NIH- and USU-led study links ALS to a fat-producing gene and designs genetic therapy.
In a study with 11 medical mystery patients, an international team of researchers led by scientists from the National Institutes of Health and Uniformed Services University (USU) discovered a new and unique form of amyotrophic lateral sclerosis (ALS). Unlike most cases of ALS, the disease began to attack these patients in childhood, got worse than usual, and was linked to a gene called SPTLC1, which is part of the body’s fat production system. Preliminary results suggested that genetic shutdown of SPTLC1 activity would be an effective strategy to combat this type of ALS.
ALS is a debilitating 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. We hope these results will help clinicians identify this new form of ALS and guide the development of treatments that will improve the lives of these children and adults. We also hope that our results can provide new clues for understanding and treating other forms of the disease.
Carsten Bönnemann, MD, lead researcher at the National Institute of Neurological Disorders and Stroke (NINDS) of the NIH and lead author of the study published in Nature Medicine
Dr. Bönnemann leads a team of researchers who use advanced genetic techniques to solve some of the most mysterious childhood neurological disorders around the world. In that study, the team discovered that 11 of these cases had ALS, which was linked 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 chair holder at USU, and Thorsten Hornemann, Ph.D., at the University of Zurich in Switzerland. Together they not only found evidence of 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 Apulia region in Italy. Her case was so upset that Pope Francis gave her a personal blessing at the Vatican before going to the United States to be taught by Dr. Bönnemann’s team to be examined in the clinical center of the NIH.
Like many other patients, Claudia needed a wheelchair to get around and a surgically implanted tracheostomy tube to make breathing easier. Neurological research by the team revealed that she and the 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.
Still, this form of ALS seemed different. Most patients are diagnosed with ALS between the ages of 50 and 60 years. The disease then worsens so quickly that patients typically die within three to five years of being diagnosed. In contrast, these patients began to develop symptoms such as toe gait and spasticity around the age of four. In addition, at the end of the study, patients lived five to 20 years longer.
These young patients had many of the upper and lower motor neuron problems indicative of ALS. What made these cases unique was the early age of onset and the slower progression of symptoms. This made us wonder what is behind this particular form of ALS.
Payam Mohassel, MD, NIH Clinical Research Fellow and lead author of the study.
The first indications arose from the analysis of the patient’s DNA. Researchers used next-generation genetic tools to read patients’ exomes, the DNA sequences that contain the instructions for making proteins. They found that the patients had noticeable changes in the same narrow section of the SPLTC1 gene. Four of the patients inherited these changes from one parent. Meanwhile, the other six cases appeared to be the result of “de novo” mutations in the gene that scientists call. These types of mutations can occur spontaneously because cells multiply quickly before or just after conception.
Mutations in SPLTC1 are also known to cause another neurological disorder known as Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1). The SPLTC1 protein is a subunit of an enzyme called SPT that catalyzes the first of several reactions required to make sphingolipids. HSAN1 mutations cause the enzyme to produce atypical and harmful versions of sphingolipids.
At first, the team thought that the ALS-causing mutations they discovered could cause similar problems. However, blood tests on the patients showed no evidence of the harmful sphingolipids.
At this point we felt like we had hit a roadblock. We could not fully understand why the mutations observed in the ALS patients did not show the abnormalities expected from what was known about SPTLC1 mutations. Fortunately, Dr. Dunn’s team got some ideas.
For decades, Dr. Dunn’s team is studying the role of sphingolipids in health and disease. With the help of the Dunn team, the researchers examined blood samples from the ALS patients and found that the levels of the typical sphingolipids were unusually high. This indicated that the ALS mutations increased SPT activity.
Similar results were observed when the researchers programmed neurons grown in Petri dishes to carry the ALS-causing mutations in SPLTC1. The mutant that carries neurons produced higher amounts of typical sphingolipids than control cells. This difference was amplified when the neurons were fed the amino acid serine, a key component of the SPT response.
Previous studies have shown that serine supplementation can 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. Dunn’s team conducted a series of experiments that showed that the mutations that cause ALS prevent another protein called ORMDL from inhibiting SPT activity.
Our results suggest that these ALS patients live essentially without a slowdown in SPT activity. SPT is controlled by a feedback loop. When sphingolipid levels are high, ORMDL proteins bind to and slow down SPT. The mutations these patients carry essentially short this feedback loop. We thought that restoring this brake might be a good strategy to treat this type of ALS.
To test this idea, the Bönnemann team created small, interfering RNA strands that are supposed to switch off the mutated SPLTC1 genes in the patients. Experiments on the skin cells of the patients showed that these RNA strands both reduced the level of SPLTC1 gene activity and normalized the level of sphingosine again.
These preliminary results suggest that we may be able to use a precise gene silencing strategy to treat patients with this type of ALS. Additionally, we are also exploring other ways to step on the brakes that slow down SPT activity. Our ultimate goal is to translate these ideas into effective treatments for our patients who currently have no therapeutic options.
View press release