Lecture 15 Part I: Charcot Marie Tooth

What is the prevalence and general inheritance of CMT?

• Occurs in 1/2,500 individuals (~125,000 in the US).

• Multigenic: over 100 genes involved.

• Can be autosomal dominant, autosomal recessive, or X-linked.

What are the CMT subtypes and their inheritance patterns?

• CMT1 & CMT2: Autosomal dominant.

  • CMT1A was specifically talked about.

• CMT3: Autosomal recessive.

• CMT4: X-linked.

What are the adult phenotypes of CMT?

• High arched feet, hammertoes, foot drop, "champagne ankles."

• Muscle weakness and atrophy in appendages.

• Sensory loss, pain, decreased vision/hearing.

• "Clumsy" walking gait.

How is CMT diagnosed?

• Genetic testing: single gene test, multigene panel, or whole exome sequencing.

• Nerve conduction studies to identify CMT type (demyelinating vs. axonal).

What tissues and cells does CMT affect, and how?

• Affects the peripheral nervous system (PNS): motor/sensory axons and Schwann cells.

• Distal nerves most affected due to long axon length.

• Demyelinating forms: Schwann cell dysfunction; axonal forms: impaired axonal transport and mitochondrial function.

What is PMP22, where is it located, and what happens when it is duplicated?

• Located at chromosomal address 17p11.2.

• Encodes peripheral myelin protein 22, produced by Schwann cells to build the myelin sheath.

• Duplication → protein overload → disrupted myelin assembly → abnormal myelin.

What are the molecular consequences of PMP22 duplication?

• Defects in myelin protein production and axonal transport.

• Misfolded proteins and altered Schwann cell signaling.

• Impaired axon communication → slowed nerve conduction → muscle atrophy from denervation.

What was the technique that was presented?

• Randall-Selitto Paw Test: a test used in pain research to measure sensitivity to mechanical pressure.

• Increasing pressure is applied to an animal’s paw.

• The point where the animal withdraws its paw = pain threshold.

How is CMT managed?

• No cure; treatment is symptom-based.

• Physical therapy, orthotics/braces, pain medications, surgical correction of foot deformities.

• Emerging: PMP22-lowering strategies and gene therapies; genetic counseling to reduce transmission risk.