• Erickson-Davis CR, Faust PL, Vonsattel JP, et al. “Hairy baskets” associated with degenerative Purkinje cell changes in essential tremor. J Neuropathol Exp Neurol 2010;69:262271.

    • Search Google Scholar
    • Export Citation
  • Grimaldi G, Mant M. Topography of cerebellar deficits in humans. Cerebellum 2012;11:336351

  • Miyata M, Miyata H, Mikoshiba K, et al. Development of Purkinje cells in humans: an immunohistochemical study using a monoclonal antibody against the inositol 1,4,5-triphosphate type 1 receptor (IP3R1). Acta Neuropathol 1999;98:226232.

    • Search Google Scholar
    • Export Citation
  • Laure-Kamionowska M, Maślińska D. Calbindin positive Purkinje cells in the pathology of human cerebellum occurring at the time of its development. Folia Neuropathol 2009;47:300305.

    • Search Google Scholar
    • Export Citation
  • Résibois A, Coppens A, Poncelet L. Naturally occurring parvovirus-associated feline hypogranular cerebellar hypoplasia—a comparison to experimentally-induced lesions using immunohistology Vet Pathol 2007;44:831841.

    • Search Google Scholar
    • Export Citation
  • Chidlow G, Wood JP, Sarvestani G, et al. Evaluation of fluorojade C as a marker of degenerating neurons in the rat retina and optic nerve. Exp Eye Res 2009;88:426437.

    • Search Google Scholar
    • Export Citation
  • Rosati M, Goedde T, Steffen F, et al. Developmental changes in voltage-gated calcium channel α(2)δ-subunit expression in the canine dorsal root ganglion. Dev Neurosci 2012;34:440448.

    • Search Google Scholar
    • Export Citation
  • Matiasek K, Pumarola I, Batlle M, et al. International veterinary epilepsy task force recommendations for systematic sampling and processing of brains from epileptic dogs and cats. BMC Vet Res 2015;11:216.

    • Search Google Scholar
    • Export Citation
  • Li H, Burbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009;25:17541760.

  • Mondal B, Paul P, Paul M, et al. An update on spino-cerebellar ataxia. Ann Indian Acad Neurol 2013;16:295303.

  • Vermeer S, van de Warrenburg BPC, Willemsen MAAP, et al. Autosomal recessive cerebellar ataxias: the current state of the affairs. J Med Genet 2011;48:651659

    • Search Google Scholar
    • Export Citation
  • Urkasemsin G, Olby N. Canine hereditary ataxia. Vet Clin Small Anim Pract 2014;44:10751089.

  • Robinson JT, Thorvaldsdóttir H, Winckler W, et al. Integrative genomics viewer. Nat Biotechnol 2011;29:2426.

  • Yasuba M, Okimoto K, Iida M, et al. Cerebellar cortical degeneration in Beagle dogs. Vet Pathol 1988;25:315317.

  • Thomas JB, Robertson D. Hereditary cerebellar abiotrophy in Australian Kelpie dogs. Aust Vet J 1989;66:301302.

  • Urkasemsin G, Linder KE, Bell JS, et al. Hereditary cerebellar degeneration in Scottish terriers. J Vet Intern Med 2010;24:565570.

  • Steinberg HS, Van Winkle T, Bell JS, et al. Cerebellar degeneration in Old English Sheepdogs. J Am Vet Med Assoc 2000;217:11621165.

  • de Lahunta A, Fenner WR, Indrieri RJ, et al. Hereditary cerebellar cortical abiotrophy in the Gordon Setter. J Am Vet Med Assoc 1980;177:538541.

    • Search Google Scholar
    • Export Citation
  • Olby N, Blot S, Thibaud JL, et al. Cerebellar cortical degeneration in adult American Staffordshire Terriers. J Vet Intern Med 2004;18:201208.

    • Search Google Scholar
    • Export Citation
  • Jokinen TS, Rusbridge C, Steffen F, et al. Cerebellar cortical abiotrophy in Lagotto Romagnolo dogs. J Small Anim Pract 2007;48:470473.

  • Sandy JR, Slocombe RF, Mitten RW, et al. Cerebellar abiotrophy in a family of Border Collie dogs. Vet Pathol 2002;39:736738.

  • Huska J, Gaitero L, Snyman HN, et al. Cerebellar granuloprival degeneration in an Australian Kelpie and a Labrador Retriever dog. Can Vet J 2013;54:5560.

    • Search Google Scholar
    • Export Citation
  • Flegel T, Matiasek K, Henke D, et al. Cerebellar cortical degeneration with selective granule cell loss in Bavarian Mountain Dogs. J Small Anim Pract 2007;48:462465.

    • Search Google Scholar
    • Export Citation
  • Tatalick LM, Marks SL, Baszler TV. Cerebellar abiotrophy characterized by granular cell loss in a Brittany. Vet Pathol 1993;30:385388.

