Genetics

Overview

Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by the progressive loss of motor neurons, leading to muscle weakness and paralysis. While the majority of ALS cases are considered sporadic with no clear family history, around 5-10% are inherited, suggesting a genetic component.

A number of genes have been identified as associated with familial ALS (fALS). The most common causative genes as of 2023 include:

C9orf72: Alterations in this particular gene represent the predominant genetic factor contributing to ALS, constituting a significant portion—ranging from 25% to 40% in familial cases (varies by population) and approximately 6% in sporadic cases.

SOD1: Mutations in the superoxide dismutase 1 gene are linked to an inherited form of ALS. The mutated protein may contribute to motor neuron degeneration.

FUS: Mutations in the fused in sarcoma gene are associated with fALS. The FUS protein plays a role in RNA processing.

TARDBP (TDP-43): Mutations in the TAR DNA-binding protein gene can lead to abnormal accumulation of TDP-43 protein.

Genetic testing can identify mutations in these genes, particularly in cases with a family history of ALS. However, the genetics of ALS are highly complex, and environmental factors may interact with genetic susceptibility.

We highly recommend speaking with your physician or a genetic counselor if you have specific questions about a family history of ALS or genetic testing.

Understanding the genetic basis of ALS is crucial for advancing research, developing targeted therapies, and providing genetic counseling for individuals with a family history of the disease. Ongoing studies continue to uncover new genetic factors and explore the intricate mechanisms underlying ALS development.

Sources

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Ghasemi, M., & Brown, R. H., Jr (2018). Genetics of Amyotrophic Lateral Sclerosis. Cold Spring Harbor perspectives in medicine, 8(5), a024125. https://doi.org/10.1101/cshperspect.a024125  

Jankovska, N., & Matej, R. (2021). Molecular Pathology of ALS: What We Currently Know and What Important Information Is Still Missing. Diagnostics (Basel, Switzerland), 11(8), 1365. https://doi.org/10.3390/diagnostics11081365  

Vance, C., Rogelj, B., Hortobágyi, T., De Vos, K. J., Nishimura, A. L., Sreedharan, J., Hu, X., Smith, B., Ruddy, D., Wright, P., Ganesalingam, J., Williams, K. L., Tripathi, V., Al-Saraj, S., Al-Chalabi, A., Leigh, P. N., Blair, I. P., Nicholson, G., de Belleroche, J., Gallo, J. M., … Shaw, C. E. (2009). Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science (New York, N.Y.), 323(5918), 1208–1211. https://doi.org/10.1126/science.1165942