Spinal Muscular Atrophy (SMA) disease overview
Spinal muscular atrophy (SMA) is a heterogeneous genetic neuromuscular disease classified as Type I (most severe) to Type IV (milder) based on the age of onset, motor milestones achieved and SMN2 copy number. SMA is caused by loss of function mutations or deletions in the SMN1 gene, which results in insufficient levels of the survival of motor neuron (SMN) protein. An additional gene, SMN2 can produce low levels of functional SMN protein but cannot compensate for the loss of SMN1 present in these patients. To find out more about the underlying genetics of SMA, visit the 'SMN1/SMN2 genes and mutations in spinal muscular atrophy' page in this section.
SMN deficiency leads to progressive loss of motor neurons and muscular atrophy.
There is a growing body of evidence which supports a paradigm shift from considering SMA as a purely neuromuscular disease to a disease associated with wide range of multi-organ complications.1–4
Listed below are some of the secondary complications observed in SMA:
- Respiratory complications - respiratory complications are a significant source of morbidity and mortality in severe SMA (Type I). These manifest as impaired cough responses, diminished ability to clear lower airways, hypoventilation, weakened pulmonary defences and recurrent infections.6,7
- Cardiovascular complications - Cardiovascular abnormalities such as septal defects and abnormalities of cardiac outflow are more frequent in severe SMA (Type I). Distal finger necrosis and microvascular abnormalities can also manifest in most severe SMA.8 Milder SMA types (Types III) may exhibit cardiac rhythm disorders.9,11
- Gastrointestinal complications - Bulbar dysfunction in patients with SMA can lead to difficulties in feeding and swallowing and is more frequent in Type I and Type II SMA, the more severe forms of the disease.1,12
- Musculoskeletal complications - Few case studies of SMA report decreased bone densities and increased rate of fractures in patients irrespective of disease severity.13 Patients with intermediate disease phenotypes (Type II and Type III) can be affected by scoliosis.14,15
- Metabolic complications - Studies in animal models of SMA have observed defects in immune, pancreatic and liver function.6,16–21 There is some evidence in human disease that associates SMA with metabolic dysfunction.20,22
It is well established that SMN protein is ubiquitously expressed and plays a vital role in essential cellular processes, including and most importantly in the biogenesis of ribonucleoproteins. Some evidence in animal models of SMA suggests that disease may be affected by the broader function of SMN protein beyond motor neurons.18,23,24 Moreover, in animal studies, interventions that restored SMN systemically rather than specifically in motor neurons improved disease phenotype.25 This has led to the development of the threshold hypothesis of disease pathogenesis.26 According to this, different cells have a different threshold for susceptibility to SMN deficiency. Hence, although motor neurons are most susceptible, other cell types may also be affected by the continued deficiency of SMN, and this may be causally linked to the whole-body complications of the disease.
In the next section, the role and function of SMN protein in the context of its broader biological functions in different cells and tissues and how its deficiency can impact disease pathophysiology is discussed.
Survival of Motor Neuron (SMN) Protein
The SMN protein though named for its functional importance in motor neurons, plays a crucial role in many fundamental processes within all cells.27
Full-length SMN (FLSMN) is a 38 kDa protein and is predominantly produced by the SMN1 gene (Figure 3). It is expressed ubiquitously and located in both the cytoplasm and nucleus of cells. SMN impacts a myriad of cellular processes such as RNA metabolism, cytoskeletal dynamics, mitochondrial function and intracellular trafficking.27
The role of SMN in RNA metabolism is well characterised. SMN is required for the assembly of the spliceosomal small nuclear ribonucleoproteins (snRNP) that process intron-containing mRNA.28,29 SMN can impact RNA trafficking and translation by interacting with other proteins and the cellular cytoskeleton. Through these mechanisms SMN is shown to affect neurite outgrowth30–32 endocytosis and intracellular trafficking.33 Thus, SMN deficiency can compromise many essential cellular processes all of which potentially contributes to disease pathogenesis in SMA.
How do low levels of SMN affect disease pathogenesis in SMA?