  • Cantile C, Salvadori C, Modenato M, et al. Cerebellar granuloprival degeneration in an Italian Hound. J Vet Med A Physiol Pathol Clin Med 2002;49:523525

    • Search Google Scholar
    • Export Citation
  • Tipold A, Fatzer R, Jaggy A, et al. Presumed immune-mediated cerebellar granuloprival degeneration in the Coton de Tuléar breed. J Neuroimmunol 2000;110:130133

    • Search Google Scholar
    • Export Citation
  • Forman OP, De Risio L, Stewart J, et al. Genome-wide mRNA sequencing of a single canine cerebellar cortical degeneration case leads to the identification of a disease associated SPTBN2 mutation. BMC Genet 2012;13:55.

    • Search Google Scholar
    • Export Citation
  • Kyöstilä K, Cizinauskas S, Seppälä EH, et al. A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery. PLoS Genet 2012;8:e1002759.

    • Search Google Scholar
    • Export Citation
  • Forman OP, De Risio L, Matiasek K, et al. Spinocerebellar ataxia in the Italian Spinone dog is associated with an intronic GAA repeat expansion in ITPR1. Mamm Genome 2015;26:108117.

    • Search Google Scholar
    • Export Citation
  • Agler C, Nielsen DM, Urkasemsin G, et al. Canine hereditary ataxia in Old English Sheepdogs and Gordon Setters is associated with a defect in the autophagy gene encoding RAB24. PLoS Genet 2014;10:e1003991.

    • Search Google Scholar
    • Export Citation
  • Zeng R, Farias FHG, Johnson GS, et al. A truncated retrotransposon disrupts the GRM1 coding sequence in Coton de Tuléar dogs with Bandera's neonatal ataxia. J Vet Intern Med 2011;25:267272.

    • Search Google Scholar
    • Export Citation
  • Reifegerste R, Grimm S, Albert S, et al. An invertebrate calcium-binding protein of the calbindin subfamily protein: structure, genomic organization, and expression pattern of the calbindin-32 gene of Drosophila. J Neurosci 1993;13:21862198.

    • Search Google Scholar
    • Export Citation
  • Schwaller B, Meyer M, Schiffmann S. “New” functions for “old” proteins: the role of the calcium binding proteins calbindin D-28k, calretinin and parvalbumin, in cerebellar physiology. Studies with knockout mice. Cerebellum 2002;1:241258.

    • Search Google Scholar
    • Export Citation
  • Bastianelli E. Distribution of calcium-binding proteins in the cerebellum. Cerebellum 2003;2:242262.

  • Abe H, Watanabe M, Yamakuni T, et al. Localization of gene expression of calbindin in the brain of adult rats. Neurosci Lett 1992;138:211215.

    • Search Google Scholar
    • Export Citation
  • Airaksinen MS, Eilers J, Garashuck O, et al. Ataxia and altered dendritic calcium signaling in mice carrying a targeted null mutation of the calbindin D28k gene. Proc Natl Acad Sci U S A 1997;94:14881493.

    • Search Google Scholar
    • Export Citation
  • Foskett JK. Inositol triphosphate receptor Ca2+ release channels in neurological diseases. Pflugers Arch 2010;460:481494.

  • Bezprozvanny I. Role of inositol 1,4,5-triphosphate receptors in pathogenesis of Huntington's disease and spinocerebellar ataxias. Neurochem Res 2011;36:11861197.

    • Search Google Scholar
    • Export Citation
  • Schorge S, van de Leemput J, Singleton A, et al. Human ataxias: a genetic dissection of inositol triphosphate receptor (ITPR1)-dependent signaling. Trends Neurosci 2010;33:211219.

    • Search Google Scholar
    • Export Citation
  • Koeppen AH. The pathogenesis of spinocerebellar ataxia. Cerebellum 2005;4:6273.

  • Vig PJ, Subramony SH, Burright EN, et al. Reduced immuno-reactivity to calcium-binding proteins in Purkinje cells precedes onset of ataxia in spinocerebellar ataxia-1 transgenic mice. Neurology 1998;50:106113.

    • Search Google Scholar
    • Export Citation
  • Hansen ST, Meera P, Otis TS, et al. Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2. Hum Mol Genet 2013;22:271283.

    • Search Google Scholar
    • Export Citation
  • Switonski PM, Szlachcic WJ, Krzyzosiak WJ, et al. A new humanized ataxin-3 knock-in mouse model combines the genetic features, pathogenesis of neurons and glia and late onset of SCA3/MJD. Neurobiol Dis 2015;73:174188.

    • Search Google Scholar
    • Export Citation
  • Chang YC, Lin CY, Hsu CM, et al. Neuroprotective effects of granulocyte-colony stimulating factor in a novel transgenic mouse model of SCA17. J Neurochem 2011;118:288303.

    • Search Google Scholar
    • Export Citation
  • Dougherty SE, Reeves JL, Lucas EK, et al. Disruption of Purkinje cell function prior to huntingtin accumulation and cell loss in an animal model of Huntington Disease. Exp Neurol 2012;236:171178.

    • Search Google Scholar
    • Export Citation
  • Marelli C, Van de Leemput J, Johnson JO, et al. SCA15 due to large ITPR1 deletion in a cohort of 333 Caucasian families with dominant ataxia. Arch Neurol 2011;68:637643.

