Spinal Muscular Atrophy: Genetic Concepts and Carrier Screening

Learning Objectives and CME/Disclosure Information

This activity is intended for healthcare providers delivering care to women and their families.

After completing this activity, the participant should be better able to:

1. Discuss the neuromuscular pathology underlying SMA
2. Compare the various types of SMA

Estimated time to complete activity: 0.25 hours

Faculty:

Susan J. Gross, MD, FRCSC, FACOG, FACMG
President and CEO, The ObG Project

Disclosure of Conflicts of Interest

Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

Faculty: Susan J. Gross, MD, receives consulting fees from Genoox, Inc., and has financial interest in The ObG Project, Inc.

Planners and Managers: The PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz, MSN, RN, CHCP have nothing to disclose.

Method of Participation and Request for Credit

Fees for participating and receiving CME credit for this activity are as posted on The ObG Project website. During the period from Dec 31 2017 through Dec 31 2019, participants must read the learning objectives and faculty disclosures and study the educational activity.

If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation. Upon registering and successfully completing the post-test with a score of 100% and the activity evaluation, your certificate will be made available immediately.

For Pharmacists: Upon successfully completing the post-test with a score of 100% and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service within 4 weeks.

Joint Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and The ObG Project. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Physician Continuing Medical Education

Postgraduate Institute for Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Continuing Nursing Education

The maximum number of hours awarded for this Continuing Nursing Education activity is 0.2 contact hours.

Read Disclaimer & Fine Print

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

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