What Is CMT2Q?
CMT2Q is a type of CMT caused by mutations in the DHTKD1 gene. This gene provides instructions for producing dehydrogenase E1 and transketolase domain–containing protein 1, an enzyme involved in mitochondrial energy metabolism. Mutations in the DHTKD1 gene disrupt normal mitochondrial function in peripheral nerve cells, leading to impaired axonal function and nerve signal transmission.
CMT2Q autosomal dominant, meaning that just one of the gene’s two copies needs a mutation to cause this subtype.
Clinical Features
CMT2Q symptom onset is variable, ranging from early childhood to late adulthood. Symptoms typically begin in the lower extremities and progress over time to involve the upper limbs. Nerve conduction studies usually show somewhat slowed conduction velocities and reduced amplitudes, consistent with an axonal form of CMT.
CMT2Q 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
- Muscle biopsy shows:
- Small, angulated muscle fibers
- Sarcomere disappearance
- Disorganized myofilaments
- Mitochondrial vacuolization
- Additional symptoms not listed here
Disease Course
CMT2Q 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.
Genetic Context
- HGNC-Approved Gene Symbol
- DHTKD1
- Gene Full Name
- Dehydrogenase E1 and Transketolase Domain Containing 1
- HGNC Gene Alias(es)
- KIAA1630, MGC3090, DKFZP762M115, OADH-E1, OADC-E1, E1a
- Chromosome
- 10p14
- Zygosity of Responsible Variant
- Heterozygous
- Mitochondrial Involvement
- Yes
- Variant Mechanism
-
Loss of Function (LoF)
Details
Mechanistic basis:
Haploinsufficiency
Confidence:
Medium
Prediction:
The literature predicts a loss-of-function mechanism acting through haploinsufficiency for CMT2Q: the reported heterozygous DHTKD1 nonsense allele (p.Y486*, Xu et al. 2012) lowers DHTKD1 transcript and protein, with reduced ATP production and elevated ROS, consistent with a single reduced copy of this 2-oxoadipate dehydrogenase being insufficient. Because the allele reduces dosage rather than yielding a toxic product, added wild-type protein is predicted to rescue, supporting haploinsufficiency over a dominant-negative or gain-of-function mechanism. The evidence rests largely on a single dominant family, holding confidence at medium.
Rationale:
The p.Y486* nonsense allele is expected to trigger nonsense-mediated decay and lower DHTKD1 dosage, reducing ATP and raising ROS, rather than yielding a truncated product that disrupts the wild-type enzyme: this points to haploinsufficiency loss of function. Confidence holds at medium because the call rests on a single dominant family and because complete biallelic DHTKD1 loss causes a separate recessive disease, 2-aminoadipic 2-oxoadipic aciduria (AMOXAD), leaving it uncertain that loss of a single copy causes dominant CMT.
Updated: May 9, 2026 | By: K. Raymond
