Leptin Unlikely to Be Biomarker for SMA Disease Severity, Researchers Find

Leptin merely correlated with body mass index, the study found.

A new report on patients with types II and III spinal muscular atrophy (SMA) has found that levels of the peptide hormone leptin are likely not a viable biomarker of disease severity, despite previous research raising the possibility.

The study did find, however, that leptin was strongly associated with body mass index (BMI), a finding that mirrors the association found in pediatric patients generally. The study was published in the journal Archives de Pédiatrie.

People with SMA have variations of the SMN1 gene that result in a loss of functional survival motor neuron (SMN) protein, which in turn leads to severe muscle weakness and atrophy. People have a variable number of the other SMN-producing gene, SMN2. In SMA, patients with more copies of SMN2 tend to have less severe disease, explained corresponding author Stefan Djordjevic, MD, of University Children’s Hospital, in Belgrade, Serbia, and colleagues.

People with SMA are categorized into one of 4 main types, based on the age of diagnosis and the level of motor function achieved. People with type I SMA usually are diagnosed within the first 6 months of life and are unable to ever sit or stand on their own, while patients with type IV SMA are diagnosed as adults and their life expectancy is similar to that of the general population.

As investigators have begun to better understand the disease, they have cast a wider net to capture its pathogenesis, Djordjevic and colleagues said.

“Limited but growing evidence suggests that SMA is a multisystem disorder affecting primarily, but not exclusively, motor neurons,” the authors said. “Therefore, there is an increasing interest in the multisystem effects of SMA, including metabolic abnormalities.”

To that end, a recent study of people with types I-III SMA suggested that hyperleptinemia was associated with lower levels of motor function in people with SMA. Leptin is produced by adipose tissue, the investigators said, and plays a role in regulating energy metabolism.

In the new study, Djordjevic and colleagues wanted to look specifically at patients with types II and III SMA to see whether they could replicate the results of the earlier study, which also found that underweight patients were more likely to have hyperleptinemia.

Djordjevic and colleagues enrolled 37 patients between the ages of 2 and 19 in their study; 22 had type II SMA and 15 had type III SMA. Most of the patients were prepubertal (62.2%).

The authors used the Hammersmith Functional Motor Scale-Expanded (HFMSE) to assess patients’ motor skills. They then used Spearman’s rank correlation coefficient to estimate the relationship between BMI, HFMSE score, and leptin levels. They found differing results.

“No statistically significant correlation was observed between the HFMSE score and leptin levels, rs(35) = 0.24, p = 0.15,” they said. “There was, however, a strong positive correlation between the BMI z-score and leptin levels, rs(35) = 0.87, p <0.001.”

The fact that higher leptin levels were associated with higher BMI in this study suggests that leptin levels are more an indication of adipose tissue than of disease status, the investigators said, noting that the same correlation can be found in the general pediatric population.

The investigators said the relationship between body fat and disease severity might be more complicated than it appears.

“For example, non-sitters are weak and usually fail to thrive due to inadequate caloric intake and high energy expenditure to breathe. Being underweight, in turn, is associated with lower leptin levels. ” they said. “By contrast, high-functioning sitters are at risk of becoming overweight/obese.”

The authors noted several limitations to their study, including the small sample size and other limitations associated with the small patient population of SMA. Still, they said the data seem to suggest that leptin is not, in fact, a strong biomarker by which to gauge disease progression or severity.


Djordjevic S, Milic-Rasic V, Brankovic V, et al. Serum leptin levels in children and adolescents with spinal muscular atrophy types 2 and 3. Arch Pediatr. Published online September 12, 2022. doi:10.1016/j.arcped.2022.08.015

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