What Is CMT4G?
CMT4G is a type of CMT caused by mutations in the HK1 gene. This gene provides instructions for producing hexokinase 1, an enzyme involved in the first step of glucose metabolism, and is essential for cellular energy production. Mutations in the HK1 gene disrupt normal energy regulation in peripheral nerve cells, leading to impaired Schwann cell function and slowed nerve signal transmission
CMT4G is autosomal recessive, meaning that both of the gene’s copies must have a CMT-causing mutation to cause this subtype.
CMT4G was originally described as hereditary motor and sensory neuropathy, Russe type (HMSNR) in the Romani community in northern Spain. This is the same community in which CMT4D was previously described. Subsequent genetic research identified an autosomal recessive mutation in the HK1 gene as the cause of this subtype. As genetic classification systems evolved, HMSNR was reclassified as CMT4G in the mid-2000s to reflect its autosomal recessive inheritance and demyelinating features.
CMT4G has been reported only in the Romani community. Although cases have been identified outside northern Spain, they have not been observed outside of individuals of Romani descent.
Symptom onset in CMT4G varies. Symptoms start in the lower extremities by mid-teens. And in the upper extremities, as late as the mid-forties. Nerve conduction studies usually show slowed conduction velocities and somewhat reduced amplitudes, consistent with a demyelinating form of CMT. Sensory nerves can be more impacted than motor nerves.
CMT4G 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
- Scoliosis (in some patients)
- Additional symptoms not listed here
Disease Course
CMT4G shows wide variability in severity and progression. Some individuals are mildly affected, while others develop a more severe disease. Disease progression is generally slow, and life expectancy is not reduced.
