Autosomal dominant Charcot-Marie-Tooth disease type 2E

Autosomal dominant Charcot-Marie-Tooth disease type 2E (CMT2E) is a rare inherited peripheral neuropathy caused by mutations in the NEFL gene, which encodes the neurofilament light chain protein. Neurofilament light chain is a critical structural component of the neuronal cytoskeleton, essential for maintaining axonal caliber and facilitating nerve signal transmission. Mutations in this gene lead to progressive degeneration of peripheral nerve axons, primarily affecting the motor and sensory nerves of the limbs. CMT2E is also known as CMT2E/1F, as some NEFL mutations can cause a demyelinating phenotype (CMT1F) rather than a purely axonal form, depending on the specific mutation. The disease primarily affects the peripheral nervous system, leading to progressive distal muscle weakness and atrophy, particularly in the lower legs and feet, followed by involvement of the hands and forearms. Key clinical features include difficulty walking, foot drop, high-arched feet (pes cavus), hammer toes, and reduced or absent deep tendon reflexes. Sensory loss in a stocking-glove distribution is common, and patients may experience decreased vibration and position sense. Onset is typically in childhood or adolescence, though age of onset and severity can vary even within the same family. Some patients with specific NEFL mutations may present with a more severe early-onset phenotype. There is currently no cure or disease-modifying treatment for CMT2E. Management is supportive and multidisciplinary, including physical therapy to maintain muscle strength and flexibility, occupational therapy, orthotic devices such as ankle-foot orthoses to assist with walking, and orthopedic surgery when needed for foot deformities. Pain management may be necessary for patients experiencing neuropathic pain. Regular monitoring by a neurologist and rehabilitation specialist is recommended to address functional decline over time. Genetic counseling is important for affected individuals and their families given the autosomal dominant inheritance pattern.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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