Neuromuscular Diseases in Infants

SMA and Duchenne Muscular DystrophyTim Lotze, M.D.

Associate Professor of Pediatric NeurologyDirector, MDA Care CenterTexas Children’s Hospital

Baylor College of Medicine

Evaluation of Neuromuscular Disease

•Clinical History• Neurological Exam• Electrodiagnostics

• Electromyography• Nerve Conduction Studies

• Genetic studies or tests• Metabolic screening labs• Chromosomal Microarray• Whole Exome Sequencing• Candidate gene analysis

• MRI spine, roots, plexus, or muscle group

• Ultrasound• Muscle and nerve biopsies

How muscles get the message to moveBrain cell >> Spinal cord motor nerve cell >> Muscle

Congenital Hypotonia

Central= Brain and Spinal CordSystemic Genetic DisordersPerinatal brain asphyxiaMetabolic Disorders

Peripheral= Motor UnitAnterior Horn CellPeripheral NerveNeuromuscular JunctionMuscle

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.

SMA TYPE I SMA TYPE II SMA TYPE III

• Onset < 6 months• Never achieve sitting• Throat weakness

• Weak cry• Aspiration

• Pulmonary weakness• Belly breathing

• Life span < 2 years

• Onset 6 -18 month• Can sit• Variable throat and pulmonary

weakness• Scoliosis• 70% alive at 25 years of age

• Onset > 18 months• Can walk• Variable throat and pulmonary

weakness• Scoliosis• Normal lifespan

2 copies SMN2 3 copies SMN2 > 3 copies SMN2

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

Clinical Presentation

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.youtube.com/watch?v=fi6A5VUTC6Y

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

Triage Visit

Spinraza Delivery Process

$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.htmlhttps://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

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

Eteplirsen for the treatment of Duchenne muscular dystrophy

Useful Resources

• www.mdausa.org• https://www.parentprojectmd.org/• http://www.curesma.org/

Thanks, and please send along questions!