Charcot-Marie-Tooth disease

Definitions & Key takeaways

Charcot-Marie-Tooth disease (CMT) is a neuromuscular disorder that progressively affects the peripheral nervous system. It can lead to progressive lower extremity weakness but can also affect the other organs. CMT symptoms vary from person to person, but can include weakness or numbness in the feet and legs, problems with balance and coordination, difficulty walking, and pain in affected areas. In some cases, CMT can also cause problems with bladder or bowel function, breathing, and heart rate.

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Introduction0:00–0:27

Charcot-Marie-Tooth disease is named after three neurologists - Jean-Martin Charcot, Pierre Marie and Howard Henry Tooth.
The disease is actually not a single disease, but a group of related diseases that are progressive hereditary disorders of peripheral nervous system.
Said differently, these disorders are inherited, worsen over time, and affect both sensory and motor nerve cells. Broadly speaking, the nervous system consists of two parts, the central nervous system, and the peripheral nervous system.

Physiology0:27–1:20

The central nervous system consists of the brain and the spinal cord, and the peripheral nervous system includes the nerves that fan out from the central nervous system and connect it with the skin, muscles, organs, and exocrine glands.
Now, zooming in to a neuron, each one is made up of three main parts. The dendrites, which are little branches that receive signals from other neurons, the soma or cell body, which has all of the neuron’s main organelles, and the axon, which transmits the signal to the next neuron in the series.
Myelin is the protective sheath that surrounds the axons of the peripheral neurons, allowing them to quickly send electrical impulses.
And this myelin is produced by Schwann cells, which are a group of cells that support neurons. There are multiple forms of Charcot-Marie-Tooth disease and all of them are related to the defective production of proteins in either the myelin sheath or the neuron’s axon.

Pathology1:20–1:20

Pathology1:20–3:01

Regardless of the part of the neuron that’s affected, signals fail to reach their target tissues, and this can affect both sensory and motor peripheral neurons.
The most common forms of Charcot-Marie-Tooth disease are CMT1 and CMT2, both of which are autosomal dominant diseases. CM T1 is caused by mutations in the PMP22 and MPZ genes, which encode proteins that are part of the myelin sheath made by the Schwann cells.
Loss of myelin slows down transmission of electrical impulses through the nerves. Over time, Schwann cells try to replace the lost myelin.
As a result, under a microscope, there’s often onion bulb formation, which is when an axon is surrounded by layers of new myelin with underlying damaged layers of myelin.
CMT2 is caused by mutations in the MFN2 gene which encodes a protein called Mitofusin-2 which is expressed in neuronal mitochondria.
When the protein is defective, mitochondrial function is disrupted and that leads to neuronal death. In both CMT 1 and CMT 2, when motor neurons are affected, muscles begin to atrophy - a classic example of “use it or lose it”.
When sensory nerves are affected, it first affects the feet and toes first, because those are the neurons with the longest axons, and are therefore most sensitive to damage.

Symptoms3:01–3:01

Symptoms3:01–3:43

Symptoms of Charcot-Marie-Tooth disease are both motor and sensory. Early motor symptoms include foot and leg weakness, which can cause a foot drop and a high-stepped gait.
Over time muscle weakness and atrophy can cause foot deformities like high arches, called pes cavus, and hammer toes, which is when the middle joint of a toe bends upwards.
Muscle atrophy and weakness can also affect the hands, resulting in difficulty doing things like playing a video game or knitting a holiday sweater.
When sensory nerves are affected it leads to tingling and burning sensations in the hands and feet. Because Charcot-Marie-Tooth disease is progressive, the symptoms gradually tend to worsen over time.

Diagnosis3:43–4:02

Charcot-Marie-Tooth disease can be diagnosed with electromyography, which measures the electrical activity of muscles, and nerve conduction studies, which measures the ability of nerves to conduct impulses.
But ultimately, doing DNA testing offers a definitive diagnosis. Unfortunately, there’s no medical cure for Charcot-Marie-Tooth disease.

Treatment4:02–4:02

Treatment4:02–4:02

Treatment4:02–4:15

Physical therapy can help improve muscle strengthening and stretching, and orthopedic surgery and devices can help correct deformities and improve mobility.

Review4:15–4:36

All right, as a quick recap. The two main types of Charcot-Marie-Tooth disease are CMT1 which involves loss of myelin on peripheral neurons, and CMT2 which involves loss of peripheral neurons themselves.
The result is a progressive loss of motor nerves to the feet and legs, and sensory nerves to the hands and feet.