A previously unknown form of a severe & progressive neurodegenerative disease that sometimes affects older adults has been identified with rare genetic mutations in children as young as 3 years age.
Amyotrophic lateral sclerosis (ALS) may be a rare nervous disorder where motor-neuron degeneration results in serious impairments in voluntary muscle movement’.
The condition, which causes increasing weakness in muscles throughout the body, makes walking, talking, & eventually even breathing a struggle, resulting in death in most patients within a couple of years of symptoms showing.
The majority of ALS cases emerge in people aged between 55-75, and most cases are considered sporadic, with the cause ultimately remaining unknown.
For some people, however, the disease presents very differently. In minority of cases, genetics appears to play a causative role & sometimes the disease shows up in much younger people.
In a new study, scientists found both these rarer manifestations of the disease coinciding, discovering an unusual set of mutations linked to a definite form of genetic ALS in children, whose mysterious muscle-wasting illnesses had puzzled their doctors for years.
In the most publicised of those heartbreaking cases, an Italian teenager called Claudia Digregorio ended up meeting with the Pope after her unidentified degenerative illness caught attention on YouTube.
At an equivalent time, scientists at the National Institute of Neurological Disorders & Stroke (NINDS) in Bethesda, Maryland began investigating Claudia’s disease, hoping to seek out answers for the underlying explanation for her condition.
Now, in a international-investigation of 10 such young patients, many of whom started experiencing ALS-like symptoms in child-hood’, researchers have identified a genetic basis for this rare sub-type of an already rare disease.
“These young patients had many of the upper & lower motor-neuron problems that are indicative of ALS,” says neurologist Payam Mohassel from the National Institutes of Health.
“What made these cases unique was the infancy age of onset and therefore the slower progression of symptoms. This made us wonder what was underlying this distinct form of ALS.”
The answer appears to stay in a group of mutations in a gene called SPTLC1, which encodes a protein that acts as a catalyst within the production of fatty molecules called sphingolipids.
The DNA of the ten young patients within the study revealed mutations within the SPTLC1 gene, with four of the patients (all from one family) inheriting their variations from one among their parents, while other 6, unrelated patients seemed to show random de novo mutations (present for the 1st time in family member) within the gene.
In either case, the mutations are problematic, resulting in excessive productions of sphingolipids, linked to abnormally high levels of an enzyme that helps make the lipids, called serine palmitoyltransferase (SPT).
“Our results suggest that these ALS patients are essentially living without a brake on SPT activity,” says biochemist Teresa M. Dunn from Uniformed Services University.
“SPT is controlled by a feedback circuit … The mutations these patients carry essentially short-circuit this feedback loop.”
Abnormalities in SPT activity thanks to mutations within the SPTLC1 gene have previously been linked to neurodegeneration in another disease, called Hereditary Sensory & Autonomic Neuropathy (HSAN1), although the pathological mechanism appears to vary .
In HSAN1, SPTLC1 mutations produce harmful sphingolipids; within the present study, the SPTLC1 mutations found produced abnormal levels of non-harmful sphingolipids, by inhibiting a protein called ORMDL from regulating SPT activity.
In turn, the oversupply of sphingolipids accumulates in human motor neurons, resulting in the starting onset form of efferent neuron disease, which the team characterizes as ‘childhood-onset ALS’.
Fortunately, there might be how to prevent this from happening, with the researchers deciding how to turn off the mutant SPTLC1 gene by using small interfering RNA (siRNA): RNA molecules that specifically target the mutant allele & inhibit the overactive SPT production.
While the experiment has only been tested within the patients’ cells for now – not yet on the patients themselves – the breakthrough points to a future where treatments might be possible, when children might hopefully be spared the worst of this debilitating & despairing disease.
“These preliminary results suggest that we could also be ready to use a precision gene silencing strategy to treat patients with this form of ALS,” says NINDS senior investigator Carsten Bönnemann.
“Our ultimate goal is to translate these ideas into effective treatments for our patients who currently haven’t any therapeutic options.”
The findings are reported in Nature Medicine.