Spinal Muscular Atrophy

WHAT IS IT? 

In the US, all women who are considering or who are currently pregnant are offered a test that looks for whether a pregnancy may be at risk for a disorder called ‘spinal muscular atrophy’ (SMA). SMA is a severe progressive disorder caused by a loss of cells in the spinal cord, which leads to the loss of muscle strength and paralysis. 

  • SMA is relatively common and affects all population groups 
  • Childhood SMA is divided into 4 groups based on severity 
    • Most severe type (Type 0) is present at birth with death by 6 months of age 
    • Least severe type (Type III) appears after 18 months of age, and while life expectancy is that of the general population, most will lose their ability to walk with advancing age  

KEY POINTS: 

Underlying Genetics 

  • All people carry a few variants (changes or mutations in their DNA) that may impair the function of an important enzyme or protein 
  • Thankfully, all genes come in pairs and as long as one copy of the gene that codes for SMA is working, enough protein is available to maintain health
  • The SMA test offered in pregnancy checks to see whether a parent is a ‘carrier’   
    • A ‘carrier’ describes someone who has a serious change, but in only one copy of a gene pair
    • Because one gene copy is still working well, there is enough protein so that ‘carriers’ are healthy and the cells in the spinal cord will work normally
    • If one parent (usually the mother is tested first) is found to be a carrier, then the other parent will be offered testing as well  
  • A baby will be ‘affected’ with SMA only if
    • Both parents are carriers and
    • Both of the baby’s gene copies are damaged (one non-working copy inherited from the mother and the other non-working copy from the father)
    • Because neither gene copy is making enough protein, the spinal cord cells will not work normally  
  • In most cases, an entire piece of  DNA, known as an exon, is missing from the gene (an exon is the section of a gene that instructs the cells to make protein – see ‘Related Topics’ below)  
  • Note: Because the gene related to SMA is complicated, even expert laboratories may not be able to detect all ‘carriers’

KEY POINTS: 

  • The SMA testing that is usually offered by obstetric providers during the routine pregnancy visit is meant for women with no personal or family history of SMA  
  • Referral to genetic counseling services may be appropriate for  
    • Individuals with a family history of SMA  
    • A woman and/or her partner who are already known SMA carriers  
  • If only one partner is an SMA carrier, the baby is not at risk for SMA 
  • If both partners are SMA carriers, the risk to the baby of being affected with SMA is ¼ or 25% 
  • Genetic testing usually does not need to be repeated in subsequent pregnancies if already on record 
  • There are medications that are used to treat SMA
    • While they don’t provide a cure, they may help to improve symptoms

Learn More – Primary Sources: 

ACOG FAQs: Prenatal Carrier Screening 

ACOG FAQs: Spinal Muscular Atrophy

MedlinePlus: Spinal Muscular Atrophy

NORD: Spinal Muscular Atrophy

NIH – GARD: Spinal Muscular Atrophy

Locate a Genetic Counselor or Genetics Services:

Genetic Services Locator-ACMG 

Genetic Services Locator-NSGC 

Genetic Services Locator-CAGC 

Locate a Maternal Fetal Medicine Specialist 

Maternal Fetal Medicine Specialist Locator-SMFM

The DNA@ObG entries are meant for healthcare providers to share with patients as an educational tool. They are not intended as and do not constitute or substitute for medical or healthcare advice or diagnosis, and may not and should not be used for such purposes. Individuals should always consult with a qualified healthcare provider about their specific circumstances, including before starting or stopping any treatment, medical or otherwise. DNA@ObG content via this web site is provided with the understanding that The ObG Project is not engaged in rendering medical, counseling, legal, or other professional services or advice.

Nusinersen: A Treatment for Spinal Muscular Atrophy (SMA) has Arrived

BACKGROUND AND PURPOSE: 

  • Spinal Muscular Atrophy (SMA) is a serious autosomal recessive disorder 
  • ACOG recommends offering SMA screening to all pregnant women or those considering pregnancy 
  • SMA is caused by deletions or loss-of-function mutations in the SMN1 gene, causing insufficient expression of the SMN protein.  
  • Another gene, SMN2 that is structurally very similar to SMN1, also produces SMN protein, but at only 5 to 10% of the SMN1 levels due to a splice-site variant excludes exon 
  • A medication called nusinersen can alter RNA splicing of SMN2, potentially improving levels and function of the SMN protein  
  • Mercuri et al. (NEJM, 2018) presents results from the phase 3 trial on the use of nusinersen in children with SMA  

