Miller School Researcher Leads New ALS Gene Discovery

Article Summary
  • Miller School researcher Dr. Stephan Züchner is senior author of a study that links juvenile-onset ALS to the SPTLC2 gene.
  • The study focused on the SPT protein complex, in which mutations in one region can cause motor neuron disease and, in another, sensory deficit disorder.
  • Dr. Züchner believes the discovery could quickly translate to clinical care and diagnosis of juvenile-onset ALS.
Dr. Stephan Züchner
Stephan Züchner, M.D., Ph.D., is senior author on a study that linked the SPTLC2 gene to juvenile-onset ALS.

An international team of researchers has shown that mutations in the SPTLC2 gene contribute to juvenile-onset amyotrophic lateral sclerosis (ALS), which affects people younger than 25.

The SPTLC2 variations alter production of sphingolipids, a fat type that is essential for brain function. The study was recently published in the Journal of Neurology, Neurosurgery & Psychiatry.

“This is the first time we’ve shown that mutations in the gene SPTLC2 are a cause for ALS,” said Stephan Züchner, M.D., Ph.D., co-director of the John P. Hussman Institute for Human Genomics and senior author on the study. “Now, having identified this genetic anomaly, labs can begin looking for potential therapies.”

Also called Lou Gehrig’s Disease, ALS slowly destroys motor neurons, leading to paralysis and death. Currently, there are no effective treatments.

Focus on SPT Protein Complex

In the study, Dr. Züchner, also the chief genomics officer at the University of Miami Miller School of Medicine, and colleagues focused on the SPT protein complex that includes SPTLC2. SPT helps synthesize sphingolipids and ceramides, another fat type. Sphingolipids form cell membranes, support cellular communication and are essential for nerve cell health.

“SPT is a really interesting protein complex,” said Dr. Züchner. “If mutations occur in one region of the complex, this results in a motor neuron disease. However, similar mutations affect other parts of the same complex, and this creates a sensory deficit disorder.”

SPTLC2 defects are linked to hereditary sensory and autonomic neuropathy type 1, which causes sensory nerve damage. However, the current study shows that different mutations in the same protein cause juvenile-onset ALS.

“Understanding SPTLC2 genetics is important on a scientific level, as well as for patient care,” said Dr. Züchner. “There is a drug in clinical trials that targets SPTLC2 to treat sensory neuropathy. However, if we gave the same drug to an ALS patient, it would probably be a disaster. The mutations are that different.”

Suspecting SPTLC2 for ALS

The study was spearheaded by neurologist and first author Maike Dohrn, M.D., a research scholar at the Hussman Institute. Dr. Dohrn had worked with sensory neuropathy patients and noted that mutations in SPTLC1, another component in the SPT complex, had been linked to ALS. She thought SPTLC2 variations might also be implicated.

The team screened genomic sequences from 700 ALS patients for SPTLC2 mutations. They found them in two people who had been experiencing early-onset muscle weakness. Additional analyses showed increased concentrations of sphingolipids and ceramides, consistent with a gain-of-function mutation.

The research team will continue to look for more patients with these mutations. These findings could quickly inform clinical care, as SPTLC2 variations could help diagnose patients with juvenile-onset ALS. In the longer term, researchers could pursue therapies that target SPTLC2.

“There are ALS drugs in trials right now, but they only target certain mutations,” said Dr. Züchner. “If an ALS patient doesn’t have that specific mutation in that specific gene, the drug won’t help. We’re going to have to find all the genetic variations that cause ALS, and we may have to target each one individually.”

Tags: ALS, Dr. Stephan Zuchner, Hussman Institute for Human Genomics