Molecular ALS subtypes linked to age of disease onset, survival
Subtypes are based on gene activity patterns, instead of where symptoms occur
Researchers have characterized three molecular subtypes of amyotrophic lateral sclerosis (ALS), each one associated with different clinical outcomes, including age of disease onset, disease duration, and survival.
These subtypes are based on unique patterns of gene activity in patient brain tissue and were independent of where the onset of symptoms occurred, such as the limbs or bulbar region (involved in speaking and swallowing), which is currently used to classify ALS types.
The subtypes showed that different underlying mechanisms may cause ALS and may also explain the wide variability, or heterogeneity, in how it presents and how patients respond to treatment.
“These results suggest independent disease mechanisms drive some of the clinical heterogeneity in ALS,” the researchers wrote in the study, “Molecular subtypes of ALS are associated with differences in patient prognosis,” which was published in Nature Communications.
Up to 10% of ALS cases are familial and can be explained by an inherited genetic mutation, but most patients have no family history.
To complicate diagnosis and treatment, the disease presents widely from patient to patient, with significant differences in age at onset, progression of symptoms, disease duration, therapeutic response, and coexisting conditions.
Emerging evidence suggests this variability may be explained by multiple subtypes, wherein nerve cell death and disease symptoms are caused by different underlying molecular mechanisms.
This view was supported by the recent discovery of three distinct molecular subtypes of ALS based on different changes in gene activity in post-mortem brain samples of patients.
Most samples had expression profiles consistent with oxidative stress, a type of damage caused by an excess of reactive oxygen-containing molecules, well characterized in ALS and other neurodegenerative diseases. In other samples, signatures of glial activation, an indicator of brain and spinal cord inflammation, were seen.
A third group, accounting for about 20% of cases, showed high expression of transposable elements (TE), also called transposons or “jumping genes.” TEs are short segments of DNA that can change their location, or jump, within a genome (the collection of all genes in a cell).
Once thought to have no function, these tightly controlled TEs have been shown to play a role in gene activity and potentially in neurodegenerative diseases when their regulation is compromised. This happens because TEs moving to a new location cause breaks in the DNA, potentially leading to mutations.
In ALS samples, for example, the activation of normally silent TEs seem to be triggered by the malfunction of TDP-43, a protein that forms toxic clumps in about 97% of all ALS cases.
Researchers at Arizona State University examined the expression of genes and TEs in 451 post-mortem brain samples from 208 patients, searching for connections between molecular ALS subtypes and clinical outcomes. They sought to establish “a direct link between the ALS subtypes and clinical outcomes, such as survival and age of onset.”
Three ALS subtypes
Large-scale gene expression analysis confirmed and expanded the three discovered ALS subtypes, which the researchers called ALS-Glia, ALS-Ox, and ALD-TD.
ALS-Glia represented samples with inflammatory glial activation, as previously reported, while ALS-Ox samples had signs of oxidative stress as well as the altered function of synapses, the regions where nerve cells communicate.
The third subtype was named ALS-TD for transcriptional dysregulation, meaning a loss of control of gene activity. These changes were responsible for TEs and other normally silenced genetic elements being activated, and the altered expression of a number of other genes, including those encoding several RNA molecules — the intermediate molecules produced from DNA that serve as templates for producing proteins.
Significant differences in patient survival across the subtypes, were seen in an outcome analysis, with the ALS-Glia subtype being associated with worse outcomes. This subtype had the shortest disease duration and a median survival of 28 months (just over two years).
Pairwise comparisons indicated significant differences in survival between ALS-Glia and ALS-Ox subtypes, and ALS-Glia and ALS-TD subtypes, but not between the ALS-Ox and ALS-TD.
The ALS-Glia subtype also showed a nonsignificant trend toward the latest disease onset (mean, 63.2 years) and the ALS-Ox subtype the earliest age of onset (mean, 60.4 years). The oldest median age at death was linked to the ALS-TD subtype and ALS-Ox had the youngest median age at death, “which likely reflects some dependency on the age of symptom onset,” the researchers noted.
Hybrid subtypes were also observed, with some patients showing gene expression patterns characteristic of both the ALS-Glia and ALS-TD subtypes, as well as the ALS-Glia and ALS-Ox subtypes. No patient samples matched all three subtypes at the same time.
“This work helps to clarify the molecular foundation of clinical and pathological heterogeneity in ALS by demonstrating that subtype-specific phenotypes [characteristics] are associated with patient outcomes, including survival and age of onset,” the researchers said.
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