Childhood Form of ALS Identified, Linked to SPLTC1 Mutations

A previously unknown form of amyotrophic lateral sclerosis (ALS) — one with onset during childhood — is caused by mutations that alter the production of certain lipids (fat molecules), scientists report.

“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,” Carsten Bönnemann, MD, of the National Institute of Neurological Disorders and Stroke (NINDS) and the study’s senior author, said in a press release.

The study, “Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis,” was published in Nature Medicine.

An international team of researchers described 11 patients, from seven unrelated families, who began to experience motor problems early in childhood that progressively worsened as time went on. All eventually were unable to walk and had varying degrees of difficulty breathing.

Clinical examinations were in line with the diagnostic criteria for ALS: the patients had ALS-like symptoms, showed signs of the motor neuron damage that characterizes ALS, and muscles in some showed signs of atrophy upon biopsy.

“The majority of patients in our cohort first manifested with early-childhood-onset spasticity and toe walking, a clinical feature suggestive of a related upper motor neuron disorder, hereditary spastic paraplegia,” the researchers wrote. But “this initial manifestation was almost universally followed by diffuse and progressive lower motor neuron degeneration, including tongue fasciculations [muscle contractures or twitches], which is … consistent with ALS.”

This “form of motor neuron disease,” they added, “is best characterized as childhood ALS.”

In addition to its early manifestation, contrasting with a typical onset age of around 50 or 60, the disease in these children also progressed more slowly than what is normally observed in adults.

Genetic testing found that all patients had mutations in a gene called SPLTC1, which provides instructions for making part of a protein called serine palmitoyltransferase, or SPT. This protein is critical for the production of a class of lipids called sphingolipids, which act as signaling molecules that help to coordinate a variety of biological processes.

Notably, mutations in SPLTC1 and related genes have previously been linked to other neurological diseases, in which the mutations result in the production of toxic forms of sphingolipids. However, the researchers did not find increased levels of these toxic lipid molecules in the patients’ blood.

Instead, they found abnormally high levels of normal sphingolipids, suggesting that the children’s SPLTC1 mutations were causing the SPT protein to be overactive.

Cell dish experiments further supported this idea: cells with the SPLTC1 mutations produced abnormally high levels of normal sphingolipids. The researchers also found that supplementing cells with L-serine, an amino acid used in the production of sphingolipids, led to further increases in sphingolipid production.

L-serine supplements have been explored as a potential way of treating ALS, but this work “indicates that l-serine supplementation as a therapeutic strategy does not improve, and may worsen, the biochemical phenotype in patients with SPTLC1-related ALS and thus should be avoided,” the researchers wrote.

Additional experiments allowed researchers to identify the molecular mechanism underpinning this excessive sphingolipid production. Normally, a group of proteins called ORMDL proteins act to regulate SPT, preventing it from producing sphingolipids at elevated levels. However, the SPLTC1 mutations in these patients led to changes in the structure of the SPT protein, such that ORMDL proteins were no longer able to regulate it as effectively.

“Our results suggest that these ALS patients are essentially living without a brake on SPT activity,” said Teresa Dunn, PhD, a study co-author with the University of Zurich in Switzerland.

“We thought that restoring this brake may be a good strategy for treating this type of ALS,” Dunn added.

The researchers created short interfering RNA (siRNA) to test this idea. Conceptually, the siRNA allowed the researchers to stop cells from producing mutant SPT, while still allowing for the production of the normal protein. Experiments on the patients’ skin cells showed that siRNA treatment restored sphingosine levels to normal.

“Delivery of siRNAs to target cells — for example, motor neurons or glia, probably requires additional modifications — but, for a severe and progressive neurodegenerative disease in children, such an approach as part of a small clinical trial may be justified,” the researchers wrote.

“These preliminary [skin cell] results suggest that we may be able to use a precision gene silencing strategy to treat patients with this type of ALS. … [or] other ways to step on the brake that slows SPT activity,” Bönnemann said. “Our ultimate goal is to translate these ideas into effective treatments for our patients who currently have no therapeutic options.”