Neuromuscular Diseases in Infants SMA and Duchenne Muscular Dystrophy Tim Lotze, M.D. Associate Professor of Pediatric Neurology Director, MDA Care Center Texas Children’s Hospital Baylor College of Medicine Evaluation of Neuromuscular Disease

Clinical History • MRI spine, roots, plexus, or • muscle group • Neurological Exam • Ultrasound • Electrodiagnostics • Muscle and nerve biopsies • Electromyography • Nerve Conduction Studies • Genetic studies or tests • Metabolic screening labs • Chromosomal Microarray • Whole Exome Sequencing • Candidate gene analysis How muscles get the message to move Brain cell >> Spinal cord motor nerve cell >> Muscle Congenital Hypotonia

Central= Brain and Spinal Cord Peripheral= Motor Unit Systemic Genetic Disorders Anterior Horn Cell Perinatal brain asphyxia Peripheral Nerve Metabolic Disorders Neuromuscular Junction Muscle

Spinal Muscular Atrophy (SMA)

• SMA is a disease that robs people of physical strength by affecting the motor nerve cells in the spinal cord, taking away the ability to walk, eat, or breathe.

• Affects about 1 in 6000 to 10,000 live births

• It is was the #1 genetic cause of death for infants

• SMA is an inherited disorder and about 1 in 50 people are healthy carriers. Clinical Presentation

All type present with proximal arm and leg weakness, sparing the face, and normal intelligence

SMA TYPE I SMA TYPE II SMA TYPE III • Onset < 6 months • Onset 6 -18 month • Onset > 18 months • Never achieve sitting • Can sit • Can walk • Throat weakness • Variable throat and pulmonary • Variable throat and pulmonary • Weak cry weakness weakness • Aspiration • Scoliosis • Scoliosis • Pulmonary weakness • 70% alive at 25 years of age • Normal lifespan • Belly breathing • Life span < 2 years 2 copies SMN2 3 copies SMN2 > 3 copies SMN2 SMA1

• Severe hypotonia • Generalized muscular weakness (proximal > distal) • Deep-tendon reflexes can be decreased or absent. • Weak intercostal muscles with bell-shape-like chest • "Belly-breathing" • Bulbar weakness • Difficulties in feeding >> g-tube • Tongue fasciculation and weak cry • Constipation, gastroesophageal reflux, metabolic dysfunction, weight loss and sleeping problems • High-level cognitive functions seem to be spared. • Established practice paremeter treatment guidelines

What is the cause of SMA?

• 95% of patients inherit 2 copies of an abnormal SMN1 gene. • SMN2 is nearly identical to SMN1 but is only able to produce the fully functional protein 10% of the time

https://www.youtu be.com/watch?v=fi 6A5VUTC6Y Nusinersen (Spinraza)

• FDA approved for SMA Dec 23, 2016 • Nusinersen helps the motor nerve to read the SMN2 recipe so missing SMN1 doesn’t matter

Spinraza Delivery Process

Triage Visit

$750K for first year and then $325K each year after What’s next? Special Delivery- SMN1 Gene Replacement Therapy (Zolgensma)

http://www.curesma.org/news/avexis-reports-trial-results.html $2.125 M for single dose Zolgensma Outcomes SMN1 Gene Transfer

• 11 of 12 (92%) achieved head control, 9 of 12 (75%) could roll a minimum of 180 degrees, and 11 of 12 (92%) could sit with assistance.

• 9 of 12 (75%) could sit unassisted for five seconds, 7 of 12 (58%) could sit unassisted for 10 seconds and 5 of 12 (42%) could sit unassisted for 30 seconds or more.

• Two patients could walk independently

http://www.curesma.org/news/avexis-reports-trial-results.html https://clinicaltrials.gov/ct2/show/NCT02122952?term=Avxs&rank=1

Duchenne Muscular Dystrophy Muscle Disorders

Molecular mechanisms of muscular dystrophies: old and new players. Davies, K.E. and Nowak, K. J. Nature Reviews Molecular Cell Biology. Volume 7. Pg. 762—773. October 2006. Duchenne Muscular Dystrophy • X-linked (deletion most common) • Symptom onset < 5 years • Loss of ambulation by age 12 years • Lifespan 20s+ • Practice Guideline: Prednisone • Complications • Cardiac >>> yearly ECHO/Holter at diagnosis/6 years • Pulmonary >>> pulmonary medicine at 10 years • Scoliosis >>> orthopedics • Contractures >>> PM&R and therapy services Duchenne Musclar Dystrophy Progression Gower’s Sign Eteplirsen for the treatment of Duchenne muscular dystrophy

Annals of Neurology Volume 74, Issue 5, pages 637-647, 10 SEP 2013 DOI: 10.1002/ana.23982 http://onlinelibrary.wiley.com/doi/10.1002/ana.23982/full#ana23982-fig-0006 Useful Resources

• www.mdausa.org • https://www.parentprojectmd.org/ • http://www.curesma.org/ Thanks, and please send along questions!