1. Charcot – Marie Tooth Disease
Introduction
One of the most common inherited neurological disorders.
Also known as hereditary motor and sensory neuropathy (HMSN) or peroneal muscular atrophy
Originally identified in 1886 by three physicians – Jean-Martin Charcot and Pierre Marie in Paris, France, along with Howard Henry Tooth in Cambridge, England.
Selected CMT as presentation topic because treatments involve surgical correction. Throughout my professional experience, provided anesthesia to patients suffering from CMT who were seeking surgical correction of hammertoes and arch corrections.
Tanya Island, CRNA, ms
Genetics presentation November 21, 2014

2. Presentation Topics Overview of the disease Genetic Inheritance
Molecular basis
Genetic testing & novel therapies
These are the topics we’ll discuss today.

3. What does CMT look like? Clinical presentation in feet
Inherited neurological disease characterized by slow progressive foot, lower leg, hand and forearm degeneration and weakness. Loss of sensation in limbs, fingers, and toes contributes to gait disturbances, foot drop, and difficulty with ambulation.
High arch, hammer toes, and muscle atrophy are classic signs of CMT.
There are two main types of CMT depending on the location of dysfunction in the peripheral nerves:
Type 1A -- demyelinated axons disrupt axonal function. Most common form.
Type 2--  diminished axonal response due to internal defects of the axons.
Type 2 -- less common and can be broken into six subtypes, based on specific gene defects.
Other less common types are: 3, 4, and X.
What does CMT look like? Clinical presentation in feet

4. Overview Symptoms Treatment Prevalence Diagnosis
Slow progressive foot, lower leg, hand & arm degeneration
Weakness, gait changes
Treatment
Braces, assistive devices
Surgical correction
Prevalence
1 in 2,500 people
No impact on M&M
Diagnosis
EMG and nerve conduction studies
Slow NCV is diagnostic
Symptoms usually appear in early adolescence and young adult years. 12 +/- 7 years.
Symptoms: Early signs of CMT are high arched feet or gait changes. Symptoms include foot-bone abnormalities, including hammer toes, high arch, alterations in function and reflexes of hands and feet. Balance and gait may be affected. Hand function may be diminished and reflexes may be reduced.  Muscle cramping, hearing deficits and scoliosis may also occur.
Pain can range from mild to severe.
Treatment options include physical therapy, bracing, ambulation assist devices, surgical operations, and environmental modifications. Life expectancy is unchanged with CMT.
Severity of disease progression varies greatly among individuals, and even among family members with the disease.
Slow NCV < 38 m/s is highly diagnostic and is a 100% penetrant phenotype regardless of age. EMG is useful in determining severity and location of symptoms.
No known cure is available.
If all diagnostic testing is inconclusive, a nerve biopsy may be performed. When the nerve is examined under microscope, formations called “onion bulbs” may be seen, which represent axons surrounded by layers of demyelinating and remyelinating Schwann cells.
Axon degeneration is a classic sign of CMT1.   

5. Genetic Inheritance Autosomal dominant Duplication of PMP22
Other forms of CMT are autosomal recessive, X- linked inheritance, and spontaneous mutation
Autosomal dominant, autosomal recessive, X-linked inheritance, and spontaneous mutation.
The 1.5-Mb duplication of PMP22 is the predominant cause of autosomal dominant CMT1, which accounts for roughly 70% of all cases.

6. Molecular Basis Chromosome 17
Instructions for production of peripheral myelin protein 22
Critical component of myelin sheath
Type 1A results from a duplication of the gene on chromosome 17 that carries instructions for producing peripheral myelin protein - 22, which is a critical component of the myelin sheath.
Type 1B results from a point mutation in a gene that carries instructions for manufacturing the myelin protein zero (P0) which is another critical component of the myelin sheath.
Deletion of PMP22 gene results in hereditary neuropathy with liability to pressure palsies. Point mutations have been described in the PMP22 gene in patients thought to have hypertrophic neuropathy of Dejerine - Sottas.
GARS gene is implicated in CMT type 2D, a form that affects hands and forearms.

7. Less common CMT1C, CMT1D, and CMT1E which have similar symptoms to CMT 1A, are caused by mutations in the LITAF, EGR2 and NEFL genes, respectively.
Schematic overview of the molecular organization of myelinated axons highlighting the proteins affected in Charcot–Marie–Tooth disease 

8. Genetic Testing & Novel Therapies
PCR
Pulsed field gel electrophoresis
One study described subcutaneous administration of a nerve growth factor, neurotrophin-3, which was observed to promote regeneration of peripheral nerves and improve sensation. The treatment made available an increased number of myelinated fibers and Schwann cells, which improved neurologic function. The sample size was 4 for each group, NT3 and no treatment.
Ongoing research -- identification of mutations and proteins that are involved in disease subtypes, efforts to differentiate disease mechanisms and pathology with an emphasis on finding improved therapies. Gene therapy experiments have been conducted on cell cultures and animal models with the purpose of delivering genes to damaged Schwann cells and muscles. Another area of research involves nerve growth factor administration, such as androgen, to stimulate nerve regeneration. Vitamin C and curry have also been identified as possible treatment strategies in animal models.

9. Questions, comments or concerns?
Controversy surrounding gene patents and copyright laws. How does it affect the patient and consumers?
Interesting graphic of Chromosomes 17-20

10. References
National Human Genome Research Institue. (2014). Learning about Charcot- Marie Tooth Disease. Retrieved from: Charcot-Marie Tooth Association. (2014). What is Charcot-Marie Tooth Disease? Retrieved from: &Itemid=159 National Institute of Neurological Disorders and Stroke. (2014). Charcot-Marie Tooth Disease Fact Sheet. Retrieved from: _tooth.htm Mayo Clinic. (2014). Charcot-Marie Tooth Disease. Retrieved from: disease/basics/definition/con OMIM. (2014). Charcot Marie Tooth Disease ICD Retrieved from: