Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance

Abstract

Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder that causes degeneration of the alpha motor neurons from anterior horn cells in the spinal cord, which causes severe progressive hypotonia and muscular weakness. With a carrier frequency of 1 in 40-50 and an estimated incidence of 1 in 10,000 live births, SMA is the second most common autosomal recessive disorder. Affected individuals with SMA have a homozygous loss of function of the survival motor neuron gene SMN1 on 5q13 but keep the modifying SMN2 gene. The most common mutation causing SMA is a homozygous deletion of the SMN1 exon 7, which can be readily detected and used as a sensitive diagnostic test. Because SMN2 produces a reduced number of full-length transcripts, the number of SMN2 copies can modify the clinical phenotype and as such, becomes an essential predictive factor. Population-based SMA carrier screening identifies carrier couples that may pass on this genetic disorder to their offspring and allows the carriers to make informed reproductive choices or prepare for immediate treatment for an affected child. Three treatments have recently been approved by the Food and Drug Administration (FDA). Nusinersen increases the expression levels of the SMN protein using an antisense oligonucleotide to alter splicing of the SMN2 transcript. Onasemnogene abeparvovec is a gene therapy that utilizes an adeno-associated virus serotype 9 vector to increase low functional SMN protein levels. Risdiplam is a small molecule that alters SMN2 splicing in order to increase functional SMN protein. Newborn screening for SMA has been shown to be successful in allowing infants to be treated before the loss of motor neurons and has resulted in improved clinical outcomes. Several of the recommendations and guidelines in the review are based on studies performed in the United States.

Keywords: SMA treatment; carrier screening; newborn screening; spinal muscular atrophy.

Figure 1

Two genes are responsible for producing the survival motor neuron (SMN) protein, SMN1 and SMN2. SMN1 provides humans with the proper quantity of SMN protein necessary for a normal phenotype. SMN2 is an inverted duplicate of SMN1 lying closer to the centromere. A C>T transition in exon 7 of SMN2 causes the SMN2 gene to produce mostly (~90%) nonfunctional protein and a small amount (~10%) of the functional SMN protein.

Figure 2

(A) A chromosome carrying a normal copy of SMN1 and SMN2. (B) The blank box indicates a deleted gene. A deletion can remove part or all of the SMN1 gene. (C) The curved arrow represents a conversion. With the C>T transition in SMN1, the SMN1 copy now closely resembles SMN2 and is considered SMN2-like. (D) Point mutations occurring in any of the SMN1 exons prior to the last exon can affect the SMN protein.

Figure 3

(A) A wild type with 2 copies of SMN1 and SMN2 on each chromosome. (B) SMA carrier with only one copy of SMN1 on one chromosome and loss of SMN1 on the other. (C) A silent SMA carrier with a duplication of SMN1 on one chromosome and no SMN1 on the other chromosome. (D) SMA carrier with one normal copy of SMN1 on one chromosome and one copy that contains a point mutation on the other chromosome.