New Pediatric Form of ALS Discovered


Normally, amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder, affects individuals between ages 50-60, with prevalence increasing with age. Once diagnosed, patients typically survive for another 3-5 years. However, a recent study has discovered a new form of ALS, one which impacts younger individuals. According to Medical XPress, researchers and scientists from the National Institutes of Health and the Uniformed Services University (USU) discovered a pediatric form of ALS linked to SPTLC1 gene mutations. Check out the full study findings published in Nature Medicine.

SPTLC1 Dysfunction

According to MedLine Plus, the SPTLC1 gene:

provides instructions on making one part of an enzyme called serine palmitoyltransferase (SPT), [which] is involved in making certain fats called sphingolipids, [important] components of cell membranes that play a role in many cell functions. The SPT enzyme initiates the first step of sphingolipid production, in which the molecules serine and palmitoyl CoA combine to form a molecule called ketodihydrosphingosine.

In short, SPTLC1 plays a role in how the body produces and uses sphingolipids.

Research and Exome Analysis

Within this study, researchers evaluated 11 pediatric patients with neurological disorders. The study began with Claudia Digregoria, a patient from Italy. She began presenting with a variety of neurological and physical symptoms. In fact, medical providers in Italy were so confused by her case that she received a blessing from Pope Francis. Later, Claudia traveled to the U.S. to be evaluated by the NIH team; her data is included in the study.

Many of the patients involved in this study showed muscle weakness, paralysis, or atrophy. Some patients required mobility assistance (wheelchairs) and/or respiratory assistance (tracheostomy tube). But researchers also noticed that, despite showing symptoms related to ALS, these patients had a slowly progressing condition. Symptoms appeared around 4 years old. Unlike the adult form of ALS, patients within the study lived 5-20+ years following diagnosis.

To understand what was causing this pediatric ALS, researchers first performed DNA analysis. Specifically, researchers performed exome sequencing, which explores protein-coding genomic regions to learn the link between genetics and disease. In this case, researchers discovered SPTLC1 gene mutations. Out of the 11 patients, 4 (36%) inherited the mutations. For the remaining patients, the mutations occurred spontaneously.

SPTLC1 and Pediatric ALS

In the past, SPTLC1 gene mutations have been associated with hereditary sensory and autonomic neuropathy type 1. Within this condition, these mutations cause abnormal and harmful sphingolipids. Unlike this condition, patients with pediatric ALS do not present with abnormal or harmful sphingolipids. However, this caused researchers some confusion. How were these mutations affecting these patients and why were they not presenting with the same abnormalities as those with HSAN1?

To discover the answer, researchers looked again to blood samples sourced from the 11 patients. Through this, they found that regular (non-harmful) sphingolipid levels were extremely high. Researchers determined that SPTLC1 mutations increased SPT activity. In short, SPTLC1 was causing the overproduction of sphingolipids.

Next, researchers tested this using neurons in Petri dishes. First, researchers programmed these neurons to have SPTLC1 mutations found in the study’s patients. Next, they analyzed these neurons in comparison with control neurons. Altogether, SPTLC1 mutated neurons had higher sphingolipid production. While serine, a type of amino acid, is suggested as a treatment for patients with hereditary sensory and autonomic neuropathy type 1, researchers advise against using it to treat those with pediatric ALS. This is because serine can increase SPT further, which would be detrimental to these patients.

Finally, researchers sought to understand why ORMDL, another protein, was not stopping overactive SPT. Normally, ORMDL plays a role in controlling this process. The researchers found that the mutations found in pediatric ALS stopped ORMDL from doing its job, therefore allowing SPT to continue uninhibited.

As a result, a gene silencing technology, which could stop SPTLC1 and reduce SPT activity, could be a beneficial therapeutic option for patients. However, more research is needed to both understand pediatric ALS and develop adequate therapies.

Amyotrophic Lateral Sclerosis (ALS)

Although doctors are not sure of the exact cause of amyotrophic lateral sclerosis (ALS) in adults, some believe that it could result from a mix of environmental and genetic factors. As is the case with pediatric ALS, there is a small subset of adult patients whose ALS is caused by genetic mutations. In these cases, the condition is considered familial.

ALS is a progressive neurological disease which impacts the neurons and nerve cells responsible for voluntary muscle control. As nerve cells in the brain, brain stem, and spinal cord die, patients experience gradual movement loss. Altogether, ALS affects males more than females. While it can affect people of all backgrounds, the disease is most prevalent in white males between ages 60-69. This disease becomes fatal as patients lose control over their muscles and lose the ability to breathe. Typically, those with ALS survive around 2-5 years following diagnosis, according to the ALS Foundation.

Symptoms vary and may be subtle at first. As symptoms appear, they include:

  • Muscle twitching or cramps
    • Note: When muscle twitching occurs, it commonly occurs in the tongue, arms, legs, or shoulders.
  • Difficulty walking or performing small movements, such as holding objects
  • Slurred or slowed speech
  • Muscle stiffness
  • Poor posture
  • Psychological stress (anxiety, depression)
  • Muscle weakness in the arms, hands, and legs
  • Difficulty speaking or swallowing
  • Unintended weight loss
  • Frequent tripping and/or falling
  • Inability to move muscles across the body
Jessica Lynn

Jessica Lynn

Jessica Lynn has an educational background in writing and marketing. She firmly believes in the power of writing in amplifying voices, and looks forward to doing so for the rare disease community.

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