Through an investigation of patients with a rare form of amyotrophic lateral sclerosis (ALS), researchers have discovered a new and unique form of the disease. The new clinical study reveals two major findings: 1) a single genetic cause of early-onset ALS and 2) a novel, metabolism-associated, molecular pathway that may contribute to neurodegeneration in other forms of the disease.

The new form of ALS began attacking the patients during childhood and worsened more slowly than usual. In this study, researchers discovered that these cases of ALS were linked to variants of SPLTC1, a gene responsible for manufacturing sphingolipids. Preliminary results suggested that genetically silencing SPTLC1 activity would be an effective strategy for combating this type of ALS.

The paper, “Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis,” is published in Nature Medicine.

“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 of the study. “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 study began with Claudia Digregorio, a young woman from the Apulia region of Italy. Neurological examinations by the team revealed that Digregorio, and others, had many of the hallmarks of ALS, including severely weakened or paralyzed muscles. In addition, some patients’ muscles showed signs of atrophy when examined under a microscope or with non-invasive scanners.

“These young patients had many of the upper and lower motor neuron problems that are indicative of ALS,” said Payam Mohassel, MD, an NIH clinical research fellow and the lead author of the study. “What made these cases unique was the early age of onset and the slower progression of symptoms. This made us wonder what was underlying this distinct form of ALS.”

Genetic analysis determined that four of the patients inherited variants in the SPTLC1 gene from a parent. The other six cases appeared to be “de novo” mutations. Mutations in SPLTC1 are also known to cause a different neurological disorder called hereditary sensory and autonomic neuropathy type 1 (HSAN1). The SPLTC1 protein is a subunit of an enzyme, called SPT, which catalyzes the first of several reactions needed to make sphingolipids. HSAN1 mutations cause the enzyme to produce atypical and harmful versions of sphingolipids.

At first, the team thought the ALS-causing mutations they discovered may produce similar problems. However, blood tests from the patients showed no signs of the harmful sphingolipids.

“At that point, we felt like we had hit a roadblock. We could not fully understand how the mutations seen in the ALS patients did not show the abnormalities expected from what was known about SPTLC1 mutations,” said Bönnemann. “Fortunately, Dunn’s team had some ideas.”

For decades, the lab of Teresa M. Dunn, PhD, professor and chair at the NIH and the Uniformed Services University (USU), had studied the role of sphingolipids in health and disease. With the help of her team, the researchers reexamined blood samples from the ALS patients and discovered that the levels of typical sphingolipids were abnormally high. This suggested that the ALS mutations enhanced SPT activity.

Similar results were seen when the researchers programmed neurons to carry the ALS-causing mutations in SPLTC1. The mutant carrying neurons produced higher levels of typical sphingolipids than control cells. This difference was enhanced when the neurons were fed the amino acid serine, a key ingredient in the SPT reaction.

Next, Dunn’s team performed a series of experiments which showed that the ALS-causing mutations prevent another protein called ORMDL from inhibiting SPT activity.

“Our results suggest that these ALS patients are essentially living without a brake on SPT activity. 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,” said Dunn. “We thought that restoring this brake may be a good strategy for treating this type of ALS.”

To test this idea, the Bönnemann team created small interfering strands of RNA designed to turn off the mutant SPLTC1 genes found in the patients. Experiments on the patients’ skin cells showed that these RNA strands both reduced the levels of SPLTC1 gene activity and restored sphingosine levels to normal.

“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 Bönnemann. “Our ultimate goal is to translate these ideas into effective treatments for our patients who currently have no therapeutic options.”

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