Amyotrophic Lateral Sclerosis (ALS)

Causes/Inheritance

Approximately 5–10% of amyotrophic lateral sclerosis (ALS) cases are familial, meaning the condition occurs in families with a known history of ALS. The remaining 90–95% are sporadic, arising in individuals without an apparent family history. While environmental factors may play a role, the past decade of research has increasingly highlighted genetic and molecular mechanisms underlying both familial and sporadic ALS.

Causes of Sporadic ALS

Sporadic ALS is not inherited in the traditional sense but is strongly associated with disruptions in key molecular pathways, particularly those involving the RNA-binding protein TDP-43. In over 95% of sporadic ALS cases, abnormal accumulation of misfolded TDP-43 protein in neurons leads to widespread dysregulation of RNA processing. This includes cryptic splicing errors, where hidden or “cryptic” exons are mistakenly incorporated into RNA transcripts, resulting in the production of dysfunctional proteins and progressive motor neuron degeneration. TDP-43 pathology has become a central focus of ALS research over the past five years, reshaping the understanding of sporadic disease mechanisms.

Other contributing factors under investigation include:

• Oxidative stress: An imbalance between reactive oxygen species and antioxidant defenses, potentially damaging motor neurons.
• Mitochondrial dysfunction: Impairments in cellular energy production that make neurons more vulnerable to degeneration.
• Immune system abnormalities: Overactive or dysregulated microglial responses may exacerbate neuronal injury.
• Glutamate excitotoxicity: Excessive glutamate signaling damages nerve cells; riluzole acts in part by reducing glutamate levels.
• Environmental exposures: Certain toxins, military service, and suspected cyanobacterial neurotoxins have been linked to increased risk, though findings remain inconclusive.

Genetic Causes of ALS

Familial ALS is caused by pathogenic mutations passed from one generation to the next, most commonly following an autosomal dominant inheritance pattern. Among these, two genes account for the majority of known familial cases:

C9orf72: The most frequent genetic cause of ALS worldwide, involving abnormal hexanucleotide repeat expansions that disrupt normal cellular function. C9orf72 mutations are also strongly linked to frontotemporal dementia (FTD), highlighting shared mechanisms between the two diseases.

SOD1: Mutations in the superoxide dismutase 1 gene lead to toxic protein aggregation, causing approximately 15% of familial ALS cases in European populations and up to 30% in Asian populations. SOD1 was the first gene identified in ALS and remains central to therapeutic development.

In addition to these major genes, a number of rarer mutations have been implicated in ALS, including FUS, TARDBP (encoding TDP-43), VCP, OPTN, UBQLN2, TBK1, and NEK1, among others. These genes are involved in critical cellular processes such as RNA metabolism, protein homeostasis, axonal transport, and autophagy. Although individually uncommon, these mutations collectively explain a portion of familial and sporadic ALS cases.

Genetic counseling is recommended for patients and their families to clarify inheritance patterns, discuss the likelihood of passing on disease-associated variants, and determine whether genetic testing is appropriate.

Additional reading

• Feldman EL, Goutman SA, Petri S, Mazzini L, Savelieff MG, Shaw PJ, Sobue G. Amyotrophic lateral sclerosis. Lancet. 2022 Oct 15;400(10360):1363-1380. doi: 10.1016/S0140-6736(22)01272-7. Epub 2022 Sep 15. PMID: 36116464; PMCID: PMC10089700. 
• Siddique N, Siddique T. Amyotrophic Lateral Sclerosis Overview. 2001 Mar 23 [Updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1450/

Last revised August 2025