CMT slides: understand the disease.
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I have created this presentation for the CMTA, to be used to explain CMT at the high school level. It is also being used to explain CMT to family and friends. Enjoy!
![Charcot-Marie-Tooth (CMT) ,[object Object],[object Object],www.charcot-marie-tooth.org](https://image.slidesharecdn.com/paphigh-school-slides-1272294529-phpapp02/85/CMT-slides-understand-the-disease-1-320.jpg)
![Charcot-Marie-Tooth ,[object Object],Jean-Martin Charcot 1825-1893 Pierre Marie 1853-1940 Howard Henry Tooth 1856-1925](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
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CMT slides: understand the disease.
- 5. A Nerve is Like a Wire Source: Carly Siskind, MS, CGC & Shawna Feely, MS
- 6. 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
- 7. Subtypes 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
- 15. Chromosomes
- 17. 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
- 20. X-linked Inheritance Unaffected Affected Unaffected Affected
- 21. Autosomal Recessive (Type 4)
- 22. Spontaneous Mutations Unaffected Unaffected Affected Spontaneous Mutation
- 23. 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.
- 24. Everyone Has Different Abilities Albert Einstein : Aspergers Tom Cruise: Dyslexia Jim Carrey: Depression Gerry Jewel: Cerebral Palsy Franklin D. Roosevelt: Polio Erik Weihenmayer: Blind
- 25. Achieving our vision of a world without CMT…
Editor's Notes
- In 1886 two French neurologists (Charcot and Marie) and one English neurologist (Tooth) described a set of characteristic physical symptoms to which was later given their names - Charcot-Marie-Tooth disease (CMT). Tooth realized that problem was in the nerves not the muscle.
- MS-250,000-300,000
- A nerve resembles a telephone wire. The outer coating protects the nerve and facilitates impulses moving strongly and quickly from the feet/hands to the brain and back. Some types of CMT affect the myelin and others affect primarily the nerve cells or axons.
- CMT is one term for many different types and subtypes of CMT.
- No Explanation-just to show all the different subtypes of CMT 40 genes found, 44 loci.
- A slide to show how what the nerve cells look like in the body.
- A high arched foot is usually one of the first signs of this disorder, although in some instances extremely flat feet are also typical of CMT. As the disease progresses, structural foot deformities take place. People may develop a pes cavus (high-arched) foot and hammertoes. The progressive muscle wasting of CMT also leads to problems with walking, running, and balance. Ankle weakness and sprains are common, and many patients develop foot drop. To avoid tripping, patients with foot drop raise their knees unusually high, resulting in the high “steppage” gait associated with CMT. In some patients, muscle weakness may also occur in the upper legs.
- Hand function may become affected. Progressive atrophy of the thenar muscles at the base of the thumb and other small muscles in the hand results in fine motor skill challenges. Tasks requiring manual dexterity become difficult. Patients have problems holding writing utensils, buttoning clothing, grasping zipper pulls and turning doorknobs.
- We all are made up of cells, which are the very smallest unit of living matter. Cells have a nucleus, which controls the cell’s activities and acts like the cell’s brain. Within the nucleus, there are chromosomes which are made up of DNA and the proteins that are attached to it. DNA (Deoxyribonucleic acid) is the building block of the gene and is made up of 4 chemical bases A,T,C,G. When certain proteins attach themselves to the DNA, it all coils ups into 'superhelixes' that we call chromosomes. So, our DNA is located inside the chromosomes of every cell in the human body, except red blood cells. The sections of DNA that make each of us different are called genes. You inherit your genes from your parent. There are 100 trillion cells in the human body and 20,000-25,000 genes in the human body. 1200-1500 genes on Chromosome 17.
- We all have 23 pairs of chromosomes (1 of each pair is from your mom and 1 is from your dad): 22 autosomes (an autosome is a chromosome that is not a sex chromosome) & 2 sex chromosomes.. Males have an X and a Y chromosome and females have 2 XX chromosomes. (Karyotype is a complete set of chromosomes.)
- DNA is the building block of the genes and a gene is made up of 4 chemical bases represented by the letters C,T,G,A. A combination of three of these DNA “letters” when put together make one DNA “word” . Each of these words is the code for a specific amino acid. The amino acids are then strung together like beads on a string to make up a protein. Proteins are the building blocks for different tissues. Book shelf analogy: Chromosomes are the book shelf, genes are the books, DNA are the pages and the codes are the words.
- In the example of CMT1A, there is a gene duplication on Chromosome 17. 3 genes instead of 2.
- To differentiate between the PMP 22 gene and the PMP 22 protein, italics are used when speaking of the gene. PMP 22 (protein) is found in only 5% of the peripheral nervous system. Did you know that Schwann cells, (named after the German physiologist Theodor Schwann) are the cells that make the myelin insulation of the nerves in the peripheral nervous system (as opposed the central nervous system, which is composed of the brain and spinal cord)? In CMT1A, the Schwann cells make too much PMP22 protein. The extra PMP22 protein that the Schwann cells make in CMT1A patients disrupts the function of the myelin and causes peripheral neuropathy.
