Scientists discover a new genetic form of ALS in children

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

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 Uniformed Services (USU) discovered a new and unique form of amyotrophic lateral sclerosis (ALS). Unlike most cases of ALS, the disease began to attack these patients during childhood, worsened more slowly than usual and was linked to a gene, called SPTLC1, which is part of the fat production system. of the body. Preliminary results suggested that genetically silencing SPTLC1 activity would be an effective strategy to combat this type of ALS.

“ALS is a paralyzing and often fatal disease that usually affects middle-aged people. We have 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, a senior researcher at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and lead author of the study published in Nature medicine. “We hope that these results will help physicians recognize this new form of ALS and lead to the development of treatments that improve the lives of these children and young adults. We also hope that our results can provide new clues to understanding and treating others. forms of the disease “.

Dr. Bönnemann leads a team of researchers who use advanced genetic techniques to solve some of the most mysterious childhood neurological disorders in the world. In this study, the team found that 11 of these cases had ALS related to variations in the DNA sequence of SPLTC1, a gene responsible for making a diverse class of fats called sphingolipids.

In addition, the team worked with scientists in laboratories led by Teresa M. Dunn, Ph.D., professor and president of the USU, and Thorsten Hornemann, Ph.D., at the University of Zurich in Switzerland. Together they not only found clues about how variations in the SPLTC1 gene lead to ALS, but also developed a strategy to counteract these problems.

The study began with Claudia Digregorio, a young woman from the Puglia region of Italy. Her case had been so annoying that Pope Francis gave her a personal blessing at the Vatican before she left for the United States to be examined by Dr. Bönnemann’s team at the NIH Clinical Center.

Like many of the other patients, Claudia needed a wheelchair to move around and a surgically implanted tracheostomy tube to help her breathe. Neurological examinations of the team revealed that she and the others had many of the characteristics of ALS, including severely weakened or paralyzed muscles. In addition, some of the patients ’muscles showed signs of atrophy when examined under a microscope or with non-invasive scanners.

However, this form of ALS appeared to be different. Most patients have a diagnosis of ALS for about 50 to 60 years. The disease worsens so rapidly that patients usually die within three to five years after diagnosis. In contrast, initial symptoms, such as walking with fingers and spasticity, appeared in these patients around the age of four years. In addition, at the end of the study, patients had lived between five and twenty more years.

“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 researcher and 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 different form of ALS.”

The first clues came from the DNA analysis of the patients. The researchers used next-generation genetic tools to read patients’ exomes, the DNA sequences that contain instructions for making proteins. They found that patients had noticeable changes in the same narrow portion of the SPLTC1 gene. Four of the patients inherited these changes from a father. Meanwhile, the other six cases appeared to be the result of what scientists call “de novo” mutations in the gene. Such mutations can occur spontaneously as cells multiply rapidly before or shortly after conception.

Mutations in SPLTC1 are also known to cause a different neurological disorder called hereditary sensory and autonomic type 1 (HSAN1) neuropathy. The SPLTC1 protein is a subunit of an enzyme, called SPT, that catalyzes the first of several reactions needed to produce sphingolipids. HSAN1 mutations cause the enzyme to produce atypical and harmful versions of sphingolipids.

At first, the team thought that the mutations causing ALS they discovered could cause similar problems. However, blood tests of the patients showed no signs of harmful sphingolipids.

“At this time, we felt that we had reached a roadblock. We could not fully understand how the mutations observed in patients with ALS did not show the expected abnormalities of what was known about SPTLC1 mutations,” the doctor said. Bönnemann. “Fortunately, Dr. Dunn’s team had some ideas.”

For decades, Dr. Dunn had studied the role of sphingolipids in health and disease. With the help of Dunn’s team, the researchers re-examined blood samples from patients with ALS and found that typical sphingolipid levels were abnormally high. This suggested that ALS mutations improved SPT activity.

Similar results were seen when researchers programmed cultured neurons in Petri dishes to carry the mutations that cause ALS in SPLTC1. Mutant carrier neurons produced higher levels of typical sphingolipids than control cells. This difference was increased when neurons were fed the amino acid serine, a key ingredient in 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 patients with ALS.

Dr. Dunn’s team then conducted a series of experiments that showed that mutations that cause ELS prevent another protein called ORMDL from inhibiting SPT activity.

“Our results suggest that these patients with ALS live essentially without slowing SPT activity. SPT is controlled by a feedback loop. When sphingolipid levels are high, ORMDL proteins bind and slow down. of SPT. feedback loop, “said Dr. Dunn. “We thought restoring that brake could be a good strategy to deal with this type of ALS.”

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

“These preliminary results suggest that we may be able to use a precision genetic 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,” he said. say Dr. Bonnemann. “Our ultimate goal is to translate these ideas into effective treatments for our patients who currently have no therapeutic options.”


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More information:
Childhood amyotrophic lateral sclerosis caused by excessive sphingolipid synthesis, Nature medicine (2021). DOI: 10.1038 / s41591-021-01346-1 , www.nature.com/articles/s41591-021-01346-1

Citation: Scientists discover a new genetic form of ALS in children (2021, May 31) recovered on May 31, 2021 at https://medicalxpress.com/news/2021-05-scientists-genetic-als-children. html

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