After 11 patients presented with a mysterious neurological condition rendering them almost paralyzed, doctors have identified a brand-new form of amyotrophic lateral sclerosis (ALS) that manifests in children. Despite most forms of ALS beginning onset in early adulthood and middle-age, this new form affected young children and became progressively worse. With ALS being a degenerative and ultimately fatal disease, the doctors dived into the genomics of the patients to identify an underlying cause. The 11 patients came from seven different families, providing a large enough sample size to discover any genetic mutations that may lead to the ALS progression. They discovered mutations within the SPTLC1 gene, which is involved in the production of fat, that led to increased activity and is likely the cause of the disease onset. Identifying a single gene as the culprit gives hope to the patients and researchers, as directed therapy towards this gene may be a viable strategy at halting the disease. "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. Our results show for the first time that ALS can be caused by changes in the way the body metabolizes lipids," said Carsten Bönnemann, MD, senior investigator at the NIH's National Institute of Neurological Disorders and Stroke (NINDS) and a senior author, in a statement. "We hope these results will help doctors recognize this new form of ALS and lead to the development of treatments that will improve the lives of these children and young adults. We also hope that our results may provide new clues to understanding and treating other forms of the disease." The results come from a study produced by the National Institutes of Health and National Institute of Neurological Disorders and Stroke, and were published in Nature. This disease, previously unknown to science, was confusing researchers around the world. The symptoms resembled ALS, but the early onset and slower progression made it distinctive from the typical ALS diagnosis. The researchers took 11 people with this mysterious disease and analyzed their symptoms, before subjecting them to next-generation or exome sequencing, which scrolls through the vast information within their genome then compares it to reference genomes to identify differences. Four variants of SPTLC1 were discovered, in both one family with multiple cases of the new ALS, and within the other unrelated patients. These mutations appeared to disrupt ORMDL proteins, which inhibit the action of serine palmitoyltransferase (SPT), a catalyst for the synthesis of lipids in the body. Without ORMDL, SPT production is unchecked and the levels of these lipids, called sphingolipids, increases. SPTLC1 is also implicated in other neurological disorders, including hereditary sensory and autonomic neuropathy type 1 (HSAN1) and even Alzheimer’s disease, and mutants appear to generate harmful versions of sphingolipids within the body. Unfortunately, a current treatment for ALS, in which the patient is supplemented with serine, may do more harm than good for these patients. Therefore, the researchers got to work on a potential therapy that could be promising. As the mutation is on one of the SPTLC1 genes (there are two per cell), the researchers postulated whether silencing the mutant version could allow the working version to take the reins and restore the lipid levels to normal. They designed a small interfering RNA therapy (siRNA) that "switched off" the mutant SPTLC1 variant, and it was successful in vitro. The therapy would need far more testing before it is made available to patients, but preliminary results seem promising. "These preliminary results suggest that we may be able to use a precision gene silencing strategy to treat patients with this type of ALS. In addition, we are also exploring other ways to step on the brake that slows SPT activity," said Dr. Bonnemann. "Our ultimate goal is to translate these ideas into effective treatments for our patients who currently have no therapeutic options." Source
