OMIA 001472-9615 : Neuronal ceroid lipofuscinosis, 2 in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 204500

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2006

Cross-species summary: CLN2

Species-specific description: The neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases characterized by intraneuronal accumulation of fluorescent granules, early neuronal death, and progressive neurodegeneration of the central nervous system. NCL2 is an early-onset disease of miniature long-haired dachshunds. Early signs include progressive loss of vision under dim light, decreased menace response, tremors of the head, myoclonus, and cerebellar ataxia. Signs appear in young dogs and progress rapidly, with death by 12 months of age., as no effective treatment has been identified. The mode of inheritance is autosomal recessive.

Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT

Mapping: CFA21

Molecular basis: The causative mutation is a single nucleotide deletion (c.325delC) in exon 4 of TPP1, which causes an amino acid codon frameshift and a premature stop codon (Awano et al., 2006). There is an analogous disease in humans (OMIM# 204500).

Clinical features: Progressive loss of vision under dim light begins in affected dogs at 6-7 months of age (Sanders et al., 2011). Unilaterally decreased menace response begins at 8 months of age, followed by intention and resting tremors of the head, and myoclonus. Cerebellar ataxia (dysmetria, incoordination) began at 9-10 months of age. Other neurological signs include altered cognitive function, motor dysfunction, and myoclonus. Tests of cognitive ability were significantly different from normal dogs at 6 months of age (Sanders et al., 2011). Other signs reported include seizures, hyperactivity, howling, aggressive behavior, hypermetria, circling, and diarrhea (Awano et al., 2006). No effective treatment has been identified, and affected dogs die by 12 months of age (Awano et al., 2006). Intrathecal administration of TPP1 caused a robust immune response and did not improve the overall function of treated dogs (Vuillemenot et al., 2011).

Pathology: Affected dogs have less than 1% TPP1 activity in the cerebral cortex (Awano et al., 2006). Autofluorescent lysosomal storage occurs throughout the central nervous system. Some cerebral cortex cells have large storage bodies, but most have little to none. Storage material is present in all layers of the cerebellum, but only moderate in Purkinje cells. In the spinal cord, most autofluorescent storage is in large motor neurons. Curvilinear aggregates in the lysosomes are identified by electron microscopy (Awano et al., 2006, Vuillemenot et al., 2011). Histopathology of the cerebellum includes white matter depletion, decreased numbers of cortical neurons, a narrowed molecular layer, a sparsely populated internal granular layer, and irregularly spaced Purkinje cells. Larger neurons in the cerebrum and spinal cord contain coarse eosinophilic, PAS positive cytoplasmic granules (Awano et al., 2006).

Prevalence: The mutation appears to be uncommon among miniature long-haired dachshunds (Awano et al., 2006).

Control: Parents of affected dogs are obligate carriers. Siblings of affected animals should be tested. Breeding of affected or carrier dogs is not recommended.

Genetic testing: A test is available to detect the causative mutation in miniature long-haired dachshunds.

Breed: Dachshund.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
TPP1 tripeptidyl peptidase I Canis lupus familiaris 21 NC_006603.3 (29926974..29921764) TPP1 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Dachshund Neuronal ceroid lipofuscinosis, 2 TPP1 deletion, small (<=20) c.325delC p.A108Pfs*6 2006 16621647 p. information obtained from Katz et al. (2017) Neurobiol Dis. doi: 10.1016/j.nbd.2017.08.017