METHODS: 

  • Multicenter, double-blind, randomized sham-controlled trial  
  • Participants: Children with SMA who had symptom onset after 6 months of age 
  • Children were assigned at a 2:1 ratio to 
    • Intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) 
    • Sham procedure (control group) 
  • Treatment was administered on days 1, 29, 85, and 274 
  • Primary outcome: Least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment 
    • HFMSE scores range from 0 to 66 with higher scores meaning better motor function 
  • Secondary outcomes  
    • Percentage of children with a clinically meaningful increase from baseline in the HFMSE score, indicating an improvement in at least two motor skills 

RESULTS:

  • When comparing the HFMSE score at month 15 
    • There was a least-squares mean increase of 4.0 points from baseline compared to a decrease of 1.9 points in the control group 
  • There was a significant between-group difference favoring nusinersen  
    • Least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1 (P<0.001) 
  • 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0.001) 
  • The trial was terminated early due to significant improvement in the treatment arm  
  • The overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively) 

CONCLUSION: 

  • Nusineren lead to clinically meaningful improvement in children with later-onset SMA 

Learn More – Primary Sources: 

Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy

Spinal Muscular Atrophy: Genetic Concepts and Carrier Screening 

WHAT IS IT?

ACOG recommends that screening for spinal muscular atrophy (SMA) be offered to all women who are considering or who are currently pregnant. SMA is a severe progressive neuromuscular disorder caused by loss of alpha motor neurons in the spinal cord, with the loss of muscle strength, leading to paralysis.

This disorder is common, with carrier frequencies in one study of 1/47 in Caucasians; 1/67 in Ashkenazi Jewish; 1/59 in Asian; 1/68 Hispanic; 1/52 Asian Indian; and 1/72 African American. In the overall US panethnic population, the carrier frequency was 1/54 with a detection rate of over 90%.  SMA affects all population groups and is only second to cystic fibrosis as a cause of death from an autosomal recessive condition.

Childhood SMA is divided into 4 clinical groups but span a continuum without clear delineation

  • Type 0: Congenital SMA
    • Presents at birth
    • Death by 6 months of age
  • Type I: Severe SMA (Werdnig-Hoffmann disease)
    • Onset < 6 months
    • Median survival 2 years of age
  • Type II: Intermediate SMA (Dubowitz disease)
    • Onset 6-18 months
    • Children can sit but not stand unaided but lose ability by mid-teens
    • Life expectancy not known with certainty – adolescence to 3rd or 4th decade
  • Type III: Juvenile SMA (Kugelberg-Welander disease)
    • Onset > 18 months
    • Patients learn to walk unaided but most will lose ability with age
    • Life expectancy that of normal population

KEY POINTS:

Genetics

  • There are two related, almost identical genes on the long arm of chromosome 5, SMN1 and SMN2
    • SMN1 is the SMA-determining gene
    • Exon 7 in SMN1 is absent in both gene copies (maternal and paternal) in over 95% of affected individuals
    • In a few individuals, exon 7 is absent in one gene copy and there is a smaller mutation in the other gene copy
    • Some individuals have additional copies of SMN2 and their presence seem to lessen the severity of SMA

Limitations to Carrier Testing – False Negatives

  • De novo mutation: In 2% of cases, SMA results from a de novo mutation and therefore in this particular situation, screening parents will not detect the pathogenic variant (usually paternal)
  • Silent Carrier (2 + 0): Healthy individuals can carry 2 copies of SMN1 on a single chromosome and no copies on their other chromosome
    • The % of ‘silent carriers’ varies from approximately 30% in African Americans to 5% in Caucasians
    • The standard carrier screening tests are based on gene dosage and result in a false negative because 2 normal copies will be detected and therefore total amount of SMN1 will be interpreted as ‘normal’
    • The (2+0) individual is a carrier because there is a 50% chance he/she will pass the abnormal (missing SMN1) chromosome to the fetus
    • There are variants that track with silent carriers (i.e., found on chromosomes with duplications and not single-copy alleles) that can be incorporated into clinical carrier screening tests to improve residual risk estimates

