Caveats in the Established Understanding of CMT1A

Charcot‐Marie‐Tooth disease type‐1A (CMT1A) is one of the most common types of inherited peripheral nerve diseases. It is caused by the trisomy of chromosome 17p12 (c17p12), a large DNA segment of 1.4 Mb containing PMP22 plus eight other genes. The size of c17p12 is formidable for any cloning technique to manipulate, and thus precludes production of models in vitro and in vivo that can precisely recapitulate the genetic alterations in humans with CMT1A. This limitation and other factors have led to several assumptions, which have yet been carefully scrutinized, serving as key principles in our understanding of the disease. For instance, one extra copy of c17p12 in patients with CMT1A results in a higher gene dosage of PMP22, thereby expected to produce a higher level of PMP22 mRNA/proteins that cause the disease. However, there has been increasing evidence that PMP22 levels are highly variable among patients with CMT1A and may fall into the normal range at a given time point. This raises an alternative mechanism causing the disease by dysregulation of PMP22 expression or excessive fluctuation of PMP22 levels, not the absolute increase of PMP22. This has become a pressing issue since recent clinical trials using ascorbic acid failed to alter the clinical outcome of CMT1A patients, leaving no effective therapy for the disease. In this article, we will discuss how this fundamental issue might be investigated. In addition, several other key issues in CMT1A will be discussed, including potential mechanisms responsible for the uniform slowing of conduction velocities. A clear understanding of these issues could radically change how therapies should be developed against CMT1A.