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2017 Katz, M.L., Rustad, E., Robinson, G.O., Whiting, R.E.H., Student, J.T., Coates, J.R., Narfstrom, K. :
Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions. Neurobiol Dis :, 2017. Pubmed reference: 28860089. DOI: 10.1016/j.nbd.2017.08.017.
2016 Kohlschütter, A., Schulz, A. :
CLN2 Disease (Classic Late Infantile Neuronal Ceroid Lipofuscinosis). Pediatr Endocrinol Rev 13 Suppl 1:682-8, 2016. Pubmed reference: 27491216.
Phillips, J.E., Gomer, R.H. :
A canine model for neuronal ceroid lipofuscinosis highlights the promise of gene therapy for lysosomal storage diseases. Ann Transl Med 4:S20, 2016. Pubmed reference: 27867988. DOI: 10.21037/atm.2016.10.16.
Tracy, C.J., Whiting, R.E., Pearce, J.W., Williamson, B.G., Vansteenkiste, D.P., Gillespie, L.E., Castaner, L.J., Bryan, J.N., Coates, J.R., Jensen, C.A., Katz, M.L. :
Intravitreal implantation of TPP1-transduced stem cells delays retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis. Exp Eye Res 152:77-87, 2016. Pubmed reference: 27637672. DOI: 10.1016/j.exer.2016.09.003.
Whiting, R.E., Jensen, C.A., Pearce, J.W., Gillespie, L.E., Bristow, D.E., Katz, M.L. :
Intracerebroventricular gene therapy that delays neurological disease progression is associated with selective preservation of retinal ganglion cells in a canine model of CLN2 disease. Exp Eye Res 146:276-82, 2016. Pubmed reference: 27039708. DOI: 10.1016/j.exer.2016.03.023.
2015 Katz, M.L., Tecedor, L., Chen, Y., Williamson, B.G., Lysenko, E., Wininger, F.A., Young, W.M., Johnson, G.C., Whiting, R.E., Coates, J.R., Davidson, B.L. :
AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease. Sci Transl Med 7:313ra180, 2015. Pubmed reference: 26560358. DOI: 10.1126/scitranslmed.aac6191.
Whiting, R.E., Pearce, J.W., Castaner, L.J., Jensen, C.A., Katz, R.J., Gilliam, D.H., Katz, M.L. :
Multifocal retinopathy in Dachshunds with CLN2 neuronal ceroid lipofuscinosis. Exp Eye Res 134:123-32, 2015. Pubmed reference: 25697710. DOI: 10.1016/j.exer.2015.02.012.
2014 Whiting, R.E., Narfström, K., Yao, G., Pearce, J.W., Coates, J.R., Castaner, L.J., Jensen, C.A., Dougherty, B.N., Vuillemenot, B.R., Kennedy, D., O'Neill, C.A., Katz, M.L. :
Enzyme replacement therapy delays pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis. Exp Eye Res 125:164-72, 2014. Pubmed reference: 24954537. DOI: 10.1016/j.exer.2014.06.008.
2013 Bond, M., Holthaus, S.M., Tammen, I., Tear, G., Russell, C. :
Use of model organisms for the study of neuronal ceroid lipofuscinosis. Biochim Biophys Acta 1832:1842-65, 2013. Pubmed reference: 23338040. DOI: 10.1016/j.bbadis.2013.01.009.
Whiting, R.E., Narfström, K., Yao, G., Pearce, J.W., Coates, J.R., Castaner, L.J., Katz, M.L. :
Pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis. Exp Eye Res :, 2013. Pubmed reference: 24135299. DOI: 10.1016/j.exer.2013.10.006.
2011 Sanders, D.N., Kanazono, S., Wininger, F.A., Whiting, R.E., Flournoy, C.A., Coates, J.R., Castaner, L.J., O'Brien, D.P., Katz, M.L. :
A reversal learning task detects cognitive deficits in a Dachshund model of late-infantile neuronal ceroid lipofuscinosis. Genes Brain Behav :, 2011. Pubmed reference: 21745338. DOI: 10.1111/j.1601-183X.2011.00718.x.
Vuillemenot, B.R., Katz, M.L., Coates, J.R., Kennedy, D., Tiger, P., Kanazono, S., Lobel, P., Sohar, I., Xu, S., Cahayag, R., Keve, S., Koren, E., Bunting, S., Tsuruda, L.S., O'Neill, C.A. :
Intrathecal tripeptidyl-peptidase 1 reduces lysosomal storage in a canine model of late infantile neuronal ceroid lipofuscinosis. Mol Genet Metab :, 2011. Pubmed reference: 21784683. DOI: 10.1016/j.ymgme.2011.06.018.
2008 Katz, M.L., Coates, J.R., Cooper, J.J., O'Brien, D.P., Jeong, M., Narfström, K. :
Retinal pathology in a canine model of late infantile neuronal ceroid lipofuscinosis. Invest Ophthalmol Vis Sci 49:2686-95, 2008. Pubmed reference: 18344450. DOI: 10.1167/iovs.08-1712.
2006 Awano, T., Katz, ML., O'Brien, DP., Sohar, I., Lobel, P., Coates, JR., Khan, S., Johnson, GC., Giger, U., Johnson, GS. :
A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis. Mol Genet Metab 89:254-60, 2006. Pubmed reference: 16621647. DOI: 10.1016/j.ymgme.2006.02.016.

Edit History


  • Created by Frank Nicholas on 12 Jul 2009
  • Changed by Martha MaloneyHuss on 23 Aug 2011
  • Changed by Vicki Meyers-Wallen on 18 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011