Genetics: Causative gene for early-onset ALS identified

A specific class of rare mutations in the gene SPTLC1 — which encodes a key metabolic molecule responsible for the production of a class of lipids called sphingolipids — exists in children with severe, early-onset amyotrophic lateral sclerosis (ALS). Clinical findings reported in Nature Medicinereveal both a single genetic cause of early-onset ALS and a novel, metabolism-associated, molecular pathway that may contribute to neurodegeneration in other forms of the disease.

ALS is a progressive neurodegenerative disease that often results in death within 3–5 years of disease onset. Most cases occur sporadically, with important insights into the key drivers of ALS gained from clinical studies linking single-gene mutations directly to the disease.

Carsten Bönnemann and colleagues sequenced the genomes of nine ALS patients from seven families who developed a severe, early-onset form of ALS. The authors identify a rare set of mutations in a single gene — SPTLC1 — that encodes a component of an enzyme involved in lipid metabolism. Experiments revealed that these newly discovered ALS-causing mutations result in unrestrained sphingolipid production and accumulation in human motor neurons — the type of neurons that specifically degenerate in the disease.

This clinical study not only describes a new set of rare, single-gene mutations that underlie an aggressive and early-onset form of ALS, but also suggests that direct metabolic disturbance is a causative factor in disease development.