Charcot-Marie-Tooth (CMT)

1. Charcot-Marie-Tooth(CMT) High School Presentation Elizabeth Ouellette www.charcot-marie-tooth.org

2. Facts the most common inherited genetic disorder that involves the peripheral nerves, affecting an estimated 150,000 people in the United States. It occurs in all races and ethnic groups, affecting about 1 in 2,500 people or 2.6 million people worldwide. a progressive disorder, causing people to lose normal use of their hands. arms, feet/legs. not usually life-threatening and does not affect the brain or intelligence. not contagious, but is usually passed down from one generation to the next. currently not curable Charcot-Marie-Tooth (CMT) disease is:

3. CMT - Peripheral Nervous System • CMT causes damage to the peripheral nerves, which link the brain and spinal cord to muscles and sensory organs. • Peripheral Nerves carry impulses from the spinal cord to muscles. • Peripheral Nerves convey sensation by carrying feelings like pain & temperature from the hands and feet to the spinal cord. • Peripheral Nerves help control balance, by carrying information about the position of the body in space.

4. A Nerve is Like a Wire Source: Carly Siskind, MS, CGC & Shawna Feely, MS

5. Many Types of CMT CMT Autosomal Dominant X-Linked Autosomal Recessive Demyelinating (Type 1) Axonal (Type 2) Intermediate (Type X) Demyelinating OR Axonal (Type 4) Source: Carly Siskind, MS, CGC & Shawna Feely, MS

6. Subtypes of CMT Source: Carly Siskind, MS, CGC & Shawna Feely, MS

7. What is Myelin? • Myelin is the layer of insulation that protects nerves. • Myelin envelops nerves, enabling them to conduct impulses from brain to different parts of the body • Myelin, in the peripheral nervous system (PNS), is produced by specialized cells called Schwann cells • Myelin is composed of different proteins and lipids. One of these proteins is called Peripheral Myelin Protein (PMP22)

8. Myelinated Peripheral Nerve

9. Characteristics and Symptoms High Arches Muscle weakness in lower legs: foot drop, poor balance and sprained ankles

10. Characteristics and Symptoms Muscle atrophy in hands causes manual dexterity difficulty. Tremor. Question How would this affect everyday life ? Thenar muscles Weakness in fingers

11. Characteristics and Symptoms Loss of nerve function can lead to tingling, burning sensation in hands and feet (painful neuropathy) Additional Symptoms: fatigue, breathing problems, scoliosis, kyphosis…..

12. Treatments Physical Therapy Moderate Activity AFOs or leg braces Occupational Therapy Surgery Now, there is hope for a cure… STAR

13. CMT: Back to Basics Charcot-Marie-Tooth disease is caused by inherited mutations in the genes involved with the structure and function of the peripheral nerves

14. Chromosomes

15. Chromosomes Chromosome = bookcase Genes = books on the bookcase DNA = letters which give the book its meaning If there is a typo in the book or if there are missing or extra pages, the book’s message (code) might be changed A mutation in the DNA of a gene = typo in a book Source: Carly Siskind, MS, CGC & Shawna Feely, MS

16. CMT & Genetic Mutations Charcot-Marie-Tooth disease is caused by inherited mutations in the genes involved with the structure and function of the peripheral nerves Chromosome 17 PMP22 gene duplication PMP22 gene duplication

17. PMP22 vs. PMP22 PMP22- a protein found in myelin PMP22– duplicated gene in CMT1A PMP22 gene duplication :  over-production of PMP22 protein  deterioration of myelin sheath CMT1A is caused by a duplication of the PMP22 gene in every cell

18. Inheritance Patterns Autosomal Dominant (CMT1A)

19. X-linked Inheritance Unaffected Affected Unaffected Affected

20. Autosomal Recessive (Type 4)

21. Spontaneous Mutations Unaffected Unaffected Affected Spontaneous Mutation

22. Activity …….Put the initials of your father in the square and the initials of your mother in the circle. ……..Put your initials in either the circle or square, depending if you are male or female. ……..Roll the dice once to determine how many children you will have. Decide on the sex. ………Take the coin and flip it. Heads-the child has CMT, and Tails-child does not have CMT. ………Do this for every child. Mark your results.

23. Everyone Has Different Abilities Franklin D. Roosevelt: Polio Erik Weihenmayer: Blind Albert Einstein : Aspergers Tom Cruise: Dyslexia Jim Carrey: Depression Gerry Jewel: Cerebral Palsy

24. The CMTA Strategy to Accelerate Research (STAR) Achieving our vision of a world without CMT…

25. Goals of STAR Grow CMT1A cell line Work in conjunction with the National Chemical Genomics Center (NCGC), where more than 300,000 compounds will be screened against the CMTA’s cell line using High Throughput Screening (HTS) The most promising candidate compounds will be further evaluated in CMT- specific animal models. Human trials Collaboration among some of the world’s best scientists to find a cure for CMT

26. Create a CMT1A Cell Line • Cell lines are cells (in this case, CMT1A cells), taken from tissue and grown in culture dishes • Researchers add a florescent marker or Luciferace to the cells to indicate luminescence every time the PMP22 protein is present

27. NIH Chemical Genomics Center Responsible for testing CMT1A cells for “hits” through High-Throughput Screening (HTS) using robotic computerized system Dr. Inglese Director of Biomolecular Screening and Profiling Division Dr. Doug Auld Sung- Wook Center founded 2004, Bethesda, MD

28. Testing Compounds • Test hundreds and thousands of compounds, or drugs, with automated robots Each plate contains 1536 wells The NCGC Chemical Library:Some of the 350,000 compounds stored heremay become treatments for CMT.

29. High-Throughput Screening Cells in cell line expresses Luciferace when PMP22 present: The more PMP22 in cells, the brighter they will glow Compounds (medications) that make cells dim  less PMP22 “Hits” are considered as candidate medications to treat CMT1A

30. Testing Medications Create CMT1A laboratory animals (rats) Take the most promising compounds found during HTS process and test them on CMT1A laboratory animals Confirm specific candidate medication successfully works on laboratory rats with CMT1A Klaus-Armin Nave – Director of Plank Institute for Experimental Medicine in Gottingen, Germany

31. Clinical TrialsCenters of Excellence Wayne State University, (Detroit, Michigan) University of Pennsylvania (Philadelphia) University of Washington (Seattle) University of Texas, Southwestern (Dallas) John Hopkins University (Baltimore, MD) University of Rochester (NY)