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Charcot-Marie-Tooth disease type 4D
Charcot-Marie-Tooth disease type 4D (CMT4D) is a severe form of Charcot-Marie-Tooth disease type 4 (see this term), a demyelinating hereditary motor and sensory neuropathy, characterized by a gait disorder manifesting in the first decade of life, followed by upper limb involvement observed in the second decade, and sensorineural deafness usually manifesting in the second or third decade of life.
CMT4D was first reported in the Bulgarian Romani community of Lom and, to date, has mainly been associated with the Roma population. The carrier rate among the Roma population in Bulgaria has been estimated to be 2%.
Onset usually occurs in the first decade of life with distal muscle weakness and atrophy, particularly severe in the lower limbs, leading to gait disturbances with easy fatigue, and frequent stumbling and falling. Proximal involvement is observed in the second decade and sensorineural deafness in the second or third decade of life. Motor involvement is greater than sensory, and both predominate distally in the limbs. All sensory modalities are affected and present with a marked reduction of motor nerve conduction velocities.
CMT4D is caused by a single ancestral mutation (p.R148X) in the NDRG1 gene (8q24), coding for protein NDRG1 that has a role in the peripheral nervous system, possibly in Schwann cell signaling that is necessary for axonal survival.
Transmission is autosomal recessive
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