Spinal muscular atrophy

Spinal muscular atrophy is one of the most common genetic causes of death during childhood.

Term spinal muscular atrophy (SMA) refers to a group of genetic disorders all characterized by degeneration of anterior horn cells and resultant muscle atrophy and weakness

• most common SMA, accounting for over 95% of cases, is an autosomal recessive disorder that results from a homozygous deletion or mutation in the 5q13 survival of motor neuron (SMN1) gene
• caused by degeneration of anterior horn cells in the spinal cord and characterised by progressive muscle weakness
• other parts of the peripheral nervous system such as the neuromuscular junction (NMJ), and possibly muscles and other organs, may also be affected

Incidence

• incidence of SMA is 1:11,000 live births [1]

Prevalence

• prevalence of the carrier state is approximately 1 in 54 [1]

Muscle weakness in SMA occurs predominantly in the axial and proximal muscle groups, with the lower limbs more affected than the upper limbs

• in more severe cases of SMA, intercostal muscles are also weakened, usually with relative sparing of the diaphragm
• survival depends primarily on respiratory function and not necessarily on motor ability
• there is often a fine tremor in the fingers
• although the face is often spared, tongue fasciculations and facial weakness are not unusual findings

Cognitive function of people with SMA is normal

Electrophysiological examination shows denervation and reinnervation

Severity

• clinical severity of SMA correlates inversely with SMN2 gene copy number and varies from an extreme weakness and paraplegia of infancy to a mild proximal weakness of adulthood
• natural history of SMA is complex and variable
  • clinical subgroups have been defined based upon best motor function attainment during development - also called Werdnig-Hoffmann disease, fatal with onset during infancy - also called intermediate form SMA, onset during childhood - also called Kugelberg-Welander disease, onset during adolescence
    • Type 1 SMA infants never sit independently
    • Type 2 SMA children sit at some point during their childhood, but never walk independently
    • Type 3 SMA children and adults are able to walk independently at some point in their childhood

Muscular atrophy is due to degeneration of cranial nerve nuclei and anterior horn cells and the failure of alpha motor neurone to properly innervate the muscles.

In the most severe cases of SMA, death occurs within the first year of life.

Other forms of SMA include:

• non-progressive SMA
• distal SMA
• facioscapulohumeral, scapuloperoneal and segmental SMA

Epitegromab (SRK-015)

• is a selective inhibitor of the activation of myostatin, a member of the TGF beta superfamily of growth factors, expressed primarily by skeletal muscle cells, and the absence of its gene is associated with an increase in muscle mass and strength
• is an anti-promyostatin monoclonal antibody under development to improve motor function in patients with spinal muscular atrophy (3)

Risdiplam

• is a small molecule that modulates SMN2 gene splicing, binding two sites in SMN2 pre-mRNA: 5' splice site (5' ss) of intron 7 and exonic splicing enhancer 2 (ESE2) in exon 7
• the unique specificity of binding two sites increases levels of full-length SMN mRNA and protein, while reducing the impact on splicing of other pre-mRNA and avoiding the possibility of off-target effects
• in a study involving infants with type 1 SMA, risdiplam resulted in higher percentages of infants who met motor milestones and who showed improvements in motor function than the percentages observed in historical cohorts (4)
• Risdiplam is recommended as an option for treating 5q spinal muscular atrophy (SMA) in people of all ages with a clinical diagnosis of SMA types 1, 2 or 3 or with pre-symptomatic SMA and 1 to 4 SMN2 copies (5)

Onasemnogene abeparvovec

• is recommended as an option for treating presymptomatic 5q spinal muscular atrophy (SMA) with a biallelic mutation in the SMN1 gene and up to 3 copies of the SMN2 gene in babies aged 12 months and under (6)

Reference:

• Sugarman EA, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet. 2012; 20(1):27-32.
• Kolb JS, Tissel SpinalJT. Muscular Atrophy. Neurol Clin. 2015 November ; 33(4): 831-846.
• Barrett D, Bilic S, Chyung Y, Cote SM, Iarrobino R, Kacena K, Kalra A, Long K, Nomikos G, Place A, Still JG, Vrishabhendra L. A Randomized Phase 1 Safety, Pharmacokinetic and Pharmacodynamic Study of the Novel Myostatin Inhibitor Apitegromab (SRK-015): A Potential Treatment for Spinal Muscular Atrophy. Adv Ther. 2021 May 8. doi: 10.1007/s12325-021-01757-z
• Darras BT et al. Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls. N Engl J Med 2021; 385:427-435
• NICE (December 2023). Risdiplam for treating spinal muscular atrophy
• NICE (April 2023). Onasemnogene abeparvovec for treating presymptomatic spinal muscular atrophy