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 3^rd or 4^th 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

Related ObG Topics:

ACOG Opinion on Expanded Carrier Screening

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

Genetic Carrier Screening in Ashkenazi Jewish Patients

ACOG and Universal Screening for Cystic Fibrosis – What You Need to Know

Screening for Hemoglobinopathies in Pregnancy – The ACOG Approach