A study of 11 medical mystery patients leads to the discovery of new genetic forms of ALS in children

NIH researchers have discovered a new form of ALS that begins in childhood. This study linked the disease to a gene called SPLTC1. As part of the study, NIH senior scientist Carsten Bonnemann, MD (right), investigated Claudia Digregorio (left), a patient in the Puglia region of Italy.Credit: Provided by NIH / NINDS

NIH and USU-led studies link ALS to fat-producing genes and plan gene therapy.

In a study of 11 medical mystery patients, an international team of researchers led by scientists from the National Institutes of Health and the University of Uniformed Services (USU) has created a new and unique form of amyotrophic lateral sclerosis (ALS). I found. Unlike most cases of ALS, the disease begins to attack these patients in childhood, worsens more slowly than usual, and is associated with a gene called SPTLC1 that is part of the body’s fat-producing system. It was. Preliminary results suggest that genetic silencing of SPTLC1 activity is an effective strategy for combating this type of ALS.

“ALS is a paralyzed, often fatal disease that usually affects middle-aged people. We have found that the genetic form of this 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 NIH, a senior researcher at the National Institute for Neuropathic Stroke (NINDS). Published research Nature Medicine. “We hope that these results will lead to the development of treatments that will help physicians recognize this new form of ALS and improve the lives of these children and young adults. Also, our results are in other forms. We hope to provide new clues for understanding and treating our illness. “

Dr. Benemann leads a team of researchers who use advanced genetic technology to solve some of the world’s most mysterious pediatric neuropathy.In this study, the team found that 11 of these cases had ALS. DNA A sequence of SPLTC1, a gene involved in the production of various classes of fats called sphingolipids.

In addition, the team is USU professor and chair Teresa M. Dunn, Ph.D. And Thorsten Hornemann, Ph.D., University of Zurich, Switzerland. Collaborated with scientists in the lab led by. Together, they found clues as to how mutations in the SPLTC1 gene lead to ALS, as well as developed strategies to combat these problems.

The study began with Claudia Digregorio, a young woman from the Puglia region of Italy. Her case was so troublesome that after Pope Francis gave her a direct blessing in the Vatican, she left for the United States and was inspected by Dr. Bönnemann’s team at the NIH Clinical Center.

Like many other patients, Claudia needed a wheelchair to move around and a surgically implanted tracheostomy tube to aid in breathing. A neurological examination by the team revealed that she and others have many of the characteristics of ALS, including severe muscle weakness and paralysis. In addition, the muscles of some patients showed signs of atrophy when examined under a microscope or with a non-invasive scanner.

Nevertheless, this form of ALS seemed different. Most patients are diagnosed with ALS, about 50-60 years old. After that, the disease worsens so rapidly that patients usually die within 3-5 years of diagnosis. In contrast, early symptoms such as walking on toes and spasticity appeared in these patients around the age of four. In addition, by the end of the study, patients lived everywhere for five to twenty years longer.

“These young patients had many of the problems with upper and lower motor neurons that indicate ALS,” said Dr. Payam Mohassel, NIH clinical researcher and lead author of the study. “What made these cases unique was the early age of onset and the slow progression of symptoms, which made me wonder what underlies this unique form of ALS. “

The first clue came from analyzing the patient’s DNA. Researchers used next-generation genetic tools to read patient exosomes, which are sequences of DNA that hold instructions for making proteins. They found that patients had significant changes in the same narrow portion of the SPLTC1 gene. Four of the patients inherited these changes from their parents. On the other hand, the other six cases appeared to be the result of what scientists call a “denovo” mutation in the gene. These types of mutations can occur spontaneously when cells proliferate rapidly before or shortly after conception.

Mutations in SPLTC1 are also known to cause another neuropathy called hereditary sensory autonomic neuropathy type 1 (HSAN1). The SPLTC1 protein is a subunit of an enzyme called SPT that catalyzes the first of several reactions required for the production of sphingolipids. Due to the HSAN1 mutation, the enzyme produces an atypical and harmful version of sphingolipid.

Initially, the team thought that the mutations that caused ALS that they found could cause similar problems. However, blood tests on the patient showed no signs of harmful sphingolipids.

“At that point, we felt like we were hit by a disorder. How the mutations seen in ALS patients did not show the abnormalities expected from what is known about the SPTLC1 mutation. I couldn’t fully understand it, “said Dr. Bönnemann. “Fortunately, Dr. Dan’s team had some ideas.”

For decades, Dr. Dan’s team has been studying the role of sphingolipids in health and illness. With the help of Danteam, researchers re-examined blood samples from ALS patients and found that typical sphingolipid levels were abnormally high. This suggested that the ALS mutation enhanced SPT activity.

Similar results were seen when researchers programmed neurons grown in Petri dishes to carry SPLTC1 with a mutation that causes ALS. Neuron-carrying mutants produced higher levels of typical sphingolipids than control cells.This difference was enhanced when neurons were given amino acid Serin, an important component of the SPT reaction.

Previous studies have suggested that serine supplementation may be an effective treatment for HSAN1. Based on their results, the authors of this study recommended avoiding serine supplementation when treating ALS patients.

Next, Dr. Dan’s team conducted a series of experiments to show that mutations that cause ALS prevent another protein called ORMDL from inhibiting SPT activity.

“Our results suggest that these ALS patients are essentially living without braking SPT activity. SPT is controlled by a feedback loop. When sphingolipid levels are high, The ORMDL protein binds to SPT and slows it down. The mutations carried by these patients essentially short-circuit this feedback loop, “Dr. Dan said. “I thought that reversing this brake might be a good strategy for treating this type of ALS.”

To test this idea, the Bönnemann team RNA It is designed to turn off the mutant SPLTC1 gene found in patients. Experiments with patient skin cells have shown that these RNA strands reduce levels of SPLTC1 gene activity and restore sphingosine levels to normal.

“These preliminary results suggest that precise gene silencing strategies may be used to treat patients with this type of ALS. In addition, they step on the brakes that slow down SPT activity. We are also looking for other ways, “says Dr. Bonnemann. “Our ultimate goal is to translate these ideas into effective treatments for patients who currently have no treatment options.”

References: “Children’s Amyotrophic Lateral Sclerosis Caused by Excessive Sphingolipid Synthesis,” Mohassel, P. et al. et al. May 31, 2021 Nature medicine..
DOI: 10.1038 / s41591-021-01346-1

This study was supported by NINDS’NIH On-Campus Research Program. NIH Grants (NS10762, NS072446); US Department of Defense Parliamentary Medical Research Program (W81XWH-20-1-0219); Swiss National Foundation (31003A_179371); It does not represent.