An multinational team of researchers lead by specialists from the National Institutes of Health and the Uniformed Services University (USU) uncovered a novel and unusual type of amyotrophic lateral sclerosis in a study of 11 medical-mystery patients (ALS). Unlike most cases of ALS, these patients’ symptoms began in childhood, progressed more slowly than typical, and were connected to a gene. Unlike most cases of ALS, these individuals’ symptoms began in childhood, progressed more slowly than expected, and were connected to a gene called SPTLC1, which is involved in the body’s fat synthesis system. Preliminary findings indicate that genetically suppressing SPTLC1 activity would be a good way to fight this kind 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 Metabolizes lipids, showing for the first time that ALS can be caused by changes in the way the body works,“ said NIH’s National Institute of Neurological Disorders and Stroke (NINDS) Principal Investigator. 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 ALS.“
Dr. Bönnemann is the leader of a team of researchers that are using modern genetic tools to solve some of the world’s most perplexing childhood neurological disorders. The researchers observed that 11 of these individuals had ALS that was connected to differences in the DNA sequence of SPLTC1, a gene responsible for the production of sphingolipids, a widely-varied family of fats.
Claudia Digregorio, a young woman from Southern Italy, was the subject of the research. Her condition was so complicated that Pope Francis blessed her in person at the Vatican before she flew to the United States to be assessed by Dr. Bönnemann’s team at the National Institutes of Health’s Clinical Center. Claudia, like many of the other patients, required a wheelchair for mobility and a surgically inserted tracheostomy tube for breathing assistance. Her and the others displayed several of the signs of ALS, including severely weakened or paralyzed muscles, according to the team’s neurological assessments. Furthermore, when inspected under a microscope, several of the patients’ muscles exhibited evidence of atrophy.
However, this kind of ALS looked to be unique. The majority of ALS patients are diagnosed between the ages of 50 and 60. Patients usually die within three to five years of being diagnosed because the condition develops so quickly. Initial symptoms such as toe walking and spasticity, on the other hand, occurred in these kids around the age of four.
“These young patients had many of the upper and lower motor neuron problems that are indicative of ALS,” said Payam Mohassel, M.D., 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.”
The analysis of the patients’ DNA provided the first hints. The researchers examined the patients’ exomes, which are DNA sequences that provide the instructions for creating proteins, with next-generation genetic techniques. The individuals all had noticeable alterations in the same section of the SPLTC1 gene, according to the researchers. Four of the patients had these abnormalities inherited from one of their parents.
Meanwhile, the other six cases looked to be the consequence of “de novo” changes in the gene, according to scientists. These mutations can develop naturally as cells grow rapidly before or shortly after conception.
SPLTC1 mutations have also been linked to a neurological condition known as hereditary sensory and autonomic neuropathy type 1. (HSAN1). SPLTC1 is a component of the SPT enzyme, which catalyzes the first of multiple processes required to produce sphingolipids. Mutations in the HSAN1 gene cause the enzyme to create unusual and toxic 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 Dr. Bönnemann. “Fortunately, Dr. Dunn’s team had some ideas.”
Serine supplementation has been proposed as a possible therapy for HSAN1 in previous investigations.
The authors of this study concluded that serine supplementation should be avoided while treating ALS patients based on their findings. Next, Dr. Dunn’s team conducted a series of tests that revealed the ALS-causing mutations prohibit another protein called ORMDL from suppressing SPT function.
“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 Dr. Dunn. “We thought that restoring this brake may be a good strategy for treating this type of ALS.”
The Bönnemann team put this theory to the test by creating a short interfering RNA strand that turned off the mutant SPLTC1 gene seen in patients. These RNA strands have been demonstrated to inhibit SPLTC1 gene activity and restore sphingosine levels in patient skin cells in experiments.
“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.”