Leukoencephalomyelopathy (LEMP)

Gene: NAPEPLD

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:

Great Dane, Rottweiler mutation: Insertion, NAPEPLD gene; c.345|346 ins. C, p.(E116R fs STOP 186), exon3, chr.18.

Leonberger mutation: Substitution, NAPEPLD type; c.538 G>C, p.(A180P), chr.18.

Medical system: Neurological

Breeds: Great Dane, Leonberger, Rottweiler

Age of onset of symptoms: Between 1 and 4 years.

Leukoencephalomyelopathy (LEMP) is a juvenile onset, neurodegenerative disease described in the Rottweiler breed since the 1980s and more recently in the Leonberger dog breed.  LEMP is a leukodystrophy, a wasting disease of myelin tissue, involving the progressive loss of myelin sheaths within the white matter of the central nervous system.    Clinical signs include progressive generalized ataxia of all 4 limbs, hypermetria during movement, and loss of conscious proprioception.  Reflexes are unaffected and there is no evidence of muscle atrophy.  Loss of myelin is evident on histological examination of neural tissue from affected animals.  Although there is some variation in time of onset and specific clinical signs between affected animals, the overall disease presentation between the two dog breeds is similar.

Molecular studies in Leonberger identified a homozygous mutation in the NAPEPLD gene as being responsible for LEMP in this breed.  The NAPEPLD gene codes for an enzyme belonging to the endocannabinoid system of the central nervous system and is involved, among other things, in the structural integrity of the myelin sheath of neurons.  In a large survey of Leonberger dogs, a carrier (M/N) frequency of 15.6% was determined.  About 1% of double mutant animals did not display symptoms, indicating variable penetration of the mutation, individual differences in disease progression, and possibly the presence of modifying genes.  It was concluded that the mutation within the Leonberger breed is a relatively recent event.

Molecular studies in the Rottweiler breed identified a separate homozygous mutation in the NAPEPLD gene as being responsible for LEMP in this breed.  A survey of 229 dogs revealed a carrier frequency of 7.1%.  A related survey in the Great Dane breed revealed a carrier frequency of 9.2%.  It was concluded that the NAPEPLD mutation seen in the Rottweiler breed is considerably older than the mutation seen in the Leonberger breed.  The availability of DNA testing will permit breeders to identify carrier animals for the NAPEPLD mutations, allowing them through selective breeding to eliminate LEMP and eventually the responsible mutations from their breeds.

References:

OMIA link: [1788-9615]

Minor KM, Letko A, Becker D, Drogemuller M, et al. (2018)  Canine NAPEPLD-associated models of human myelin disorders.  Scientific Reports 8:5818  [pubmed/29643404]

Oevermann A, Bley T, Konar M, et al. (2008) A novel leukoencephalomyelopathy of Leonberger dogs.  J Vet Intern Med. 22(2):467-71. [pubmed/18371035]

Gamble DA, Chrisman CL. (1984) A leukoencephalomyelopathy of Rottweiler dogs. Vet Pathol 21:274-80.  [pm/6730216]

Contributed by:  Marilou Guité and Alexandre Dubé, class of 2028, Veterinary Medicine Faculty, University of Montreal.  (Translation: DWS).