Charcot-Marie-Tooth disease type 3

Charcot-Marie-Tooth disease type 3 is a disorder that primarily affects the peripheral nerves, resulting in impaired nerve conduction and muscle weakness. This condition, sometimes referred to as Dejerine-Sottas syndrome, is linked to genetic variants in several genes, including EGR2, MPZ, PMP22, and PRX, that are crucial for maintaining normal myelin in peripheral nerves. It has been described as very rare, affecting fewer than 1 in 1,000,000 people, and typically presents in infancy or early childhood. The clinical presentation and severity vary widely among affected individuals.

The clinical features of Charcot-Marie-Tooth disease type 3 are predominantly related to demyelination of peripheral nerves. Characteristic findings include segmental peripheral demyelination and remyelination, decreased motor and sensory nerve conduction velocities, and prominent onion bulb formation that reflects chronic nerve remodeling. Patients almost invariably exhibit sensory ataxia, distal lower limb muscle weakness, proximal muscle weakness, motor delay, impaired distal vibration sensation, and a broad-based gait. Other features seen consistently are the presence of myelin tomacula, tongue fasciculations, pes planus, scoliosis, and areflexia, while nystagmus is observed in a subset of individuals. Not all individuals experience all features, and severity varies considerably.

Charcot-Marie-Tooth disease type 3 is associated with pathogenic variants in several genes, namely EGR2, MPZ, PMP22, and PRX, which play important roles in the formation and maintenance of myelin in peripheral nerves. Disruption in the function of these genes impairs the integrity of the myelin sheath, leading to the demyelination and subsequent nerve conduction deficits that underpin the clinical presentation. The condition can be inherited in multiple ways, with both autosomal dominant and autosomal recessive patterns reported. In cases of autosomal recessive inheritance, the condition is more common when parents share a common ancestor, increasing the likelihood that both carry the rare genetic variant. Families are encouraged to seek genetic counseling for a better understanding of recurrence risks and family planning options.

Currently, management focuses on supportive care and symptom management since no treatments have been specifically approved for Charcot-Marie-Tooth disease type 3. Treatment is tailored to the individual and typically involves a multidisciplinary team that may include neurologists, physical therapists, and other specialists who conduct regular surveillance to monitor for emerging complications. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. In addition, genetic counseling is recommended to help guide families through the implications of the inherited nature of this condition and to discuss appropriate supportive measures.

Charcot-Marie-Tooth disease type 3 is a lifelong condition characterized by significant variability in clinical outcomes. While many individuals benefit from current standards of care and maintain a good quality of life into adulthood, others may experience progression of weakness over time. Outcomes described in medical literature continue to evolve as standards of care improve, and factors such as age at diagnosis and access to specialized care can influence the disease course. Patients and families are advised to connect with specialized clinics and genetic counselors to stay informed about emerging management strategies and to receive ongoing support.

Clinical trials are underway exploring new treatment approaches for Charcot-Marie-Tooth disease type 3. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility as ongoing research seeks to enhance our understanding and improve management options.