What is the pathophysiology of Charcot-Marie-Tooth type 1A (CMT1A)?

Updated: May 22, 2018
  • Author: Timothy C Parsons, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

The extra PMP22 gene copy within the 1.5 mB duplication on chromosome 17 is believed to cause most cases. [12] PMP22 is a 160 amino acid integral membrane protein that is expressed at high levels in myelinating Schwann cells, localizing to compact myelin and making up 2–5% of total myelin protein. [31, 32] PMP22 expression in CMT1A nerve biopsies is increased [33] , but the process by which protein overexpression actually causes the Charcot-Marie-Tooth phenotype remains unclear.

Abnormal expression of PMP22 seems to alter Schwann cell growth and differentiation both in vivo and in vitro, and may impair the ability of the Schwann cell to maintain normal myelin stability and turnover. A putative interaction between PMP22 and MPZ could play a role in maintaining myelin compaction and stability, and an imbalance in one could explain why changes in expression in either gene can lead to the clinically and pathologically indistinguishable CMT1A and CMT1B phenotypes. [34]

Despite the evidence of demyelination found on pathological and electrophysiological studies and the more recent implication of myelin proteins, the signs and symptoms of weakness and sensory loss are likely the result of axonal degeneration rather than demyelination. Anatomical evidence of progressive length-dependent axonal loss following demyelination in CMT1 exists. [35] Children with CMT1A have slow nerve conduction velocities in the first years of life, generally preceding the development of signs and symptoms. [36] Krajewski and colleagues demonstrated that compound motor action potential amplitudes correlate best with weakness in CMT1A rather than nerve conduction velocities. [37]

In vivo studies of CMT1A patients have demonstrated altered axonal excitability, in the form of elevated stimulation thresholds and a markedly abnormal threshold electrotonus. These findings suggested that demyelination causes exposure of fast K+ channels, which are normally sequestered under the myelin. [38]


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