SMA is caused by the deficiency in functional SMN protein. SMN plays an important role in motor neuron survival. Motor neurons are particularly susceptible to SMN deficiency. There is some evidence in animal studies that cell-specific defects in SMN splicing and the accumulation of p53 within SMN deficient motor neurons contributes to their selective susceptibility.34,35 However, restoring SMN within motor neurons alone is not sufficient to completely rescue disease phenotype.36–38 This suggests that SMN deficiency in other cell types may also contribute to disease pathology (Figure 2).
Different cells have a different threshold for susceptibility to SMN deficiency. Motor neurons are most susceptible, other cell types such as sensory neurons and tissues (heart, bone) may also be affected by the deficiency of SMN which may manifest differently in different SMA subtypes from most severe (SMA type 1) to mild (SMA type IV). Click here to find out more about SMA subtypes.
Animal models provide further insights into the contribution of cell-specific deficiencies of SMN protein to disease pathology.39–41 Beyond motor neurons, SMN can affect other cells, including Schwann cells, astrocytes and impact muscle fibre growth.42 Moreover, in animal models, synaptic dysfunction of the neuromuscular junction (NMJ) and sensory-motor synapses can precede motor neuron death.43–47 Hence, in addition to the loss of motor neurons, motor dysfunction in SMA could result from defects in NMJ and sensory-motor circuits. Sensory neuron defects and morphological and functional abnormalities at the NMJ are also reported in SMA patients.48–50
While the loss of motor functions and muscular atrophy is a crucial feature of SMA, it can be associated with additional multi-organ complications (see 'Disease overview' page in this section). These may be consequential to the progressive loss of motor function or associated with tissue-specific effects of SMN deficiency. Studies in animal models suggest that SMN may be involved in the development of the cardiovascular, respiratory, immune and gastrointestinal systems.23,51–54 In line with this, cardiovascular, bone and metabolic complications are reported in patients with SMA. However, investigating the contribution of cell specific deficiency of SMN in human disease is complicated as people with severe SMA (SMA Type I) may die before damage to other organs can be discerned. Nonetheless, the implications of non-motor neuron involvement in disease pathogenesis and the importance of restoring SMN function systemically is being increasingly recognised. This is further supported by data from animal models which indicate restoring SMN function systemically is more beneficial in disease.25
SMN1/SMN2 genes and mutations in spinal muscular atrophy
Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease. It not the absence but rather a deficiency of SMN protein that causes SMA.
The complete absence of functional full-length SMN protein is embryonically lethal. In humans, there are 2 SMN genes; SMN1 and SMN2 (Figure 3).
SMN1 is primarily responsible for the production of full-length functional SMN protein, whereas the SMN2 gene can only produce low levels of functional SMN protein. Alternative splicing of SMN2 pre-mRNA leads to a truncated transcript lacking exon 7 (SMN2Δ7) which is translated into truncated non-functional SMN (SMN2Δ7). Only few SMN2 transcripts include exon 7 and are translated into low levels of full length functional SMN.
People affected by SMA, have bi-allelic mutations or deletion in the SMN1 gene but retain an intact SMN2 gene. Variation in SMN protein insufficiency impacts disease severity, which can be linked to SMN2 copy numbers.
The disease locus of SMA is mapped to chromosome 5q13 region, which contains the SMN1 gene.56 Healthy individuals have two copies of the SMN1 gene.57,58 The majority of SMA patients have homozygous deletion of SMN1. In few cases small deletions, missense mutations and splice mutations in SMN1 on the other chromosome, may occur. Regardless, these mutations affect SMN1 gene function in a way that severely reduces SMN protein levels.59 This reduced level of functional SMN protein is the underlying cause of SMA pathogenesis.
