Skeletal Muscle Biomarkers Altered in Type of SMA, Study Says


In the majority of the 49 patients with a type of spinal muscular atrophy called spinal muscular atrophy Jokela, creatine kinase was elevated, particularly in males.

A study leveraging skeletal muscle-derived markers has revealed that biomarkers of muscle mass and damage are altered in the serum of patients with a type of spinal muscular atrophy (SMA) linked to the CHCHD10 variant.

All patients had spinal muscular atrophy Jokela (SMAJ), a type of SMA characterized by adult-onset of muscle cramps, lower limb predominant muscle weakness, hyporeflexia, and walking difficulties.

In the majority of the 49 patients, creatine kinase (CK) was elevated, particularly in males, according to the report, published in Frontiers in Neurology. Nearly all the male patients (95%) included in the study and 60% of the female patients had elevated CK. The researchers concluded that the marker could serve as a potential biomarker in the disease, although they noted longitudinal studies with validated measures of disease severity are needed.

Unexpectedly, the researchers found that neurofilament (NfL)—an axonal injury protein that has shown to be elevated in other motor neuron diseases—was not elevated in patients with SMAJ compared with controls (median 14.9 pg/ml vs 13.6 mg/pl). According to the researchers, normal NfL levels could help differentiate between SMAJ and amyotrophic lateral sclerosis (ALS)—a disease patients with SMAJ may initially be diagnosed with—or potentially more generally between rapidly and slowly progressing motor neuron diseases.

Notably, levels of Glial fibrillary acidic protein (GFAP)—a centrally expressed marker of astrogliosis—were lower in patients with SMAJ compared with controls (median, 118 pg/ml vs 177 pg/ml).

“The fact that SMAJ is slowly progressive and largely restricted to lower limbs may mean that the number of actively degenerating spinal motor neurons is not sufficient to elevate NfL. Nonetheless, this hypothesis is not supported by the elevation of serum NfL in patients with similarly slowly progressive inherited peripheral neuropathies,” wrote the researchers, adding, “The absence of GFAP increase in SMAJ serum suggests that astrocytic injury or activation is not an important part of the disease process; the significantly lower levels of GFAP in patients with SMAJ compared with controls may suggest impaired astrocytic activation, but more studies are needed before any strong conclusions regarding this can be drawn.”

Across their SMAJ cohort, the researchers identified a total of 6 metabolites that were significantly altered. In addition to CK, creatine was also increased. Creatinine, taurine, and N-acetyl-L-carnosine were decreased, suggesting they may also be indicators of decreased muscle mass in the disease.

Metabolite profiling revealed that pyruvate was elevated in patients with SMA while succinate was decreased, signaling a metabolic response to mitochondrial dysfunction, although lactate was not different.

“Increased pyruvate, together with decreased succinate, suggests a block in the TCA cycle, and, thus, glycolysis may be upregulated,” explained the group. “The altered metabolites may thus be directly involved in compensatory pathways for balancing an energy deficiency in SMAJ. Interestingly, a recent study of ALS-linked CHCHD10 variant has reported similar findings for pyruvate and succinate in a patient’s fibroblasts.”

Findings from that same study and from mouse models of Chchd10 have suggested that upregulation of integrated stress response is part of the pathogenesis and creates increased expression of FGF-21 and GDF-15.


Järvilehto J, Harjuhaahto S, Palu E, et al. Serum creatine, not neurofilament light, is elevated in CHCHD10-linked spinal muscular atrophy. Front Neurol. Published online February 17, 2022. doi:10.3389/fneur.2022.793937

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