Introduction:
Autosomal Recessive disorder characterised by progressive degeneration of alpha motor neurons of spinal cord leading to progressive muscular atrophy- “Neuronopathy”
Caused by homozygous biallelic deletions of exon 7 in SMN1 gene (Chromosome 5q11.1-13.3) (95% of cases) located at telomeric end of chromosome
Few cases (<5%) - Point mutation in SMN 1 gene
SMN1 has a pseudogene called SMN2 - inverted duplication in opposite direction; differs from SMN1 in only 5 nucleotide base pairs in exon 7 of SMN2 gene
Natural history of disease- Onset and progression of disease:
Severity of disease inversely related to SMN2 copy numbers- more the SMN2 copy numbers less the disease severity and progression
Role of SMN gene in survival of alpha motor neurons:
Help in soma protein synthesis, axolemmal transport, axon path findings, synaptic vesicle maturation and repair of neuromuscular junction
Figure 1: Role of SMN gene product in survival of motor neurons
Pathophysiology:
Usually in health- majority of functional SMN protein is formed by SMN1 gene product; SMN2 gene undergoes substitution of cytosine by Thymine at 840th nucleotide leading to extrusion of exon 7 from SMN2 gene (defective splicing)- majority of protein is truncated and thus is degraded, only about 10% functional protein formed by SMN2 pseudogene in health
But in normal healthy individuals , protein product of SMN1 is sufficient to survive alpha motor neurons in anterior horn cells of spinal cord. The trouble starts when both SMN1 copies are deleted and now alpha motor neurons depend only on SMN2 gene product for their survival- so more the SMN2 copies more likelihood of alpha motor neuron survival and lesser the severity and progression of disease.
Figure 2: Pathophysiology of SMA and relationship of natural history to SMN2 copy numbers
Diagnosis Algorithm:
First line investigation- MLPA (multiplex ligation dependent Probe amplification) for exon 7 SMN1 gene deletion and quantification of SMN2 copies- helps in assessing disease severity and response to novel therapeutics
If Exon 7 copies present ( no deletion) and high suspicion of SMA ( classic phenotype, consanguineous parents and positive family history)- proceed with SMN 1 gene sequencing
If both MLPA and gene sequencing negative- proceed with next generation sequencing (Clinical/ whole exome plus mitochondrial genome)
Principles of management:
Goals- Maintain mobility and ambulation, prevent complications and treatment of complications
Requires multidisciplinary team of experts- for both child and family ( as they are devastated by diagnosis of progressive disease and prohibitive cost of novel therapeutics)
Figure 3: Multidisciplinary model for management of SMA
Novel Therapeutics:
Three approaches-
Replace SMN1 deleted gene product- AAV9 vector with SMN1 gene as package insert- ZOLGENSMA ( Costliest drug on earth- 2.1 million US dollars)
Increase SMN2 copy numbers ( prevent exon 7 splicing in SMN2 gene so that entire gene is expressed and more functional protein is synthesized)- 2 novel therapeutics FDA approved- Risdiplam (oral small molecule splicing inhibitor, DCGI approval in India in August 2021; cost 6 lac/ month) and Nusinersen (Inhibits Intron splice site silencer N1 protein- leads to exon 7 inclusion in SMN2 mRNA; intrathecal administration, one vial (12mg/5ml)- cost approx. 87 to 90 lac/vial)- Both Risdiplam and Nusinersen require life long administration
SMN2 independent- Cell protection, NMJ repair, SMN protein stabilization and muscle stem cells- Only experimental
Figure 4 : SMN dependent and independent therapeutic approaches
Figure 5: Mechanism of action and mode of administration of Nusinersen, Risdiplam and Zolgensma (All 3 drugs are FDA approved)
Figure 6: Site of action of Risdiplam- Exon splice enhancer 2 and 5’ss region on either side of exon 7
Figure 8 : Site of action of Nusinersen- ISS-N1 site at exon intron junction- Prevents splicing of exon 7 by hnRNP
Summary:
•Progressive motor neuron degeneration- Neuronopathy
•Biallelic homozygous 5q exon 7 deletion> point mutation
•Varied spectrum and natural history- severity inversely related to SMN2 copy number
•Multidisciplinary holistic approach for diagnosis and management
•Novel therapeutics- Nusinersen and Risdiplam (DCGI approved Aug 2021) -enhances exon 7 inclusion in SMN2 mRNA and increases functional SMN protein; Life long therapies
•Zolgensma- Gene therapy; single dose therapy; costliest drug on earth
Tought for the day- While there is life, there is hope!!