Trio of ALS Molecular Subtypes With Varying Patient Survival Identified

A patient stratification analysis identified 3 unique molecular subtypes of amyotrophic lateral sclerosis (ALS), which are associated with differences in patient prognosis. The findings are published online in Nature Communications. 

“These results suggest independent disease mechanisms drive some of the clinical heterogeneity in ALS,” wrote corresponding author Barbara S. Smith, PhD, of the Arizona State University School of Biological and Health Systems Engineering in Tempe, and coauthors. "Some of the subtype-specific genes and transcripts identified in this study have not been previously associated with ALS, offering additional insight into disease pathologies and potential targets for diagnostic or personalized therapeutic development."

Researchers performed the analysis using RNA-sequencing expression data from the postmortem frontal and motor cortex of 208 patients with ALS. During patient stratification, researchers considered locus-specific transposable elements as distinct molecular features.

The analysis identified 3 molecular subtypes of ALS that were defined by the following differences in survival: (1) glial activation (ALS-Glia); (2) oxidative stress and altered synaptic signaling (ALS-Ox); and (3) transcriptional dysregulation (ALS-TD).

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“Supported by our differential expression results, disturbances to protein quality control (proteotoxic stress) is a defining hallmark of ALS-Ox patients, while the hallmark of the ALS-TD patient phenotype is dysregulated RNA metabolism,” researchers wrote. “In ALS-Glia patients, we observe upregulation of inflammatory genes, implicating activated microglia and astrocytes in the accelerated progression of disease pathology.”

Patient survival was significantly different among the 3 subtypes, the study found. The ALS-Glia subtype was linked with the shortest disease duration, with a median survival of just 28 months, and tended (although the trend was nonsignificant) to have the oldest age at onset.

“In summary, this work helps to clarify the molecular foundation of clinical and pathological heterogeneity in ALS by demonstrating that subtype-specific phenotypes are associated with patient outcomes,” researchers wrote, “including survival and age of onset.”

Reference

Eshima J, O'Connor SA, Marschall E; NYGC ALS Consortium; Bowser R, Plaisier CL, Smith BS. Molecular subtypes of ALS are associated with differences in patient prognosis. Nat Commun. Published online January 6, 2023. doi:10.1038/s41467-022-35494-w