Novel form of genetic ALS affects young children

An international team of researchers at the NIH and other institutions have identified a novel form of ALS in a small set of children, starting at approximately 4 years of age, linked to the SPTLC1 gene, according to a press release.

Researchers at the NIH and Uniformed Services University of the Health Sciences in Bethesda (USU), among other institutions, discovered the new disease, a novel form of ALS that progressed slower than usual. They linked the disease to SPTLC1, a gene involved in the body’s fat production system, according to the press release.

“ALS is a paralyzing and often fatal disease that usually affects middle-aged people. We found that a genetic form of the disease can also threaten children,” Carsten Bönnemann, MD, senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke, said in the press release. “Our results show for the first time that ALS can be caused by changes in the way the body metabolizes lipids.”

Under Bönnemann’s lead, a team of researchers used advanced genetic testing to examine cases of undiagnosed neurological disorders in children from around the world. The analysis identified 11 cases of ALS linked to variations in the DNA sequence of SPLTC1, which manufactures “a diverse class of fats” known as sphingolipids, according to the press release.

Initial symptoms in these children, including toe walking and spasticity, first developed when the children were aged approximately 4 years, according to the press release. By the study’s end, patients lived from 5 to 20 years longer than most patients with ALS, who are typically diagnosed between 50 and 60 years of age and die within 3 to 5 years of the diagnosis.

To develop a treatment for this new form of ALS, Bönnemann and colleagues analyzed variations in the SPLTC1 gene. Through that analysis, they found “conspicuous changes” in the same region of the SPLTC1 gene among the patients. Additionally, four patients inherited the changes in the gene from a parent, while six cases were caused by de novo mutations in the gene.

“Our results suggest that these [patients with ALS] are essentially living without a brake on SPT [enzyme] activity,” Teresa M. Dunn, PhD, professor and chair at USU, said in the release. “SPT is controlled by a feedback loop. When sphingolipid levels are high, then ORMDL proteins bind to and slow down SPT. The mutations these patients carry essentially short-circuit this feedback loop.”

The SPLTC1 protein is a subunit of the SPT enzyme. When Bönnemann’s team assessed genetically silencing the SPLTC1 mutant gene, they found that patients’ RNA strands reduced SPLTC1 gene activity and lowered sphingosine to normal levels.

“These preliminary results suggest that we may be able to use a precision gene silencing strategy to treat patients with this type of ALS,” Bönnemann said. “In addition, we are also exploring other ways to step on the brake that slows SPT activity.”

References:

Mohassel P, et al. Nature Medicine. 2021;doi:10.1038/s41591-021-01346-1.

National Institute of Neurological Disorders and Stroke. Scientists discover a new genetic form of ALS in children. Available at: https://www.ninds.nih.gov/News-Events/News-and-Press-Releases/Press-Releases/Scientists-discover-new-genetic-form-ALS-children. Accessed June 1, 2021.