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 adenoassociated 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.

Newborn Screening for 5q Spinal Muscular Atrophy: Comparisons between Real-Time PCR Methodologies and Cost Estimations for Future Implementation Programs

“…Considering just up to three copies of SMN2 is against the current international recommendations [40], as already discussed. The Brazilian guidelines must be revised to also make eligible patients with up to four SMN2 copies and discuss the ethical implications of milder later-onset cases of SMA that will be identified in a NBS program [45]. Moreover, pre-symptomatic SMA patients without a previous familial history of SMA must also be eligible, considering the high carrier frequency of around one in 50, depending on ethnicity [3].…”

Combination Therapy with Nusinersen and Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy Type I

“…A large number of these patients also present with congenital heart defects. Death occurs in the first weeks of life, before the age of 6 months [ 16 , 17 ].…”

“…Onset is after 6 months of age (between 6 and 18 months) [ 15 ]. Patients are able to sit but cannot maintain the standing position without support or independent ambulation [ 16 ]. These patients can also have difficulties swallowing, tongue fasciculations and respiratory failure.…”

Growth patterns in children with spinal muscular atrophy

“…The classical form is a monogenic disorder, due to mutations in the Survival of Motor Neuron 1 ( SMN1 ) gene that leads to degeneration of alpha motor neurons in the spinal cord [ 2 ]. SMA has an incidence of about 1 in 6000 to 1 in 10,000 live births [ 3 ] and is categorized into five different phenotypes based on the age of onset and the highest level of motor function achieved [ 4 ].…”