Spinal Muscular Atrophy (SMA)


Spinal muscular atrophy (SMA) is caused by mutations in the SMN1 gene, which normally encodes for the SMN protein.1 SMN is essential for the survival of motor neurons, and the mutation prevents functional SMN protein from being made by this gene. 

Functional SMN protein can also be made from the SMN2 gene. The copy number of the SMN2 gene varies from person to person. Higher numbers of SMN2 gene copies produce a greater amount of functional SMN protein which, in turn, is associated with less severe disease.2

SMA is classified into 5 types based on severity and age at symptom onset. SMA type 0 is the most severe.

SMA Type 0 Causes

Infants born with SMA type 0 or congenital SMA usually have just one copy of the SMN2 gene,3 which does not provide enough SMN protein to prevent the disease phenotype.

SMA Type 0 Symptoms

Patients with SMA type 0 usually have reduced fetal movement in utero. At birth, they have significant muscle weakness and respiratory distress. Some may also have contracture or joint deformities, as well as cardiac defects.4 Infants born with SMA type 0 usually die within a few months of birth.

SMA Type 0 Diagnosis

SMA type 0, like other types of SMA, can be diagnosed using genetic testing from a blood sample.5 This test looks for mutations in the SMN1 gene.

SMA Type 0 Prevalence

Researchers estimate a prevalence of 1 to 2 per 100,000 people for all types of SMA.6 The exact prevalence of SMA type 0 is not known but it is the rarest form of the disease. Because affected infants usually die due to respiratory distress within a few months, they may not always receive a diagnosis.7

SMA Type 0 Genetics

Similar to other types of SMA, SMA type 0 is inherited in an autosomal recessive pattern.8 The parents of a child with SMA must both be carriers of the disease, ie, have one faulty copy and one healthy copy of the SMN1 gene. Carriers do not normally have disease symptoms, as the healthy copy of the gene can compensate for the faulty one, and usually do not know they are a carrier until they have a child affected by the disease. 

Two SMA carriers have a 25% chance of having a child with SMA. They also have a 50% chance of having a child who is a carrier like themselves. Finally, they have a 25% chance of having a child who is neither a carrier nor has the disease.

SMA Type 0 Treatment Options

There is currently no cure for any type of SMA. Infants born with SMA type 0 will require respiratory and feeding support.9 However, this is usually not sufficient to keep them alive. 

Nusinersen (Spinraza) is the first treatment that the US Food and Drug Administration (FDA) approved for SMA patients. It works by increasing the production of full-length SMN protein from the SMN2 gene by targeting SMN2 pre-RNA so it includes exon 7. Nusinersen is administered as a series of intrathecal injections. 

A second treatment that the FDA approved is onasemnogene abeparvovec-xioi (Zolgensma). It is a gene therapy for children under the age of 2 with infantile-onset SMA. Zolgensma delivers a fully functional SMN1 gene to motor neurons using adeno-associated virus 9 (AAV9). 

It is not clear whether either treatment can be beneficial for patients with SMA type 0 due to the severity of the disease and the fact that they also have heart, bone, and skin illnesses or symptoms.

Researchers reported the case of a patient with SMA type 0 who was treated with both nusinersen and onasemnogene abeparvovec.10 Treatment improved the patient’s motor skills but breathing and swallowing difficulties persisted, as did skin problems.   

Risdiplam (Evrysdi) is another disease-modifying treatment FDA-approved for SMA. It is a small oral molecule treatment that aims to increase the production of SMN protein from the SMN2 gene. It is a splicing modifier that increases exon 7 inclusion in SMN2 mRNA. It is not yet known whether it can benefit infants affected by SMA type 0.

Reviewed by Michael Sapko, MD on 7/1/2021

References

  1. Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin. 2015;33(4):831–846. doi:10.1016/j.ncl.2015.07.004
  2. Butchbach MER. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci. 2016;3:7. doi:10.3389/fmolb.2016.00007 
  3. Cuscó I, Bernal S, Blasco-Pérez L. et al. Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy. Neurol Genet. 2020;18;6(6):e530. doi:10.1212/NXG.0000000000000530
  4. Spinal muscular atrophy. Medline Plus. Accessed May 25, 2021.
  5. Spinal muscular atrophy fact sheet. National Institute of Neurological Disorders and Stroke. Accessed May 25, 2021.
  6. Verhaart IEC, Robertson A, Wilson IJ. et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy – a literature review. Orphanet J Rare Dis. 2017;4;12(1):124. doi:10.1186/s13023-017-0671-8
  7. Al Dakhoul S. Very severe spinal muscular atrophy (Type 0). Avicenna J Med. 2017;7(1): 32–33. doi:10.4103/2231-0770.197512
  8. About spinal muscular atrophy. National Human Genome Research Institute. Accessed May 25, 2021. 
  9. Types of SMA. Cure SMA. Accessed May 25, 2021.

Matesanz SE, Curry C, Gross B. et al. Clinical course in a patient with spinal muscular trophy type 0 treated with nusinersen and onasemnogene abeparvovec.J Child Neurol. 2020;35(11):717-723. doi:10.1177/0883073820928784.

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