Congenital Myasthenic Syndrome (Retriever type)

 

Gene: COLQ

Transmission: Autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease. Both parents of an affected animal must be carriers of at least one copy of the mutation. Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutations:

Golden Retriever mutation: Substitution, COLQ gene; c.1010 T>C, I337T, exon 14

Labrador Retriever mutation: Substitution, COLQ; c.880 G>A, p.(G294R)

Medical systems: Neurological, muscular, neuromuscular

Breeds: Golden Retriever, Labrador Retriever

Age of onset of symptoms: 6 weeks

Congenital myasthenic syndromes are a group of hereditary disorders that interfere with the transmission of nerve signals to muscle at the neuromuscular junction. In mammals, this signaling is made by the neurotransmitter acetylcholine, and the enzyme acetylcholinesterase is essential in this process. An autosomal recessive mutation in the COLQ gene which codes for acetylcholinesterase has been identified in the Labrador Retriever; another mutation in the same gene has been identified in the Golden Retriever. These mutations cause a reduction in acetylcholinesterase, which increases the quantity of acetylcholine at the neuromuscular junction. As a result, the muscle becomes desensitized to this neurotransmitter and responds less to nerve stimulation. The disease gives rise to clinical signs that appear in young puppies and include generalized muscle weakness, jerky gait, falls, difficulty in defecation position and pronounced fatigue. Symptoms worsen with physical activity to include respiratory difficulty and paralysis of all four legs.  Diagnosis is difficult, since most symptoms correspond to several types of neuromuscular disease, but can be established by physical examination, neurological examination, electrodiagnostic tests such as electromyography (EMG), muscle biopsy and now DNA tests. There is no treatment for the animal suffering from the disease, and the prognosis is, for the time being, bleak. With DNA tests available for the causative mutations, breeders can begin to identify carriers with the aim of eliminating the mutation and the disease from their breed.

 

References:

OMIA link: [1928-9615]

Donner J, Freyer J, Davison S, et al. (2023) Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs.  PLoS Genet. 19(2):e1010651. [pubmed/36848397]

Mignan T, Targett M, Lowrie M. (2020) Classification of myasthenia gravis and congenital myasthenic syndromes in dogs and cats. J Vet Intern Med 34:1707-1717. [pubmed/32668077]

Tsai KL, Vernau KM, Winger K, Zwueste DM, et.al. (2020) Congenital Myasthenic Syndrome in Golden Retrievers Is Associated With a Novel COLQ Mutation. J Vet Intern Med. 34(1):258-265. [pubmed/31769119]

Rinz CJ, Levine J, Minor KM, et al. (2014) A COLQ missense mutation in Labrador Retrievers having congenital myasthenic syndrome. PLoS One 9(8):e106425. [pubmed/25166616]

Mihaylova V, Müller JS, Vilchez JJ, et al. (2008) Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes. Brain. 131(Pt 3):747-59. [pubmed/18180250]

 

Contributed by:  Charlotte Gosselin and Audrey Grenier, class of 2027, Veterinary Medicine Faculty, University of Montreal.  (Translation: DWS).