The duplication of the SMN gene in humans gave rise to SMN2.60 Unlike SMN1, the number of copies of SMN2 can vary widely in healthy individuals from 0–8 copies per person. Although SMN1 and SMN2 are nearly identical, there is a translationally silent C-to-T transition at the sixth position of exon 7 and an A to G substitution at the 100th position of intron 7.61 This change disrupts the exon splicing sequence and causes exon 7 skipping in most transcripts from SMN2. Transcripts that lack exon 7 produce a truncated, unstable SMN which is rapidly degraded. Occasionally some SMN2 transcripts may include exon 7 and produce full-length functional SMN. SMN2 can only produce about 10–20% of functional SMN protein, and all functional SMN protein in SMA patients is derived from this pool.
The number of copies of SMN2 genes in SMA correlates inversely with age of onset and disease severity. The most severe phenotypes of SMA (SMA Type I and II) occur in people with less than 3 copy numbers of SMN2.62 However, in a few cases more copies of SMN2 did not rescue disease severity suggesting additional disease modifiers.63,64 Besides copy number, variations in the SMN2 gene can also modify disease phenotype. For instance, variants that increase inclusion of exon 7 and subsequently the amount of full-length SMN transcript are associated with milder disease.65–67 Restoring SMN protein is a viable therapeutic strategy to ameliorate disease and in the next page in this section we discuss these strategies.
Restoring Survival Motor Neuron (SMN) in disease
Survival Motor Neuron (SMN) protein can be restored either by correcting for the absence of SMN1 gene by gene therapy or by modifying the splicing of the pre-existing SMN2 gene present in all SMA patients.
For the former, onasemnogene abeparvovec (Zolgensma®) is the gene therapy for SMA approved for use in clinics. It is a one-time IV infusion that delivers the corrected SMN1 gene packaged in an adeno-associated virus (AAV9) vector (Figure 4).
Since the SMN2 gene is retained in all individuals with SMA, modifying SMN2 activity or its splicing to increase functional SMN protein is also a compelling therapeutic strategy. These strategies can work to enhance SMN2 transcription, target SMN2 promoter activity or alter SMN2 splicing using antisense oligonucleotides (ASO) or small molecules (Figure 4).
Some efforts to increase SMN2 gene expression have utilised histone deacetylase inhibitors (HDACi) such as sodium butyrate, valproic acid and trichostatin A.70–72 These molecules inhibit HDAC activity and affect chromatin structure, causing DNA relaxation and increasing gene transcription. Although effective in animal models,70,71 these strategies lack specificity and were ineffective in clinical studies.73–75 RG3039 is a quinazoline derivative which can upregulate SMN2 promoter.76 It has shown to be effective in animal models of SMA.77 SMN2 splicing is being therapeutically targeted to enhance exon 7 inclusion which results in an increase in full length functional SMN protein78 (see the 'SMN1/SMN2 genes and mutations in spinal muscular atrophy' page in this section). One such strategy uses antisense oligonucleotides (ASOs) which target intronic splice silencer elements (ISS)79 Nusinersen (Spinraza®) is the only EMA and FDA approved ASO treatment for SMA.80,81 It is a 29-O-(2-methoxyethyl) modified ASO which targets intronic splicing silencer N1 (ISS-N1) and enhances full-length SMN mRNA transcript. Timing of intervention is a crucial determinant for the treatment efficacy as treatment in genetically diagnosed but pre-symptomatic infants is most efficacious.82–84
Small molecules capable of modulating SMN2 pre-mRNA splicing are in various stages of development. RG7916/risdiplam is a pyridazine derivative that demonstrates remarkable specificity in SMN2 splicing and is currently in late stage trials.87,88 Underlying molecular mechanisms for its specificity are still being investigated.89 LMI1070/branaplam is also a pyridazine derivative that can correct SMN2 splicing by stabilising the interaction between the U1-snRNP complex and SMN2 pre-mRNA.85,86 Small molecules offer a significant advantage as they can be administered orally and distribute throughout the body including the brain.90 This could potentially restore SMN deficiency systemically and may benefit the whole-body complications of the disease. To find out more about SMA treatment and ongoing clinical trials, click here.
Learn more about the treatment options for spinal muscular atrophy, including the guidelines, current clinical trials and the future lansdscape here.
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M-XY-00000009 Date of preparation: March 2020.