Molecular Biomarkers for the Diagnosis, Prognosis, and Pharmacodynamics of Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy (SMA) is a progressive degenerative illness that affects 1 in every 6 to 11,000 live births. This autosomal recessive disorder is caused by homozygous deletion or mutation of the SMN1 gene (survival motor neuron). As a backup, the SMN1 gene has the SMN2 gene, which produces only 10% of the functional SMN protein. Nusinersen and risdiplam, the first FDA-approved medications, act as SMN2 pre-mRNA splicing modifiers and enhance the quantity of SMN protein produced by this gene. The emergence of new therapies for SMA has increased the demand for good prognostic and pharmacodynamic (response) biomarkers in SMA. This article discusses current molecular diagnostic, prognostic, and pharmacodynamic biomarkers that could be assessed in SMA patients’ body fluids. Although various proteomic, genetic, and epigenetic biomarkers have been explored in SMA patients, more research is needed to uncover new prognostic and pharmacodynamic biomarkers (or a combination of biomarkers).

Cerebrospinal Fluid Proteomic Changes after Nusinersen in Patients with Spinal Muscular Atrophy

“…In our study, NEFL concentration was significantly decreased in the whole cohort after 6 months of treatment, and NEFL was identified within the 4 top proteins with the highest predictive ability for motor improvement at 2 years. Neurofilaments have received considerable interest as markers of disease severity and treatment response in SMA and other neurological disorders [20]. Phosphorylated neurofilament-heavy chain (pNfH) was shown to be strongly elevated in symptomatic infants and children with SMA in comparison with healthy controls, and levels dropped rapidly after starting nusinersen [21].…”

“…Because CSF is in direct contact with the degenerating ventral horn motor neurons affected by SMA, proteomic changes might parallel disease progression and response to treatment. Among other proteins, neurofilament light chain (NEFL) and phosphorylated neurofilament heavy chain (pNfH) are promising candidates [20]. Neurofilaments are neuronal cytoskeletal proteins that leak into CSF and blood with neuronal damage and axonal loss.…”

“…Neurofilaments are neuronal cytoskeletal proteins that leak into CSF and blood with neuronal damage and axonal loss. They are useful biomarkers of disease activity in many neurological disorders [20], so are not specific to any single disease. In SMA patients, pNfH levels are elevated compared to healthy controls and decrease rapidly after starting nusinersen [21].…”

Spinal Muscular Atrophy: An Evolving Scenario through New Perspectives in Diagnosis and Advances in Therapies

“…SMA type 1 (SMA 1) is the most common form of SMA (50-60% of cases) and manifests early in the first six months of life, with severe weakness and generalized hypotonia, poor motor abilities, areflexia, and feeding, swallowing, and breathing difficulties with premature death within 24 months [24]. The mean age at onset of symptoms is 2.5 months.…”

“…Advantages and limitations of multiplex qPCR and MLPA as molecular genetic tests for SMA diagnosis[22][23][24][25].…”