What is Spinal Muscular Atrophy?

Spinal muscular atrophy (SMA) is the most common inherited lethal condition in infants and is characterized by progressive muscle weakness and atrophy. Although the lethal form is most common, there are milder varieties of the condition. Furthermore, rare cases may go undiagnosed because of the lack of symptoms present in the affected individual. Carrier screening, diagnostic genetic testing, and Newborn Screening are all available to identify those with or at risk for SMA. Historically, treatment has been supportive and did not address the root cause of the condition. However, recent new therapies have become accessible that radically improve the quality of life of those suffering with SMA.

Causes of SMA

SMA is caused by changes to the SMN1 gene (survival motor neuron), which is located on the long arm of chromosome 5. Deletions in SMN1 are present in about 95% of those affected, causing lack of protein product that is critical for motor neuron development. Less common SMN1 mutations may be nonsense, missense, splice site mutations, among others. SMA is inherited in an autosomal recessive fashion, meaning two carriers have a 25% risk of having an affected child with each pregnancy.

Variations in SMN2 impacts disease severity. This gene produces much less protein product than SMN1, and people can have varying copy numbers of this modifying gene. The more copies of SMN2, the less severe the clinical presentation. Genetic testing for both SMN1 and SMN2 is common when performing diagnostic testing or carrier screening. Although SMN2 copy number may assist in prognosis, there are likely other modifying genes that impact severity. For example, the PLS3 (Plastin 3) gene located on the X chromosome has been suggested as a modifier, but clinical testing for PLS3 is not routinely available.

There are four types of SMA:

  • Type I – Onset of muscle weakness is within 6 months of life. The affected infant can neither walk or sit independently. It is typically lethal by about 2 years of age. It is common for those affected with SMA Type I to have 1-2 copies of SMN2.
  • Type II – The presentation of symptoms is typically in late infancy. Those affected may sit unassisted but need help with walking and movement. Respiratory insufficiency is common and life span may be as long as 20-30 years. It is common for those affected with SMA Type II to have 2-3 copies of SMN2.
  • Type III – With this mild form of the condition symptoms start to show symptoms at about 3 years of age. Many can have independent ambulatory function, but ambulation may be lost later in adult life. Respiratory weakness is rare. Clinical presentation, however, is extremely variable. Most affected individuals live into adulthood. It is common for those affected with SMA Type III to have 3 or more copies of SMN2.
  • Type IV – This is the mildest and least common form of SMA. Symptoms present in adulthood and there may or may not be loss of ambulation. Some have no symptoms at all. Life expectancy is normal. It is common for those affected with SMA Type IV to have 3 or more copies of SMN2.

Spinal Muscular Atrophy Testing

Routine genetic testing typically analyzes for the presence or absence of exon 7 in SMN1 and copy number analysis of SMN2. Two or more copies of SMN1 is a “normal” result; 1 copy of SMN1 is an asymptomatic carrier; and 0 copies of SMN1 means the person is affected with SMA and is at risk of symptoms. SMN1 copy number assessment is complicated by the fact that 2 copies of SMN1 may be present on the same chromosome. This is known as a “2+0” carrier. Testing cannot determine if the genes are on the same or opposite chromosomes; it can only tell how many copies are present in the patient. About 3-4% of the general population are 2+0 silent carriers. SMA carrier screening should be offered to all women who are currently pregnant or considering a future pregnancy, as recommended by the American College of Obstetrics and Gynecology (ACOG).

Another test offered by some labs checks for the presence or absence of a single nucleotide polymorphism (SNP) that can modify the risk for being a 2+0 carrier. If the SNP is present, it increases the risk of being a 2+0 carrier. In contrast, if this SNP is not detected, it increases the detection rate and lowers the residual risk when there are 2 copies of SMN1. It is most informative in the Asian, Ashkenazi Jewish, Black, and Hispanic populations.

Newborn Screening (NBS) in the United States is a public health initiative that tests infants for heritable diseases where symptoms may not be obvious at birth. The Department of Health and Human Services (HHS) recommends SMA be included in NBS. Conditions recommended for NBS are based on the availability of early treatment that significantly improves patient outcome, the logistics of implementing testing technology into NBS (high sensitivity and specificity and high throughput), and a positive net benefit of screening. As of May 1st, 2021, 36 states offer SMA on their NBS panel. A substantial argument in favor of including SMA in NBS in all 50 states is the availability of treatments that significantly improve patient quality of life.

Nusinersen is an antisense oligonucleotide that facilitates the incorporation of exon 7 into the mRNA transcript of SMN2. This causes more full-length protein product to be generated and ameliorates symptoms. Improved outcomes with nusinersen treatment include improved motor milestones as measured by the Hammersmith Infant Neurological Examination (HINE), less need for permanent ventilation, and increased lifespan. Treatment starts with a loading dose period consisting of four doses. The first three loading doses are administered every 14 days with the final loading dose given 30 days following the third dose. After the loading dose schedule is complete, there are three maintenance doses per year for the life of the affected patient. The estimated cost of the treatment is $750,000 the first year, and $375,000 each year thereafter.

Onasemnogene abeparvovec is a gene replacement therapy for SMA. The treatment uses a non-replicating adeno-associated virus capsid as the delivery vehicle to administer wild-type SMN1 gene to motor neuron cells. Unlike nusinersen, it is a single-dose therapy. Patient response in clinical trials was outstanding, as was the case with nusinersen. Patients treated with onasemnogene abeparvovec gene therapy had less need for ventilation, could achieve different muscle milestones such as sitting and walking, and lifespan was increased compared to the control group. However, the cost of onasemnogene abeparvovec is $2,125,000.

The tools clinicians possess for the diagnosis, genetic testing, and treatment of SMA have expanded considerably in the last few decades. Carrier screening is available for SMA and should be offered to all women who are currently pregnant or considering a future pregnancy. Molecular genetic testing for SMA can be confounded by patients who are 2+0 carriers. Furthermore, genetic testing may assist in the prognosis of disease progression for affected individuals. NBS for SMA is not consistent among states in the United States. While molecular treatments improve outcomes, cost may unfortunately be a barrier for some patients who qualify for treatment.



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Department of Health and Human Services, Health Resources and Administration: https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp/index.html

Cure SMA (NBS): https://www.curesma.org/newborn-screening-for-sma/

Gene Reviews: https://www.ncbi.nlm.nih.gov/books/NBK1352/