Genetic Counseling and Spinal Muscular Atrophy Nancy Kuntz, MD - - PowerPoint PPT Presentation

CME / CE

Genetic Counseling and Spinal Muscular Atrophy

Nancy Kuntz, MD Professor of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine

SMA

Spinal Muscular Atrophy

• Autosomal recessive neurodegenerative disorder
• 96% of SMA patients have deletions in exons 7 and 8 (or 7 alone) in the

SMN1 gene

• Incidence of SMA
• 1 in ~10,000 live births
• Incidence of SMA carriers
• 1 in ~ 50 - 100

Verhaart IEC et al et al. Orphanet J Rare Dis. 2017; 12: 124

Flow of Genetic Information

Image courtesy Dr. Kuntz

Image courtesy Dr. Kuntz

Flow of Genetic Information

mRNA DNA Protein Translation Post- translational modification Mature protein Transcription Nuclear Extra-nuclear

Flow of Genetic Information

Autosomal Recessive Inheritance

Autosomal Recessive Inheritance

SMA disease

• Two deletions in exon 7 of SMN1 gene

SMA carrier

• One deletion in exon 7 of SMN1 gene
• Not always one deletion on two genes

Verhaart IEC et al. Orphanet J Rare Dis. 2017; 12: 124. Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/.

Multiple Specialties

Mercuri E et al. Neuromusc Disord. 2018; 28: 103-115. Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/.

Genetic Counseling

Counseling Parents

• How to explain probabilities
• 25% chance with each

pregnancy

• Prenatal testing
• prenatal testing
• pre-implantation genetic diagnosis (PGD)
• SMN2 copies

Image courtesy Wikimedia Commons.

Counseling Siblings

• Carriers
• Partners
• no testing
• prenatal testing
• Adoption
• pre-implantation genetic diagnosis (PGD)
• SMA type 4

State by State

According to CureSMA (as of Sept 2019)

• 10 states are doing NBS
• 18 states are planning on

doing NBS for SMA

• 3 states are conducting a

pilot program

https://www.curesma.org/newborn-screening-for-sma/

Copies of SMN2 Gene

Glascock J et al. J Neuromusc Dis. 2018; 5: 145-158. Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/.

Copies of SMN2 Gene

Vill J et al. J Neuromusc Dis. 2019; 6: 503-515. Schorling DC et al. J Neuromusc Dis. In press. Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/.

Copies of SMN2 Gene

Vill J et al. J Neuromusc Dis. 2019; 6: 503-515. Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/.

Nusinersen

• Uniformly 2’-O-methoxyethyl modified (MOE) antisense drug
• Corrects the splicing disorder in SMN2, resulting in the production of

fully functional SMN protein in model systems

• High specificity for the SMN2 gene and has not been demonstrated to

interact with high affinity to any other region of the genome Onasemnogene Abeparvovec

• Gene therapy
• One time intravenous infusion of AAV-directed gene therapy to provide a

functional copy of SMN1 gene Many others in development

Approved Treatments

Spinal Muscular Atrophy

• Autosomal recessive

neurodegenerative disorder

• Severity varies with type

Serra-Juhe C, Tizzano EF. Eur J Hum Genet. 2019; 27: 1774-1782. Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/.

Finding Assistance/Resources

• CureSMA (curesma.org)
• MDA (mda.org)
• National Society of Genetic Counselors (nsgc.org)
• American Board of Genetic Counselors (abgc.net)

Summary

• SMA is a genetic progressive neurodegenerative disorder
• SMA is on RUSP list
• Newborn screening currently in 12 states
• Newborn screening can shorten diagnostic delays and help guide

treatment and prevent irreversible damage due to the progressive nature of the the disease