USU, NIH Researchers Discover New Genetic Form of ALS

By Dillon Parker

An international team of researchers led by scientists at the Uniformed Services University (USU) and the National Institutes of Health (NIH), discovered a new and unique form of amyotrophic lateral sclerosis (ALS) in a study of 11 medical-mystery patients from around the world. 

NIH researchers tested out a gene silencing therapy against a new genetic form
of childhood ALS on skin cells from patients. The new form ALS was linked to
the gene SPTLC1. (Photo courtesy of NIH/NINDS)

ALS, more commonly known as Lou Gehrig’s Disease, is a rare neurological disorder that attacks cells in the brain and spinal cord, preventing communication between the nervous system and the body’s muscles. In contrast to most ALS patients who are diagnosed later in life and experience rapid onset symptoms, this new form of ALS begins in childhood, progresses more slowly than usual, and is linked to a genetic mutation.

“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 Dr. Carsten Bönnemann, senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and a senior author of the study published in Nature Medicine.

The investigation began with Claudia Digregorio, a young woman from the Apulia region of Italy, whose case was so mysterious she received an in-person blessing from Pope Francis at the Vatican before she journeyed to the U.S. to be examined by Bönnemann and other NIH researchers. Examinations by the team revealed that she and the 10 others identified for the study had many of the hallmarks of ALS, including severely weakened or paralyzed muscles.

A scan of a childhood ALS patient's thigh. The scan shows signs that the
muscle has atrophied. (Photo courtesy of NIH/NINDS)

Bönnemann’s team began investigating the patients’ DNA in collaboration with the researchers at USU, led by Dr. Teresa M. Dunn, chair of USU’s Department of Biochemistry and Molecular Biology and a senior author of the study. This collaboration led to the discovery that the mutation of the SPTLC1 gene leads to an overabundance of sphingolipids in this new form of ALS. Sphingolipids play an essential role in the functioning of cells in the nervous system, and their overaccumulation can result in cell death. SPTLC1 is a part of the enzyme SPT, which helps produce sphingolipids. Dunn’s team had studied the role of sphingolipids in health and disease for decades, and performed a series of experiments which showed that the ALS-causing mutations prevent another protein called ORMDL from inhibiting SPT activity, thus causing the overaccumulation of sphingolipids.

“Our results suggest that these ALS patients are essentially living without a brake on SPT activity,” said Dunn. “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.”

The researchers began examining ways to “turn off” the mutant SPTLC1 and found preliminary evidence using skin cells that the introduction of small interfering strands of RNA can reduce SPTLC1 activity and restore sphingolipid 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 Bonnemann. “Our ultimate goal is to translate these ideas into effective treatments for our patients who currently have no therapeutic options.”