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).

Keywords: nusinersen; pharmacological biomarkers; prognosis; spinal muscular atrophy; survival motor neuron 1 protein.

Figure 1

The normal spinal cord of a 4-month-old infant (left) and spinal cord of a 5-month-old infant with SMA type 1 due to homozygous deletion of SMN1 exon 7 (right). Both are transverse sections through the cervical part of the spinal cord. SMA1 is characterized by a significant loss of anterior horn a-motoneurons. CON, control; SMA1, spinal muscular atrophy type 1. Cresyl violet stain. The selected sections are part of the Zagreb Collection of human brains at the Croatian Institute for Brain Research, curated by Goran Šimić. Scale bars = 1 mm.

Figure 2

Tissue biopsied from the biceps brachii muscle of a 12-month-old infant with homozygous deletion of SMN1 exon 7 and only two SMN2 genes, as well as type 1 spinal muscular atrophy. The arrows show fascicles (groups) of atrophic muscle fibers with pyknotic nuclei interspersed with reinnervated clusters of hypertrophied muscle fibers (arrowheads). There are no signs of severe muscle fiber destruction or phagocytosis. Hematoxylin and eosin stain. The selected section is a part of the Zagreb Collection of human brains at the Croatian Institute for Brain Research, curated by Goran Šimić. Scale bar = 250 μm.