CMM1 - Congenital Mirror Movement disorder 1
In mammals, each side of the body is controlled by the opposite side of the brain. In order for movements to be coordinated, the nerve pathways in the spinal cord must remain strictly on their respective side of the body. A frameshift mutation in the EFNB3 gene leads to the loss of this separation in case both copies of the gene are defect. In consequence, the nerve pathways for the movement of the hind limbs cross again in the midline. As a result both sides of the body will be stimulated simultaneously, so that affected animals are not able to move their hind legs independently of each other. This leads to a characteristic two-legged synchronous hopping behaviour similar to that of rabbits (‘bunny hopping’).
CMM1 is inherited in an autosomal recessive manner and has so far only been described in dogs of the Weimaraner breed.
Clinical Symptoms - Prognosis
Clinically, only animals in which both copies of the EFNB3 gene carry the mutation and therefore cannot fulfill their function become affected.
First symptoms appear as soon as the puppies are trying to move by their own in a coordinated manner, usually from the 2nd to 4th week of life.
Typical signs are:
- Characteristic gait with synchronized saltatorial locomotion of the hind legs, which look like the hopping of rabbits
- Inability to move the hind legs independently of each other
- Difficulty getting up and increased stumbling
- The movement disorder persists as the animal gets older.
Severity:
Severity depends on the extent of misguided axons and the gait may be affected to varying degrees; severely affected puppies can only move by hopping and have problems with normal walking or running.
The disorder can affect all limbs, presenting as movement impairment in all four legs (tetraparesis).
- Typical gait with synchronized hopping of the hind legs (“bunny hopping”)
- Weakness and poor coordination, mainly in the hind limbs
- Difficulty standing up and frequent stumbling
CMM1 is not curable. Due to the suffering associated with the disease, early euthanasia is usually performed..
Development of CMM1
In mammals, each hemisphere of the brain controls the motor function of the opposite side of the body (e.g., left hemisphere > right side of the body). The cell bodies of the motor neurons responsible for voluntary movement are located in the brain, and the muscles are controlled via nerve fibers (axons) that extend from these cells.
For coordinated control of movement, the motor nerve pathways originating from the brain must remain strictly separated in the spinal cord during development and only innervate the muscles on the correct side of the body.
The EFNB3 gene encodes the protein Ephrin-B3. During embryonic development of the nervous system, this protein plays a crucial role in ensuring that the nerves (axons) descending from the brain are correctly guided in the spinal cord to the appropriate muscles on each side of the body. To achieve this the Ephrin-B3 proteins form a barrier along the midline of the spinal cord, preventing the nerve fibers from crossing the midline again as they grow.
If the mutation is present in a homozygous state, the barrier cannot be formed, allowing the axons to innervate the muscles on both sides of the body in an uncoordinated manner. As a result, nerve impulses from the motor neurons reach both sides of the body simultaneously, causing both sides to move in a synchronized saltatorial motion.
Mutation and DNA testing
The underlying genetic cause was identified as a 2-bp duplication in EFNB3 encoding ephrin-B3, a transmembrane protein important for axon guidance and spinal midline barrier formation during neurodevelopment.
The identified variant, XM_038536724.1:c.643_644dup, is predicted to lead to a frameshift and introduction of a premature stop codon XP_038392652.1:p.(Ala216Valfs*79).
The mutation test detects the two-base-pair duplication (c.643_644dup) in the EFNB3 gene.
Affected Breeds
The c.643_644dup mutation in the EFNB3 gene has so far only been described in dogs of the Weimaraner breed and can be traced back to an original animal of this breed. The occurrence would therefore be limited to dogs of the Weimaraner breed.
However, the gene variant can also occur in mixed breeds in which “Weimaraners” have been involved.
Genotyping results and their meaning
Genotype result N/N = healthy-homozygous normal
The dog examined does not have the c.643_644dup mutation in either copy of the EFNB3 gene. The hereditary disease CMM1 will not occur in this dog and will not be inherited. In breeding, the dog can be mated with any other dogs (N/N or N/cmm1) without offspring being affected by CMM1. If mated to a carrier animal (N/cmm1), on average 50% of the offspring would be carriers, but they would all be healthy due to recessive inheritance.
Genotype result N/cmm1 = healthy - heterozygous for the mutation
The examined dog has the c.643_644dup mutation in one of the two EFNB3 genes. The other copy is normal at this site. The dog itself will not develop CMM1, but can pass the mutation on to its offspring with a probability of 50 %. Heterozygous CMM1 carriers may only be bred to animals that are homozygous free (N/N) of the variant.
Genotype result cmm1/cmm1 = affected - homozygous for the mutation
Both copies of the EFNB3 gene have the c.643_644dup mutation. Affected dogs show CMM1 symptoms from early puppyhood. Therapy is not possible.
Literature
- Schwarz, C., Bartenschlager, F., Kershaw, O., Braun, J., Guevar, J., Jagannathan, V., Epplen, J. T., Reineking, W., Baumgärtner, W., Bhatia, K. P., Gruber, A. D., & Leeb, T. (2025). EFNB3 frameshift variant in Weimaraner dogs with a condition resembling a congenital mirror movement disorder. Movement Disorders, Advance online publication. https://doi.org/10.1002/mds.30243
- Online Mendelian Inheritance: https://www.omia.org/OMIA002353/9615/)