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
Susan J. Gross, MD, FRCSC, FACOG, FACMG
President and CEO, The ObG Project
Disclosure of Conflicts of Interest
Postgraduate Institute for Medicine (PIM) requires faculty, planners, and others in control of educational content to disclose all their financial relationships with ineligible companies. All identified conflicts of interest (COI) are thoroughly vetted and mitigated according to PIM policy. PIM is committed to providing its learners with high quality accredited continuing education activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of an ineligible company.
The PIM planners and others have nothing to disclose. The OBG Project planners and others have nothing to disclose.
Faculty: Susan J. Gross, MD, receives consulting fees from Cradle Genomics, 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 Jan 25 2023, 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.
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
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
Indicated for the treatment of children with SMA <2 years
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
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)
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Disclosure of Unlabeled Use
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information
presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
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