Medication now available for SMA

Nusinersen

  • The FDA approved the first medication (nusinersen) in 2016, to treat children and adults with spinal muscular atrophy (SMA)
  • The FDA approval was based on a clinical trial in 121 patients with infantile-onset SMA who were diagnosed before 6 months of age and who were less than 7 months old at the time of their first dose
    • Patients were randomized to receive an injection of nusinersen into the fluid surrounding the spinal cord, or undergo a mock procedure without drug injection (a skin prick)
    • Forty percent of patients treated with nusinersen achieved improvement in motor milestones as defined in the study, whereas none of the control patients did

Onasemnogene abeparvovec-xioi

  • Indicated for the treatment of children with SMA <2 years
  • Gene therapy
    • Adeno-associated virus vector-based gene therapy
    • Vector delivers a fully functional copy of human SMN gene into the target motor neuron cells
    • One-time IV administration
  • Studies
    • Primary evidence of effectiveness from ongoing clinical trial
    • Compared to the natural history of patients with infantile-onset SMA patients in treatment arm demonstrated significant improvement in their ability to reach developmental motor milestones (e.g., head control and the ability to sit without support)

Learn More – Primary Sources:

ACOG Committee Opinion 691: Carrier Screening for Genetic Conditions

FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality

GeneReviews: Spinal Muscular Atrophy

FDA approves first drug for spinal muscular atrophy

ACMG: Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics

ACMG: Carrier screening for spinal muscular atrophy

Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens

An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy

ACOG Opinion on Expanded Carrier Screening

SUMMARY:

ACOG has published two committee opinions on carrier screening. Committee Opinion 691 reviews the recommendations based on disorders. Committee Opinion 690 addresses the issues related to use of screening strategies such as expanded gene panel testing.

Key Highlights

  • Spinal Muscular Atrophy (SMA) has joined cystic fibrosis (CF) as a recommendation for all women who are pregnant or considering pregnancy
  • Hemoglobinopathies
    • Test all patients for CBC and RBC indices as part of antepartum care (ideally preconception)
    • Add Hgb electrophoresis if
      • Increased risk based on ethnicity:  African, Middle Eastern, Southeast Asian, West Indian and Mediterranean ancestry
      • MCV is less than 80 fL with normal iron studies
  • Ashkenazi Jewish Testing (central and Eastern Europe descent)
    • Recommended testing remains for 4 disorders
      • Canavan; CF; Familial dysautonomia; Tay Sachs Disease
    • Additional tests to ‘consider’ has been expanded to the following
      • Usher syndrome, Familial hyperinsulinism, Joubert and Maple syrup urine disease in addition to Bloom/Gaucher/Fanconi anemia/ML4/Neimann-Pick disease
  • Tay Sachs Disease
    • In addition to Ashkenazi Jews, offer if either partner is French-Canadian descent or Cajun
    • Screening can be performed using DNA-based testing (mutation analysis) or hexosaminidase enzyme in serum or leuckocytes (leukocyte only with oral contraceptives)
    • Enzyme testing picks up approximately 98% of carriers regardless of ethnicity
    • Mutation analysis is highly effective in at risk populations – detection rate is limited in other populations
  • Committee Opinion 690 reviews expanded carrier screening, including a discussion on counseling and what disorders should be included | Important summary statements include the following

Ethnic-specific, panethnic, and expanded carrier screening are acceptable strategies for prepregnancy and prenatal carrier screening. Each obstetrician–gynecologist or other health care provider or practice should establish a standard approach that is consistently offered to and discussed with each patient, ideally before pregnancy. After counseling, a patient may decline any or all carrier screening.

Expanded carrier screening does not replace previous risk-based screening recommendations. If obstetrician–gynecologists or other health care providers do not offer expanded carrier screening in their practice, screening recommendations for individual disorders should follow guidelines for carrier screening as outlined in Committee Opinion No. 691, Carrier Screening for Genetic Conditions.

Note: ACMG has published a document on preconception and prenatal carrier screening that includes a tiered approach to the selection of disorders | For the summary and links see ‘Related ObG Topics’ below)

Learn More – Primary Sources:

ACOG Committee Opinion 690: Carrier Screening in the Age of Genomic Medicine

ACOG Committee Opinion 691 Carrier Screening for Genetic Conditions

Expanded Carrier Screening in Reproductive Medicine—Points to Consider: A Joint Statement of the ACMG, ACOG, NSGC, PQF, and SMFM

Genome sequencing and carrier testing:  decisions on categorization and whether to disclose  results of carrier testing

Locate a genetic counselor or genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Locate a Maternal Fetal Medicine Specialist: SMFM