charcot-marie-tooth (cmt) high school presentation elizabeth ouellette
TRANSCRIPT
Charcot-Marie-Tooth(CMT)
High School Presentation
Elizabeth Ouellette
www.charcot-marie-tooth.org
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:
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.
A Nerve is Like a Wire
Source: Carly Siskind, MS, CGC & Shawna Feely, MS
CMT
Demyelinating(Type 1)
Axonal(Type 2)
Autosomal Dominant X-Linked Autosomal Recessive
Demyelinating OR Axonal(Type 4)
Intermediate(Type X)
Many Types of CMT
Source: Carly Siskind, MS, CGC & Shawna Feely, MS
CMT subtype Gene HNPP PMP22 (deletion)
CMT1A PMP22 (duplication)
CMT1B MPZ
CMT1C LITAF/SIMPLE
CMT1D EGR2
CMT1E PMP22 (point mutation)
CMT1X GJB1 (Cx32)
CMT2A MFN2
CMT2B RAB7
CMT2D GARS
CMT2E NFL
CMT2F HSP27/HSPB1
CMT2L HSPB8
CMT4A GDAP1
CMT4B1 MTMR2
CMT4B2 SBF2
CMT4C SH3TC2
CMT4D NDRG1
CMT4E EGR2
CMT4F PRX
CMT4J FIG4
dHMN V GARS and BSCL2
HSN SPTLC1
Subtypes of CMT
Source: Carly Siskind, MS, CG
C & Shaw
na Feely, MS
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)
Myelinated Peripheral Nerve
Characteristics and SymptomsHigh Arches
Muscle weakness in lower legs: foot drop, poor balance and sprained ankles
Characteristics and Symptoms
Muscle atrophy in hands causes manual dexterity difficulty. Tremor.
QuestionHow would this affect everyday life ?
Thenar muscles
Weakness in fingers
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…..
Treatments
Physical TherapyModerate ActivityAFOs or leg bracesOccupational TherapySurgery
Now, there is hope for a cure… STAR
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
Chromosomes
ChromosomesChromosome = bookcase
Genes = books on the bookcaseDNA = 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
CMT & Genetic MutationsCharcot-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
PMP22 vs. PMP22CMT1A is caused by a duplication of the PMP22
gene in every cell
PMP22- a protein found in myelin PMP22 – duplicated gene in CMT1A PMP22 gene duplication :
over-production of PMP22 protein deterioration of myelin sheath
Inheritance PatternsAutosomal Dominant (CMT1A)
X-linked Inheritance
Unaffected Affected Unaffected Affected
Autosomal Recessive (Type 4)
Spontaneous Mutations
Unaffected Unaffected
Affected
SpontaneousMutation
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.
Everyone Has Different Abilities
Albert Einstein : Aspergers
Tom Cruise: Dyslexia Jim Carrey: Depression Gerry Jewel: Cerebral Palsy
Franklin D. Roosevelt: Polio Erik Weihenmayer: Blind
Achieving our vision of a world without CMT…
Goals of STARCollaboration among some of the world’s best
scientists to find a cure for CMT
1. Grow CMT1A cell line2. 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)
3. The most promising candidate compounds will be further evaluated in CMT- specific animal models.
4. Human trials
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
NIH Chemical Genomics Center
Responsible for testing CMT1A cells for “hits” through High-Throughput Screening (HTS) using robotic computerized system
Dr. IngleseDirector of Biomolecular
Screening and Profiling Division
Center founded 2004,Bethesda, MD
Dr. Doug Auld Sung- Wook
Testing Compounds
The NCGC Chemical Library:Some of the 350,000 compounds stored here
may become treatments for CMT.
Each plate contains 1536 wells
Test hundreds and thousands of compounds, or drugs, with automated robots
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
Testing Medications
Klaus-Armin Nave – Director of Plank Institute for Experimental Medicine in
Gottingen, Germany
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
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)