Nature discovers a new genetic form of ALS in children

A study led by the National Institutes of Health and USU linked amyotrophic lateral sclerosis with a fat-making gene and developed a gene therapy

In a study of 11 medical mystery patients, an international research team led by scientists from the National Institutes of Health and the United States Uniform Service University (USU) discovered a new and unique type of amyotrophic lateral sclerosis Disease (ALS)

"Amyotrophic lateral sclerosis is a paralytic disease that is usually fatal and usually affects middle-aged people

The research team led by Dr.

In addition, the team also collaborated with laboratory scientists led by USU professor and chairman Dr.

The research was started by Claudia Di Gregorio, a young woman from the Apulia region of Italy

Like many other patients, Claudia needed a wheelchair to move, and a tracheostomy tube was surgically implanted to help breathing

However, this type of amyotrophic lateral sclerosis seems to be different

Payam Mohassel, MD, a clinical researcher at the National Institutes of Health and the lead author of the study, said: "These young patients have a lot of upper and lower motor neuron problems in patients with amyotrophic lateral sclerosis

The first clue comes from the analysis of the patient's DNA

It is well known that mutations in SPLTC1 can also cause a different neurological disease called hereditary sensory and autonomic neuropathy type 1 (HSAN1)

At first, the research team thought that the mutations they found that caused als might cause similar problems

"At the time, we felt we were encountering obstacles

For decades, Dr.

The researchers saw similar results when they programmed neurons growing in petri dishes to carry the SPLTC1 mutation that causes als

Previous studies have shown that supplementation with serine may be an effective way to treat HSAN1

Next, Dr.
Dunn’s team conducted a series of experiments that showed that the mutation that caused als prevented another protein called ORMDL from inhibiting SPT activity
.

"Our results show that these patients with amyotrophic lateral sclerosis have basically no brakes on SPT activity.
SPT is
controlled by a feedback loop
.
When sphingolipid levels are high, ORMDL protein binds to SPT and slows down the speed of SPT.

The mutations carried by these patients basically short-circuit the feedback loop," said Dr.
Dunn
.
"We think that restoring this brake may be a good strategy to treat this type of ALS
.
"

To test this idea, Bönnemann's team created small interfering RNA strands designed to shut down the mutated SPLTC1 gene found in patients
.
Experiments on skin cells of patients showed that these RNA chains both reduced the activity of the SPLTC1 gene and restored the sphingosine levels to normal levels
.

"These preliminary results indicate that we may be able to use precise gene silencing strategies to treat this type of ALS patients
.
In addition, we are also exploring other ways to slow down the activity of SPT," said Dr.
Bönnemann
.
"Our ultimate goal is to translate these ideas into effective treatments for patients who currently have no treatment options
.
"

Original search:

Mohassel, P.
et al.
, Childhood Amyotrophic Lateral Sclerosis Caused by Excess Sphingolipid Synthesis.
Nature Medicine, May 31, 2021 DOI: 10.
1038/s41591-021-01346-1