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

Flow of Genetic Information Image courtesy Dr. Kuntz

Flow of Genetic Information DNA Transcription Nuclear mRNA Translation Protein Extra-nuclear Post- translational modification Mature protein

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

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/.

Approved Treatments 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

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