- In the case of autosomal dominant genes, a single abnormal gene on one of the autosomal chromosomes (one of the first 22 "non-sex" chromosomes) from either parent can cause the disease. Autosomal means the condition can equally affect males as well as females. If one parent has CMT there is a 50/50 chance of passing the gene on to the child.
- Regarding the X-linked form of inheritance, the gene that is mutated and causing the condition is on the X chromosome (not the female chromosome - both men and women have X chromosomes). The mutated CMT gene is carried on the X chromosome. Mothers have a 50/50 chance of passing the CMT gene on to her sons and daughters. A new mutation is also possible. A father cannot pass the condition on to his son. The father will pass it on to all of his daughters.
- The least common forms of CMT are inherited in an autosomal recessive manner. All Type 4 patients have inherited the autosomal recessive form of CMT. In autosomal recessive forms, both parents have to be “carriers” of the defective gene before a child can be affected. Neither parent shows signs of any symptoms of CMT, but the child who inherits autosomal recessive CMT gets a double dose of the affected gene, causing him or her to have the disease, usually in a more severe form. Two parents each with an autosomal recessive CMT gene have a 1 in 4 chance of passing it on to their children. It can affect both males and females
- Our Sphynx cat, Tortellini, is a hairless cat and is an example of a natural and spontaneous mutation, which resulted in her thinking she is a monkey. Yohan does not think he is a monkey, thank God, but he also had a spontaneous mutation, a de novo mutation making him the first in our family to have CMT.
- The square is your dad, and the circle your mom. You are either a circle or a square, depending if you are male or female.
- 32 nd President of US. He contracted polio. Fitting his hips and legs with iron braces, he laboriously taught himself to walk a short distance by swiveling his torso while supporting himself with a cane. In private, he used a wheelchair. He usually appeared in public standing upright, supported on one side by an aide or one of his sons. FDR used a car with specially designed hand controls, which further gave him the illusion of mobility . Everyone has differing abilities. Focus on strength and what you CAN do, as opposed to what is not possible. achieve your heart’s desire.
- 04/26/10 15:11 © 2007 Microsoft Corporation. All rights reserved. Microsoft, Windows, Windows Vista and other product names are or may be registered trademarks and/or trademarks in the U.S. and/or other countries. The information herein is for informational purposes only and represents the current view of Microsoft Corporation as of the date of this presentation. Because Microsoft must respond to changing market conditions, it should not be interpreted to be a commitment on the part of Microsoft, and Microsoft cannot guarantee the accuracy of any information provided after the date of this presentation. MICROSOFT MAKES NO WARRANTIES, EXPRESS, IMPLIED OR STATUTORY, AS TO THE INFORMATION IN THIS PRESENTATION.
- The first project of STAR was to create a CMT 1A cell line. This step has been completed. The cell line is now at the National Institute of Health where it awaits testing through High-Throughput Screening.
- Each cell in the CMT1A cell line contains a florescent marker (Luciferace) similar to the glow seen in fire flies. Since thousands of medicines can be placed and tested in the wells of tissue culture plates, researchers are able to observe which medicines dim the fluorescent glow, suggesting that a particular compound is lowering the amount of PMP22 being produced. Since CMT1A involves the overproduction of PMP22, this procedure should quickly produce “candidate” medicines to control that overproduction.
- Now that the CMT1A line has been generated, it will be used in the High-Throughput Screening (HTS) facility housed at the National Institute of Health’s Chemical Genomics Center under the direction of Dr. Jim Inglese. Using a robotic computerized system, Dr. Inglese and his colleagues will be able to rapidly test hundreds of thousands of candidate medications to determine if they reduce the amount of PMP22 protein in the CMT1A cells. Sung-Wook Jang has committed to a three-year term as a CMTA post-doctoral fellow at the NCGC. Sung-Wook, who has a Ph.D in Cellular and Molecular Biology from the University of Wisconsin in Madison, will work closely with scientists at the NCGC and be responsible for the development and performance of screening efforts using the NIH compound library to find therapies for Charcot-Marie-Tooth. Doug Auld, who received a Ph.D at the University of North Carolina at Chapel Hill, followed by a post-doc in the Department of Biology at MIT is supervising Sung Wook’s thesis work. Doug Auld is now Group Leader for Genomic Assay Technologies at the NIH Chemical Genomic center.
- There are 1,536 wells in each plate. Each compound is tested at different doses (7 levels of dosing), to determine the best dilution of compound needed to reduce PMP22. This allows our researchers to accelerate the testing of hundreds and thousands of compounds in very little time (2-3 weeks).
- Since there are surely many potential but undiscovered compounds currently available to lower PMP22 levels and treat CMT1A, our aim is to develop a screening methodology to identify as many compounds simultaneously, in the least amount of time possible. This is feasible with currently available technology through a process known as “high-throughput screening,” in which various compounds are tested using robots on a cell line to screen tens of thousands of candidate compounds to determine whether they can lower PMP22 levels.
- Klaus-Armin Nave is Director, Department of Neurogenetics, Max Planck Institute for Experimental Medicine Göttingen and Professor of Biology, University of Heidelberg. He is responsible for creating the CMT1A mouse model, a project done in parallel with the cell line preparation and testing. As soon as we have identified a few compounds to treat CMT1A, those compounds will be immediately tested on the rat models to prove efficacy.