A One Health Approach to Neuronal Ceroid Lipofuscinoses

The AKC Canine Health Foundation (CHF) often employs a One Health approach to achieve its mission of advancing the health of all dogs and their owners. Dogs and humans get many of the same spontaneous diseases, share a similar genome, and closely share the same environments. By studying disease mechanisms in one species, the knowledge gained may be applied to benefit both species. An example of the One Health model is the study of a degenerative neurologic disease known as neuronal ceroid lipofuscinosis (NCL).

NCL describes a broad class of rare, fatal disorders of the nervous system with an autosomal recessive inheritance pattern. There are many varieties of this disease in people. Originally classified by their severity and the age at which symptoms first appear, NCLs are now classified according to their underlying genetic mutation. Mutations in at least 13 different genes have been identified in people, resulting in 14 forms of the disease designated CLN1 through CLN14. The causative mutation affects cells’ ability to degrade specific molecules usually broken down inside lysosomes – organelles that function as the cell’s recycling centers. As waste products accumulate, the cells eventually die. Symptoms such as tremors, seizures, blindness, loss of muscle control, and cognitive decline progress and affected individuals usually die at a young age.

Over the past twenty years, NCL-like diseases have been described in over 20 different dog breeds and mixed breed dogs, as well as in other species. Fourteen sequence variations in eight equivalent canine genes result in similar signs starting between age seven months and seven years. Signs in dogs are accompanied by generalized brain atrophy, retinal degeneration in the eye, and the accumulation of lysosomal storage bodies in the central nervous system and other tissues. Much of the research on canine NCL has been completed at the University of Missouri Neurodegenerative Research Laboratory thanks, in part, to more than $375,000 invested by CHF and its donors to better understand NCL-like diseases.

CHF-funded researchers recently published two case studies about canine NCL:

• Kolicheski et al¹ published a case study in the Journal of Veterinary Internal Medicine describing a novel splice donor mutation causing CLN1-like disease in a Cane Corso dog. The suspected pathologic mutation occurred at the gene that directs the production of an enzyme called palmitoyl-protein thioesterase 1 (PPT1). PPT1 breaks down proteins in the lysosome and if dysfunctional or present in decreased amounts, will result in protein build-up. NCL had not previously been reported in the Cane Corso.
• In the journal Molecular Genetics and Metabolism, Villani et al² describe a mixed-breed dog with NCL caused by the same nonsense mutation in gene CLN5 that has been associated with NCL in Border Collies, Australian Cattle Dogs, and an Australian Cattle Dog/German Shepherd Dog mix. The affected mixed-breed dog described in this case, however, had the genetic background of three breeds (Treeing Walker Coonhound, Beagle, and Shetland Sheepdog), not previously known to be affected by NCL. Since the same founding mutation event seems responsible for NCL in multiple breeds, the authors suggest that this variant of the mutation arose in a common ancestor of multiple breeds. This would indicate that NCL-causing mutations are likely present, but rare, in other breeds and that any breed of dog or mixed-breed showing signs similar to NCL should be tested for this mutation.

CHF recently awarded Grant 02604: Clinical, Pathologic, and Molecular Genetics Investigations of Canine Lysosomal Storage Diseases and Related Diseases to assist researchers in defining the genetic mutations responsible for NCL and other lysosomal storage disorders in affected dogs. Their goal is to help veterinarians diagnose this rare group of diseases and to help breeders make sound breeding decisions. In addition, research into NCL treatment with enzyme replacement therapy, genetic therapy, or cell implantation therapy is ongoing. For example, enzyme replacement therapy has already proven successful in Dachshunds and in children suffering from CLN2. Through continued collaboration and use of a One Health approach, CHF-funded researchers are working towards better health for dogs and humans affected by NCL.

Support CHF-funded research at www.akcchf.org/donate.

References:
1. Kolicheski, A., Barnes Heller, H. L., Arnold, S., Schnabel, R. D., Taylor, J. F., Knox, C. A., … Katz, M. L. (2017). Homozygous PPT1 Splice Donor Mutation in a Cane Corso Dog With Neuronal Ceroid Lipofuscinosis. Journal of Veterinary Internal Medicine, 31(1), 149–157.
https://doi.org/10.1111/jvim.14632
2. Villani, N. A., Bullock, G., Michaels, J. R., Yamato, O., O’Brien, D. P., Mhlanga-Mutangadura, T., … Katz, M. L. (2019). A mixed breed dog with neuronal ceroid lipofuscinosis is homozygous for a CLN5 nonsense mutation previously identified in Border Collies and Australian Cattle Dogs. Molecular Genetics and Metabolism.
https://doi.org/10.1016/j.ymgme.2019.04.003