Variant Mechanism - Charcot-Marie-Tooth Disease

The variant mechanism is the functional route by which a pathogenic variant causes disease, as distinct from which gene is affected. In Charcot-Marie-Tooth disease (CMT), the gene identifies the cause, but the mechanism explains how the variant does harm: by reducing the protein’s normal activity (loss of function), by producing a mutant protein that interferes with its normal counterpart (dominant-negative), or by adding a new toxic activity or an excess of normal activity (toxic gain of function). A single subtype can act through more than one route.

Each CMT subtype’s mechanism call is presented in the CMT Variant Mechanisms Browser.

The Dorsal Root

A Name That Does Too Much Work

Jean-Martin Charcot's name appears throughout medicine, but nowhere does it create more confusion than in the foot. Learn why the CMT foot and Charcot neuroarthropathy, also known as Charcot foot, share a name yet differ in how they develop, appear, and are managed.

Close-up of a doctor’s hand holding a prescription pad while a patient’s wrist is wrapped with metal chains.

When Medicine Lost Its Compass

Evidence failed not because it was wrong, but because it was weaponized. I lived the downstream effects of that failure for more than a decade. This is what happens when medicine forgets that data always ends in a human being.

Illustrated graphic showing large ‘404’ numerals with people interacting with data screens and servers, alongside text reading ‘CMT Genetic Testing Error 404: Gene Not Found’ and ‘Examining Why Less Than Half of All Who Have Charcot-Marie-Tooth Disease Are Not Able to Obtain Genetic Confirmation of Their Disease.

Error 404: Gene Not Found

CMT genetic testing often fails to identify the cause of the disease, even when comprehensive panels are used. Here, we discuss why this happens, what genetic tests can and cannot do, and why a negative result still matters.