Axonal Excitability and Ultrasound Patterns in Charcot-Marie-Tooth Disease and Other Demyelinating Disorders

Charcot-Marie-Tooth neuropathy (CMT) is the most prevalent hereditary neuromuscular disorder, estimated to affect 11.8 to 82.3 individuals per 100,000 in Europe. While genetic assessment is increasingly gaining significance, neurophysiology continues to play a crucial role in classifying CMT into axonal, intermediate or demyelinating forms. Despite its diagnostic importance, standard neurophysiology techniques may prove inadequate to reliably capture disease progression, advocating for the adoption of newer methodologies in the near future. Among these, axonal excitability testing, providing information about the properties of axonal membranes insight into the behaviour of voltage-gated ion channels, pump and exchangers involved in impulse conduction, could have potential additional diagnostic and prognostic value in neuromuscular disorder.

Axonal excitability techniques provide insights into ion channel function, serving as an in vivo surrogate markers of axonal membrane potential in human axons. Recent advancements in this field have standardized procedures, increased execution speed, and minimized patients' discomfort enabling routine clinical application. These advancements include the development of standardized semi-automated recording setups and the publication of international guidelines. It is plausible that progressive ion-channel dysfunction and spontaneous baseline depolarization of nerves maybe associated with disease severity and response to therapy (in patients with acquired polyneuropathies).

Investigators plan to study a series of patients with different types of CMT with this technique and compare results with diseased controls affected by dysimmune neuropathies and corresponding mouse models, by conventional nerve conduction studies, by electrical nerve stimulation to study neuronal excitability as below depicted, and by examining myelinated skin nerves by performing skin biopsy in a subset of patients.

Moreover, literature data demonstrate that nerve ultrasound supports the diagnosis and follow-up of neuromuscular disorders. In the context of neuropathies, nerve ultrasound enables an anatomical and structural evaluation that provides useful data for the differential diagnosis between hereditary and acquired forms. In particular, in Charcot-Marie-Tooth disease, nerve ultrasound allows the identification of pathognomonic patterns that can significantly guide genetic testing (e.g CMT1A).

In severe acquired forms, where the pathological process is so extensive that clear electrophysiological findings are not always present, nerve ultrasound can detect specific alterations that may help guiding the diagnosis. Moreover, nerve ultrasound can identify certain features that may suggest (and correlate with) the severity of the disease.