Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:
1. Identify patient populations appropriate for spinal muscular atrophy (SMA) screening.
2. Distinguish the various phenotypes of SMA and interpret SMA carrier screening test results.
3. Plan patient-specific counseling regarding residual risk based on results of SMA carrier screening.
Spinal muscular atrophy (SMA) is a neuromuscular disease resulting in the degeneration of the anterior horn cells of the spinal column. This can lead to progressive proximal muscle weakness. SMA is caused by a mutation in the survival motor neuron gene (SMN1). This gene is responsible for the production of a protein essential to motor neuron function. The estimated incidence of SMA is around 1 in 10,000 live births.1,2 SMA is estimated to be the second most common fatal autosomal recessive disorder after cystic fibrosis, with a carrier frequency ranging from 1/40 to 1/60.3,4 The phenotype of SMA is highly variable. SMA is classified into 5 phenotypes based on maximum motor function achieved and age at onset of symptoms.5,6
SMA involves the survival motor neuron 1, or SMN1 gene, on the q arm of chromosome 5. SMA inheritance is described as autosomal recessive; however, the genetics are complex and can be affected by gene conversion, de novo mutations, and the concept of the "2+0" carrier.
SMA, Type 0-IV
Because the phenotype varies significantly, 5 types of SMA have been characterized. Type 0 describes the most severe, in utero type of SMA, with life expectancy only until around 6 months of life. Type I, or Werdnig-Hoffmann, is the most common type, with symptomatic onset before 6 months and death from respiratory failure within the first 2 years of life. Type II SMA has typical onset before age 2 and a lifespan that varies from 2 years of age to the third decade of life. Type III, or Kugelberg-Welander, has onset after 18 months of life and a variable symptom profile, with many patients having normal life expectancies. Type IV refers to adult-onset disease. Table 1 demonstrates type 0-IV SMA with clinical characteristics. Type of SMA is defined by age of onset and highest motor milestone.5,6
Genetics of SMN1 and SMN2
In 1995, the SMN1 gene on chromosome 5q13 was linked to SMA.7 Nearer to the centromere of chromosome 5 and downstream of SMN1 is the SMN2 (survival motor neuron 2) gene. Most cases (around 94%) of SMA are caused by the homozygous deletion of the SMN1 gene. The other 6% of cases are compound heterozygotes with one deleted copy of the SMN1 gene and a point mutation in the other copy, or patients affected by de novo mutations.8
Individuals in the general population normally have 2 SMN1 gene copies, but may have up to 4. Copy numbers of SMN2 gene in the population range from zero to 3.3,9 Approximately 80% to 90% of SMN protein is produced in response to the SMN1 gene. The remaining comes from SMN2. Therefore, those with homozygous SMN1 deletions may still produce functional SMN protein through SMN2. A homozygous deletion of SMN2 does not lead to SMA when at least one SMN1 gene is present. Gene conversion between SMN1 and SMN2 genes can randomly occur in the gamete, further complicating the genetics of SMA.10 In addition, the number of SMN2 genes can affect the phenotype in those with homozygous deletions of SMN1.8,11,12 However, the SMN2 copy number with homozygous SMN1 deletion is not diagnostic for the SMA phenotype.
Because of the complex genetics and limitations in the molecular diagnostic assays available, prediction of phenotype in affected fetuses is limited. If a patient is identified as a carrier for SMA, the subtype cannot be determined if there is no family history of the disorder. Therefore, prenatal care providers should have a basic understanding of carrier screening results, residual risk, and genetics of SMA. They should also know when to refer patients to genetic counselors or maternal-fetal medicine given the complex counseling required.
Carrier Screening
Current society guidelines recommend screening preconception or in pregnancy for SMA carrier status. The American College of Medical Genetics and Genomics (ACMG) recommended SMA screening for all patients preconception or early in pregnancy in 2008.4 In 2017, the American College of Obstetricians and Gynecologists (ACOG) recommended that providers offer SMA screening to all patients who are pregnant or considering pregnancy. In addition, the ACOG recommends that, in patients with a family history of SMA, molecular testing of the affected individual and carrier testing of that parent be reviewed before screening. If those results are not available, the ACOG recommends testing of the low-risk partner.13
SMA disease can be diagnosed based on homozygous deletion of SMN1 in patients with symptoms. However, carrier testing requires a quantitative polymerase chain reaction assay that gives a measure of SMN1 copy number. Detection of a single copy of the SMN1 gene indicates a carrier. However, the location or configuration of the gene can be relevant, as some patients (approximately 3%-4%) have 2 SMN1 copies on the same chromosome (in cis configuration) and no copies on the other. This technically makes them carriers as one chromosome is missing the SMN1 allele. Although rare, the typical carrier testing assay does not identify these carriers, who have a 50% chance of passing on the chromosome with a single inactivated SMN1 gene and could have an affected offspring. These "2+0" carriers may occur more frequently in certain ethnic groups, which affect residual risk. Some laboratories offer testing for a variant gene, which is associated with an increased risk of both copies of SMN1 being in the "cis" configuration.
