Last Updated: September 12, 2022
Introduction to Spinal Muscular Atrophy: SMA
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene that encodes the protein identified as survival motor neuron 1. SMA is characterized by loss of lower motor neurons (anterior horn cells) in the spinal cord and in brainstem nuclei, leading to progressive symmetrical muscle weakness and atrophy. It affects approximately 1 in 6,000 to 1 in 10,000 individuals and is the most common inherited cause of childhood mortality.
In 2018 screening for SMA was added to the Recommended Uniform Screening Panel of disorders in the newborn. The screening of neonates for SMA involves molecular analysis for homozygous deletion of exon 7 in both copies of the SMN1 gene. The standard test involves real-time PCR for detection of the exon 7 deletions.
Molecular Biology of SMA
The SMN1 gene is located on the telomeric end of chromosome 5 (5q13.2) and is composed of 11 exons that generate three alternatively spliced mRNAs, each of which encode a distinct protein isoform. The mRNA that encodes the isoform d protein (294 amino acids) is the predominant mRNA generated from the SMN1 gene.
A nearly identical gene located near the centromeric region of the q arm of chromosome 5 (also 5q13.2) is identified as SMN2. The SMN2 gene is composed of 11 exons that generate four alternatively spliced mRNAs, each of which encode distinct protein isoforms. The isoform a protein (282 amino acids) is believed to be the predominant form produced from the SMN2 gene, however, due to low levels of synthesis of full-length SMN2 mRNA, the SMN2 gene does not appreciably contribute to the pool of SMN protein.
Because of the near 100% identity between the SMN1 and SMN2 genes they are distinguished by using the terminology that designates the physical location of the gene. Thus, SMN1 is correctly referred to as survival motor neuron 1, telomeric and SMN2 is correctly referred to as survival motor neuron 2, centromeric.
The SMN1 and SMN2 genes are contained within a 500 kb inverted duplication on the q arm of chromosome 5 (region designated 5q13.2). This duplicated region contains at least four genes as well as repetitive elements. The presence of the repetitive elements makes this region of the q arm prone to rearrangements and deletions. In addition it is thought that gene conversion events may involve the SMN1 and SMN2 genes, leading to varying copy numbers of each gene.
Mutations in the SMN1 gene are associated with spinal muscular atrophy, whereas mutations in the centromeric SMN2 gene do not lead to disease. The SMN2 gene is thought to be a modifier of disease caused by mutation in the SMN1 gene. The critical sequence difference between the two genes is a single nucleotide in exon 7, which is thought to be an exon splice enhancer. Because historical exon designations in these genes accounted for an exon 2a and 2b, exon 7 is not specifically the seventh exon but the nomenclature is maintained nonetheless.
The SMN protein is found in both the cytosol and the nucleus. Within the nucleus, the SMN protein co-localizes to subnuclear structures that contain high concentrations of small ribonucleoprotein (snRNP) complexes. The SMN protein is the catalyst in the assembly of the snRNP complexes that form the spliceosome, thus, it plays a critical role in the splicing of numerous mRNAs.
The loss of SMN1 causes SMA, with approximately 95% of affected individuals having homozygous deletions of exon 7 in the SMN1 gene. Most of the remaining 5% of patients with SMA are compound heterozygotes for an SMN1 deletion and an SMN1 point mutation.
The variability of clinical presentation in SMA is primarily due to the presence of the nearly identical SMN2 gene. Both the SMN1 and SMN2 genes encode mRNAs that contribute to functional SMN protein. However, the SMN2 gene produces much less of full-length mRNA and, therefore, much less functional SMN protein. Due to the repetitive elements in the 500 kb duplicated region that contains the SMN1 and SMN2 genes, individuals have variable numbers of copies of the SMN2 gene. The presence of multiple copies of the SMN2 gene results in milder SMA symptoms. Indeed, individuals that harbor five or more copies of the SMN2 gene generally have no symptoms even in the presence of exon 7 deletion in the SMN1 gene.
Clinical Features of SMA
There are five clinical designation of SMA identified by age of onset.
SMA type 0 is the most severe form of SMA with death occurring in the neonatal period.
SMA type 1 is also known as Werdnig-Hoffman disease. SMA type 1 infants display symptoms in the period from birth to 6 months of age. These infants never learn how to sit by themselves and succumb to the disorder before reaching the age of 2 years. SMA type 1 represents the most common form of SMA representing roughly 60% of cases.
SMA type 2 is also known as Dubowitz disease. SMA type 2 infants begin to display symptoms between 6 months and 18 months. The infants will learn to sit independently but generally never learn how to walk unaided and will succumb to the disorder but live longer than SMA type 1 infants. The major contribution to morbidity and mortality in SMA type 1 and type 2 patients is pulmonary disease.
SMA type 3 is also known as Kugelberg-Welander disease. SMA 3 patients usually begin to display symptoms in the period of 18-24 months and will display a significant degree of variability in the onset and progression of the disease but will have normal life expectancy.
SMA type 4 patients present in adulthood, usually older than 21 years of age, and have normal life expectancy.
The original characteristic clinical phenotype described for SMA patients was muscle weakness, hypoventilation, and gastrointestinal problems. However, given that SMA patients are now living longer, the constellation of involved tissues has been expanded to include disruption in sensory pathways, cardiac arrhythmias, vascular defects such as distal digital necrosis, decreased bone mineral content, and abnormal glucose metabolism. These observation clearly indicate that loss of SMN1 encoded function affects many organ systems beyond the spinal chord and skeletal muscle.
Treatment of SMA
Prior to 2016 the method of management of SMA patients was solely palliative. In patients with the highest levels of weakness, tracheostomy is recommended for protection of the airway and a gastric tube is used to ensure adequate nutritional intake in those patients that exhibit difficulty feeding.
In 2016 the US FDA approved a new therapy based on the use of an antisense oligonucleotide (ASO) that interacts with the mRNA produced from the SMN2 gene and induces the production of functional protein that is identical to the SMN1 encoded protein. This ASO therapy is called nusinersen (trade name Spinraza). Although the use of nusinersen was approved for all types of SMA, clinical trials demonstrated efficacy only with type 1 patients. The most significant drawback to this therapy is that a single dose costs in excess of $125,000 and six doses are required in the first year of intervention and three doses per year thereafter.
A viral delivery-based therapeutic approach called onasemnogene abeparvovec (trade name Zolgensma) was approved for use in 2019 by the US FDA. This therapy utilizes an adeno-associated virus (AAV) delivery system to drive the expression of a functional SMN1 mRNA in patients. Although a highly successful treatment approach, the cost is prohibitive for most patients as it is over $2,000,000 per treatment.
In 2020 the US FDA approved a small molecule therapy called risdiplam. Risdiplam functions by modifying the splicing of the SMN2 mRNA so that exon 7 is included. The result of this function of risdiplam is increased amounts of functional SMN2 protein. Risdiplam is an orally delivered drug that needs to be taken for the rest of the patient’s life. The initial annual cost for risdiplam is on the order of $750,000 with an annual price tag of around $100,000 after that.