Global metabolic disruption found in children with SMA in new study
Metabolic changes seen in CSF may be potential therapeutic targets
Children with spinal muscular atrophy (SMA) exhibit widespread metabolic disruption — changes that affect the body’s metabolism — relative to children without SMA, according to a new Chinese study.
Metabolic analyses of the cerebrospinal fluid (CSF), the fluid surrounding the brain and spinal cord, indicated metabolic disruption across several different systems, identifying possible treatment targets for future study.
“Our study provides new insights into the metabolic perturbations associated with SMA,” the researchers wrote. “Further investigations are needed to fully understand the functional implications of these alterations and their potential as therapeutic targets in SMA.”
The study, “Dysregulation of cerebrospinal fluid metabolism profiles in spinal muscular atrophy patients: a case control study,” was published in the Italian Journal of Pediatrics.
Investigating metabolic disruption in pediatric SMA patients
SMA is caused by mutations in the SMN1 gene, leading to a deficiency in the SMN protein that’s believed to be important for the health of nerve cells involved in muscle control. Still, the mechanisms through which SMN loss leads to the symptoms of SMA are not fully understood.
Metabolites are molecules made or used as part of the body’s metabolism — the set of all reactions through which the body breaks down food and other substances to produce cellular energy and materials needed for normal body function.
Metabolomics, or large-scale studies of all metabolites in the body — known as the metabolome — can offer clues as to what processes might be disrupted in a disease state. This may help scientists better understand how a condition such as SMA arises, and to identify possible treatment targets.
Previous studies using blood or urine samples from patients overall have indicated substantial disruptions to the SMA metabolome relative to healthy people. However, no study to date has made such a comparison using CSF samples. Performing such a study could offer insights into nervous system function in SMA, according to the researchers.
As such, the team, from the School of Medicine at Xiamen University, performed a metabolomic study using CSF samples from 15 pediatric SMA patients. The children, seen at the Women and Children’s Hospital, had not been previously treated with disease-modifying therapies and were receiving Spinraza (nusinersen), an injection therapy for SMA, for the first time. Also included were 14 children without SMA (a control group) who had CSF samples collected due to fever-induced seizures.
Overall, the metabolome of the SMA children was clearly different from that of their healthy counterparts, according to the team, with 118 metabolites found at significantly different levels between the two groups.
These altered metabolites were involved in a range of biological pathways, but were predominantly clustered into a few main categories, including metabolism of proteins and amino acids (protein building blocks), as well as fat metabolism.
Findings highlight metabolites of interest for further study
One metabolite of interest was methylmalonic acid, which was elevated in the SMA group. While a role for methylmalonic acid in SMA has not been previously described, the scientists indicated that some SMA symptoms, including decreased muscle tone and poor feeding, overlap with those seen in a condition called methylmalonic acidemia, which is caused by methylmalonic acid elevations.
This might therefore indicate that methylmalonic acid toxicity is involved in SMA progression. Methylmalonic acidemia is treated clinically with vitamin B12, which could ultimately have therapeutic potential in SMA.
“Vitamin B12 is a useful supplement for methylmalonic acidemia patients, and it may be a potential medicine for high methylmalonic acid SMA patients,” the researchers wrote.
Another possible metabolite of interest was N-acetylneuraminic acid, found to be lower than normal in SMA patients. Treatment with this metabolite has previously been shown to be of benefit in a SMA worm model and may therefore serve as a “potential treatment to improve function in SMA patients,” the researchers wrote.
[These findings overall] suggest that multiple metabolic pathways are affected in SMA, highlighting the complex nature of the disease.
Altogether, the findings “suggest that multiple metabolic pathways are affected in SMA, highlighting the complex nature of the disease,” the team wrote.
As one study limitation, the researchers noted that some participants in the control group had bacterial or viral infections, which can influence CSF metabolites. Moreover, it could not be established from the findings whether metabolic alterations are a direct result of SMN deficiency or are an indirect consequence of nutritional deficiencies in SMA.
Future long-term studies to track metabolic changes over time “could provide more definitive evidence of causality and yield more robust conclusions,” the researchers wrote.
The team also indicated that it will be important to look for alterations to metabolites of interest in animal models of SMA, which could facilitate the identification of new therapeutic targets.
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