Residual Risk
Residual risk is the chance that a patient may still be a carrier despite having a negative screening test. Residual risk remains, even in patients who have 2 or 3 copies of SMN1 on carrier screening. Table 2 estimates the carrier risks for patients from different ethnic groups in individuals with 2 copies of SMN1 (residual risk is even lower in patients with 3 copies of SMN1, and is often reported on results of carrier screening). Because the "2+0" carriers are more commonly of African American ancestry, the carrier detection is lower in this group and residual risk is higher with SMN1 carrier testing. If a patient's screening results return with 2 copies of the SMN1 gene, they are unlikely to be an SMA carrier. However, patients should be informed of the residual carrier risk based on ethnicity.
Some laboratories may include results on an SMN1 variant gene. Approximately one-fifth of "2+0" SMA carriers carry one or both identified variants when SMN1 copies were in cis configuration.14 Although absence of these linked variants does not exclude "2+0" carrier status, the presence of the variant does increase residual risk (due to the increased likelihood of "2+0" carrier status) in individuals with 2 SMN1 copies. Laboratory results that indicate 2 copies of the SMN1 gene with a variant should report the residual risk. Patients should be counseled regarding their residual risk despite having 2 SMN1 copies.
If a patient's screening results indicate one copy of SMN1 (diagnosing them as a carrier), the patient should be referred for genetic counseling, and encouraged to bring her partner if possible. If a patient has only one copy of SMN1, the partner can be tested, presuming that paternity is certain. If the partner carries 2 copies, the residual risk is low of having an affected offspring. Results and risks should be discussed by certified genetic counselors. If the partner has only one copy of SMN1 or is unavailable for testing, prenatal genetic diagnosis can be offered with chorionic villus sampling or amniocentesis. Postnatal testing is also an option. In addition, several states have incorporated SMA into their newborn genetic screen.
Emerging Therapies for SMA
Both the coding regions and protein products of SMN1 and SMN2 have been characterized.7 Since then, therapies to target the mechanism of SMA have been developed. In 2016, the FDA approved nusinersen (Spinraza). This medication is an antisense oligonucleotide that promotes production of SMN protein from the pseudogene SMN2. Spinraza is administered intrathecal with 4 loading doses in the first month followed by maintenance therapy every 4 months. This medication prolongs survival in in type 1 SMA and increases the motor milestones met by patients with type 2 SMA.15-17 In addition to the intrathecal therapy, an orally deliverable medication, risdiplam (Evrysdi) has been approved for therapy for SMA.18
In addition to SMN-targeted therapy, medications for upregulation of muscle growth, RNA therapy, neuroprotection through mitochondria, and gene modification of SMN are being investigated. However, these therapies are currently very expensive.19,20 Improvement in therapy, life expectancy, and quality of life with emerging therapies will continue to inform prenatal genetic counseling.
Additional Considerations
* Some laboratories offer SMA screening within expanded carrier panel screening.
* Some (but not all) laboratories offer complete SMA testing, including reflex sequencing for SMN2 copy number analysis in carriers of SMA.
* Any patient with a family history of SMA or known carriers should be referred to a certified genetic counselor.
Summary
SMA is an autosomal recessive disorder caused by mutation or deletion of 2 SMN1 genes. The disease causes significant neonatal and infant morbidity and mortality. Therefore, the ACOG and the ACMG recommend offering carrier screening to all pregnant patients or patients considering pregnancy. Because the inheritance of SMA can be complex, prenatal care providers should appropriately refer patients to certified genetic counselors if a patient tests positive as a carrier. If carrier screening is negative, providers should understand the residual risk and inform the patient of residual risk.
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