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SOD1

~50% of SOD1-ALS patients do not have a known family history 4,5,7,10,13

More than 10% of ALS patients are estimated to have genetic ALS8

Of those, approximately 1 in 5 genetic ALS patients have the SOD1 mutation13

But only half of those have a known family history of ALS.4,5,7,10,13

Mutations in the SOD1 gene were the first identified genetic cause of ALS.11,13

SOD1-ALS accounts for approximately ~2% of total ALS cases and ~15% of fALS cases.8,10,13 However, it should be noted that ~50% of SOD1-ALS patients do not have a known family history.4,5,7,10,13

SOD1 is an enzyme that is responsible for the removal of superoxide free radicals, which is important for cellular health. Mutated SOD1 gene is prone to misfolding that can interfere in multiple cellular processes and may result in oxidative damage to cells.4,14

C9orf72

C9orf72 is the gene most commonly mutated in genetic ALS.10

The C9orf72 mutation involved in genetic ALS is what is called a “repeat expansion,” meaning the mutated gene has too many copies of the same string of nucleotides, which is thought to be pathogenic. In healthy individuals without repeat expansion of the C9orf72 gene, there are typically less than 20 to 30 repeats, but in people with a C9orf72 mutation, the repeat can occur in the order of hundreds or even thousands.6,15

Patient portrayal

Genetic testing for all ALS patients?

The importance of discovering which genetic form of ALS may be affecting the patient.

Genetic testing for all ALS patients may help provide a better understanding of the basis of their condition, allowing accurate risk assessment and a more comprehensive healthcare decisions and life choices.8 Clinical trials specific to genetic forms of ALS offer a reason to discover which ALS-associated mutation(s) a patient may carry.

Genetic testing for patients with seemingly sporadic ALS.

Even though the percentage of sALS cases with a genetic component is smaller than fALS cases (approximately 10% of sALS cases compared to ~70% of fALS cases), their total number may account for the majority of ALS cases associated with genetic causation. This is because sALS cases make up about 90-95% of all ALS cases.4–7

Total estimated ALS population: 222,8017
Est. population: 200,5204
sALS
~90-95% of total4
Est. population: 22,280
fALS
~5-10% of total4
~10% of sALS patients have a known genetic component13
Est. population: 20,0526
~70% of fALS patients have a known genetic component13
Est. population: 15,5966
sALS
~90-95% of total4
Est. population: 200,5204
~10% of sALS patients have a known genetic component13
Est. population: 20,0526
fALS
~5%-10% of total4
Est. population: 22,280
~70% of fALS patients have a known genetic component13
Est. population: 15,5966
Patient estimates based on 222,801 patients worldwide (2015). Worldwide ALS patient population estimates based on representative country incidence rates applied to their continent's population, as well as a pooled analysis of Europe.7

The science of genetic ALS is evolving rapidly, as is our understanding of its pathogenesis. New technology is enabling the ongoing discovery of additional genes and mutations, and clinical trials are actively enrolling eligible patients. The need to stay up to date with information – especially when it comes to the thinking on genetic testing – is important to helping those living with ALS.

References

1. Brown RH, Al-Chalabi A. Amyotrophic Lateral Sclerosis. NEJM. 2017; 377: 162-72.

2. Nguyen HP, Van Broeckhoven C, van der Zee J. ALS Genes in the Genomic Era and their Implications for FTD. Trends Genet. 2018;34(6):404-423.

3. Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 2014;17(1):17-23.

4. Zarei S, Carr K, Reiley L, et al. A comprehensive review of amyotrophic lateral sclerosis. Surg Neurol Int. 2015;6:171.

5. Byrne S, Walsh C, Lynch C, et al. Rate of familial amyotrophic lateral sclerosis: a systemic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2011;82:623-627.

6. Volk E, Weishaupt JH, Andersen PM, et al. Current knowledge, and recent insights into the genetic basis of amyotrophic lateral sclerosis. Medgen. 2018;30:252-258.

7. Arthur KC, Calvo A, Price TR, et al. Projected increase in amyotrophic lateral sclerosis from 2015 to 2040. Nat Commun. 2016;7:12408.

8. Roggenbuck J, Quick A, Kolb SJ. Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians. Genet Med. 2017;19(3):267-274.

9. Rosen DR. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;364(6435):362.

10. Zou ZY, Zhou ZR, Che CH, et al. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2017;88(7):540-549.

11. Bali T, Self W, Liu J, et al. Defining SOD1 ALS natural history to guide therapeutic clinical trial design. J Neurol Neurosurg Psychiatry. 2017;88(2):99-105.

12. Vajda A, McLaughlin RL, Heverin M, et al. Genetic testing in ALS: A survey of current practices. Neurology. 2017;88(10):991-999.

13. Bunton-Stasyshyn RK, Saccon RA, Fratta P, et al. SOD1 Function and Its Implications for Amyotrophic Lateral Sclerosis Pathology: New and Renascent Themes. Neuroscientist. 2015;21(5):519-529.

14. Robberecht W, Philips T. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci. 2013.

15. Leko MB, Zupunski V, Kirincich J, et al. Moleucular mechanisms of neurodegeneration related to C9orf72 hexanucleotide repeat expansion. Hindawi. Behavioural Neurology. 2019: 1-18.