Charcot-Marie-Tooth disease (CMT) can be difficult to understand, even for people who have lived with it for years. Symptoms vary widely from person to person, and disease progression is unpredictable. Two people with CMT may have very different experiences even within the same family, and many are told at some point that their symptoms “don’t quite fit.”
A newly published review helps explain why this variability is very real for so many.
Published in Nature Reviews Disease Primers by CMTA Strategy To Accelerate Research (CMTA-STAR) Advisory Board members and renowned CMT experts Joshua Burns, PhD, Maurizio D’Antonio, PhD, and Steven S. Scherer, MD, PhD, along with Vincent Timmerman, PhD, Bipasha Mukherjee-Clavin, MD, PhD, Matilde Laurá, MD, Eppie M. Yiu, FRACP, PhD, and Jonathan De Winter, the review brings together what is currently known about CMT into a single, organized publication.
Why variability is part of CMT
CMT is caused by mutations in more than 140 different genes. These mutations affect peripheral nerves in fundamentally different ways. Some disrupt the myelin sheath that insulates nerves. Others damage the axons that carry signals. Still, others affect peripheral nerve mitochondria, protein quality control, or how cells transport essential materials.
Those differences help explain why symptoms, age of onset, and progression can look so different across people living with CMT. The review documents how some forms of CMT cause primarily foot and ankle weakness, while others affect hand function early. Some subtypes involve hearing loss, vocal cord issues, or breathing difficulties. Some progress slowly over decades. Others cause significant disability in childhood. For the CMT community, capturing this variability matters.
Guiding pediatric clinical care
The review draws on clinical practice guidelines for managing CMT in children, offering evidence-based and consensus-based recommendations for common symptoms, such as weakness, mobility impairment, and sensory issues. These guidelines support families and care teams in making informed decisions about rehabilitation, bracing, surgery, and symptom management for children with CMT.
Variability is the norm
Many symptoms people experience, such as balance challenges, hearing involvement, breathing or vocal cord issues, pain, fatigue, or differences in progression, are sometimes treated as unusual or incidental. Many have heard, “That’s not CMT.” But this review reinforces that variation is part of CMT itself, even when those features are not present in every person or every subtype.
The review includes detailed documentation of which CMT subtypes are most often associated with specific symptoms. For example, mutations in the TRPV4, MTMR2, GDAP1, EGR2, MFN2, and CNTNAP1 genes often include vocal cord paresis. Mutations in the AIFM1, PRPS1, TRPV4, NEFL, MPZ, SH3TC2, NDRG1, GJB1, and INF2 genes often include hearing loss. Mutations in the TRPV4, AIFM1, and certain other genes can cause skeletal issues beyond typical foot deformities. The review also addresses why some people with CMT experience significant fatigue.
Fatigue affects 36–61% of people with CMT
Nature Reviews Disease Primers, 2026
The review reveals that fatigue affects 36–61% of people with CMT and that the causes are complex. The review shows that fatigue relates to the underlying disease process itself, but the authors also identify connections to pain, sleep disorders like restless legs syndrome, poor sleep quality, and mood disorders, including anxiety and depression. By documenting these multiple contributing factors, the review explains why fatigue management often requires addressing them simultaneously rather than focusing on a single cause.
Genetic testing and the CMT experience
The review connects genetics, symptoms, and disease mechanisms in a way that helps make sense of how CMT develops and changes over time. For individuals navigating genetic test results, clinical evaluations, or conversations with care teams, having a clear and consistent reference can help reduce confusion and support more informed discussions about diagnosis and care. A VUS is a gene mutation (variant) for which current evidence is insufficient to confirm whether it causes disease, often because the mutation is rare, newly discovered, or has not yet been studied in enough individuals to establish its significance.
Even with CMTA-STAR-supported next-generation sequencing research, about half of people with CMT are unable to obtain genetic confirmation of their diagnosis. The review outlines what is known, what remains uncertain, and why some types of CMT are harder to diagnose genetically than others. The review also addresses diagnostic challenges, such as distinguishing CMT from acquired neuropathies (e.g., diabetic neuropathy) and identifying CMT caused by SORD gene mutations, which can be missed by standard genetic testing but detected by urine sorbitol screening.
Shared reference for researchers, providers, and patients
Importantly, this work reflects broad international collaboration across the CMT research community. Aligning how CMT is described, classified, and studied provides a shared reference point at a time when measurement tools and clinical trial readiness are increasingly important.
This CMTA-supported body of work reflects broader global efforts to advance our understanding of CMT. The review includes comprehensive information on outcome measures used in clinical trials, biomarkers under development to track disease progression, and animal and cell models that enable researchers to test potential therapies, many of which are housed in CMTA’s accessible Research Toolbox.
