Amyotrophic Lateral Sclerosis (ALS) Genetic Testing: What You Need to Know
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Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease or motor neuron disease in the United Kingdom and Europe, is a neurodegenerative disease that affects nerve cells in the brain and spinal cord.1 This disease worsens over time and often begins with muscle twitching and weakness in an arm or leg, trouble swallowing, or slurred speech. Eventually ALS affects control of the muscles needed to move, speak, eat and breathe.1
Is ALS Genetic?
The exact cause of ALS remains elusive in most cases, but it is generally believed to result from a combination of genetic and environmental factors.2 However, it is estimated that 5-10% of cases are due to a monogenic cause. Understanding the role of genetics in ALS can provide insights into the disease's causes, progression, and potential treatments.2
Intricacies of ALS
Symptoms of ALS, which can vary significantly among individuals, include muscle cramps, difficulty speaking, swallowing or breathing, muscle twitches, and limb weakness. ALS typically commences with muscle weakness or stiffness, progressing to muscle wasting and paralysis.
Clinical Features
Limb Onset
• Muscle weakness
• Atrophy in limbs
• Muscle twitches
• Muscle cramps
Bulbar Onset
• Difficulty chewing or swallowing
• Slurred speech
Frontotemporal Dementia
Less Common Presentations
• Respiratory involvement at onset
• Axial/trunk involvement
Epidemiologic Features
Data from the CDC indicates that approximately 31,000 individuals are currently suffering from ALS in the United States alone.3 On average, 5,000 new cases are diagnosed annually. Notably, ALS exhibits a higher incidence among men than women. The disease typically manifests in individuals aged between 55 and 75 years, with a life expectancy of 2 to 5 years following symptom onset.4
The Role of Genetics in ALS
ALS is a complex neurodegenerative disorder with multifaceted etiology. While the precise cause remains unidentified in most cases, genetics play a significant role in the development of this condition. Genetic variants, most commonly in genes such as C9orf72, SOD1, TARDBP, and FUS, are important risk factors or causes of ALS.5 New data also suggests that intermediate repeat expansions in ATXN2 increase the risk for ALS.6 These variants can disrupt nerve cell function, leading to motor neuron degeneration and eventually, cell death.
Familial ALS
Also known as inherited ALS, familial ALS accounts for approximately 5-10% of all ALS cases.7 In these instances, the disease results from the inheritance of a causative variant in a specific single gene. Genes associated with familial ALS include C9orf72, SOD1, TARDBP, and FUS. Genetic testing can help determine the presence of these variants and can assist in diagnosis and earlier intervention.
Sporadic ALS
Sporadic or isolated ALS, which comprises the remaining 90-95% of ALS cases, occurs in individuals without a known family history of the disease.7 It is important to note that ‘sporadic’ versus ‘familial’ ALS are clinically indistinguishable. Sporadic ALS may also be caused by monogenic variants. It can also be due to a combination of genetic and environmental risk factors. Recent research has identified such risk genetic variants including the NEK1 gene, which is associated with an increased susceptibility to ALS.8 Genetic testing can also help determine the presence of these variants.
Genetic Testing for ALS
Genetic testing is a key tool in understanding genetic components of ALS.
Genetic testing can help aid in diagnosing ALS. However, it's important to understand that not all cases are caused by genetic factors, and a negative test result does not rule out the possibility of developing the disease. Furthermore, the presence of a genetic variant does not guarantee that an individual will develop ALS, as other factors, such as environmental and lifestyle factors, also play a role.
At PreventionGenetics, the C9orf72 hexanucleotide repeat expansion will be performed first as this is the most common cause of ALS. If C9orf72 testing is negative, then the ALS sequencing panel and ATXN2 repeat expansion testing will be performed. Concurrent testing is available upon request.
We also offer an ALS sponsored testing program and have a team of genetics experts dedicated to furthering the molecular diagnosis of ALS. Our team of experts includes Dr. Luke Drury and Dr. Sali Farhan, both members of the ALS ClinGen Gene Curation and Variant Curation Panels.
Learn more about our ALS Panel.
View our sponsored testing programs.
Current Research and Future Directions
With the emergence of precision therapeutics for ALS, understanding the genetic etiology is more important now than ever. We can help. Recent advancements in ALS genetics research have provided significant insights into the genetic factors contributing to this devastating disease.
Our ability to quickly and accurately analyze a comprehensive list of ALS genes has helped make PreventionGenetics the genetic testing lab behind several of the clinical trials and research studies available for ALS patients. We currently support 9 different pharmaceutical companies with their ALS clinical trials and many other research studies.
References
1. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis/symptoms-causes/syc-20354022
2. MedlinePlus. https://medlineplus.gov/genetics/condition/amyotrophic-lateral-sclerosis/#:~:text=About%2090%20to%2095%20percent,depending%20on%20the%20gene%20involved.
3. CDC. (2019, January 31). Amyotrophic lateral sclerosis. Www.cdc.gov. https://www.cdc.gov/als/WhatisALS.html
4. Stages of ALS. (n.d.). The ALS Association. https://www.als.org/understanding-als/stages
5. ALS Genes and Mutations. The ALS Association. (n.d.). Www.als.org. https://www.als.org/research/als-research-topics/genetics#:~:text=Which%20Genes%20Have%20Been%20Linked
6. Glass JD, Dewan R, Ding J, Gibbs JR, Dalgard C, Keagle PJ, Shankaracharya, García-Redondo A, Traynor BJ, Chia R, Landers JE. ATXN2 intermediate expansions in amyotrophic lateral sclerosis. Brain. 2022 Aug 27;145(8):2671-2676. doi: 10.1093/brain/awac167. PMID: 35521889; PMCID: PMC9890463.
7. FYI: Familial Amyotrophic Lateral Sclerosis (FALS) and Genetic Testing. (n.d.). The ALS Association. https://www.als.org/navigating-als/resources/familial-amyotrophic-lateral-sclerosis-fals-and-genetic
8. Yao L, He X, Cui B, Zhao F, Zhou C. NEK1 mutations and the risk of amyotrophic lateral sclerosis (ALS): a meta-analysis. Neurol Sci. 2021 Apr;42(4):1277-1285. doi: 10.1007/s10072-020-05037-6. Epub 2021 Jan 18. PMID: 33462636.
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