CMT4D is caused by mutations in the NDRG1 gene. This gene provides instructions for producing N-myc downstream regulated 1, a protein involved in cellular growth, differentiation, and maintenance of peripheral nerve myelin. Mutations in the NDRG1 gene disrupt normal Schwann cell function and impair myelin integrity, leading to slowed nerve signal transmission.
CMT4D is autosomal recessive, meaning that both of the gene’s copies must have a CMT-causing mutation to cause this subtype.
CMT4D was first described in 1996 in the town of Lom, Bulgaria. When initially identified, it was classified as hereditary motor and sensory neuropathy, Lom type (HMSN-Lom), to reflect its clinical presentation and geographic origin.
Subsequent genetic research identified mutations in the NDRG1 gene as the cause of this subtype. As genetic classification systems evolved, HMSN-Lom type was reclassified as CMT4D because it is an autosomal recessive, demyelinating neuropathy.
Although additional cases have been reported since its original description, CMT4D has been reported only within the Romani community.
Clinical Features
Symptom onset in CMT4D typically occurs before age 10. Symptoms usually begin in the lower limbs and progress to the upper body. People with CMT4D experience total deafness by their thirties. Nerve conduction studies usually show severely slowed conduction velocities and somewhat reduced amplitudes, consistent with a demyelinating form of CMT. Conduction velocities may become too slow to record on exam.
CMT4D symptoms may include:
- Weakness in the feet and lower legs
- Muscle atrophy
- Foot drop
- A steppage-style walking pattern
- Reduced sensation
- Reduced or absent reflexes
- Foot deformities, including high arches and hammertoes (clawed toes)
- Progressive involvement of the hands and forearms
- Difficulty with fine motor skills and manual dexterity
- Total deafness by the thirties
- Additional symptoms not listed here
Disease Course
CMT4D is typically a severe disease. Although severe, progression is generally slow, and life expectancy is not reduced.