    • Search Google Scholar
    • Export Citation
  • Novak M, Davis M, Li A, et al. PAW32 ITPR1 gene deletion causes spinocerebellar ataxias 15/16: a genetic, clinical and radiological description of a novel kindred. J Neurol Neurosurg Psychiatry 2010;81:e32.

    • Search Google Scholar
    • Export Citation
  • Bildfell RJ, Mitchell SK, de Lahunta A. Cerebellar cortical degeneration in a Labrador Retriever. Can Vet J 1995;36:570572.

  • de Lahunta A, Averill DR Jr. Hereditary cerebellar cortical and extrapyramidal nuclear abiotrophy in Kerry Blue Terriers. J Am Vet Med Assoc 1976;168:11191124.

    • Search Google Scholar
    • Export Citation
  • Montgomery DL, Storts RW. Hereditary striatonigral and cerebello-olivary degeneration of the Kerry Blue Terrier. Vet Pathol 1983;20:143159.

    • Search Google Scholar
    • Export Citation
  • O'Brien DP, Johnson GS, Schnabel RD, et al. Genetic mapping of canine multiple system degeneration and ectodermal dysplasia loci. J Hered 2005;96:727734.

    • Search Google Scholar
    • Export Citation
  • Higgins RJ, LeCouteur RA, Kornegay JN, et al. Late-onset progressive spinocerebellar degeneration in Brittany Spaniel dogs. Acta Neuropathol 1998;96:97101.

    • Search Google Scholar
    • Export Citation

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Hereditary ataxia in four related Norwegian Buhunds

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  • 1 Neurology/Neurosurgery Unit, Centre for Small Animal Studies, Animal Health Trust, Lanwades Park, Newmarket CB8 7UU, England.
  • | 2 Section of Clinical and Comparative Neuropathology, Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-Universitaet Muenchen, 80539 Munich, Germany.
  • | 3 Canine Genetics Research Group, Animal Health Trust, Lanwades Park, Newmarket CB8 7UU, England.
  • | 4 Neurology and Neurosurgery Department, Dick White Referral, Six Mile Bottom CB8 0UH, England.
  • | 5 Canine Genetics Research Group, Animal Health Trust, Lanwades Park, Newmarket CB8 7UU, England.
  • | 6 Canine Genetics Research Group, Animal Health Trust, Lanwades Park, Newmarket CB8 7UU, England.
  • | 7 Neurology/Neurosurgery Unit, Centre for Small Animal Studies, Animal Health Trust, Lanwades Park, Newmarket CB8 7UU, England.

Abstract

CASE DESCRIPTION Two 12-week-old Norwegian Buhunds from a litter of 5 were evaluated because of slowly progressive cerebellar ataxia and fine head tremors. Two other females from the same pedigree had been previously evaluated for similar signs.

CLINICAL FINDINGS Findings of general physical examination, CBC, and serum biochemical analysis were unremarkable for all affected puppies. Brain MRI and CSF analysis, including PCR assays for detection of Toxoplasma gondii, Neospora caninum, and canine distemper virus, were performed for 3 dogs, yielding unremarkable results. Urinary organic acid screening, enzyme analysis of fibroblasts cultured from skin biopsy specimens, and brainstem auditory-evoked response testing were performed for 2 puppies, and results were also unremarkable.

TREATMENT AND OUTCOME The affected puppies were euthanized at the breeder's request, and their brains and spinal cords were submitted for histologic examination. Histopathologic findings included a markedly reduced expression of calbindin D28K and inositol triphosphate receptor 1 by Purkinje cells, with only mild signs of neuronal degeneration. Results of pedigree analysis suggested an autosomal recessive mode of inheritance. Candidate-gene analysis via mRNA sequencing for 2 of the affected puppies revealed no genetic variants that could be causally associated with the observed abnormalities.

CLINICAL RELEVANCE Findings for the dogs of this report suggested the existence of a hereditary form of ataxia in Norwegian Buhunds with histologic characteristics suggestive of Purkinje cell dysfunction. The presence of hereditary ataxia in this breed must be considered both in clinical settings and for breeding strategies.

Abstract

CASE DESCRIPTION Two 12-week-old Norwegian Buhunds from a litter of 5 were evaluated because of slowly progressive cerebellar ataxia and fine head tremors. Two other females from the same pedigree had been previously evaluated for similar signs.

CLINICAL FINDINGS Findings of general physical examination, CBC, and serum biochemical analysis were unremarkable for all affected puppies. Brain MRI and CSF analysis, including PCR assays for detection of Toxoplasma gondii, Neospora caninum, and canine distemper virus, were performed for 3 dogs, yielding unremarkable results. Urinary organic acid screening, enzyme analysis of fibroblasts cultured from skin biopsy specimens, and brainstem auditory-evoked response testing were performed for 2 puppies, and results were also unremarkable.

TREATMENT AND OUTCOME The affected puppies were euthanized at the breeder's request, and their brains and spinal cords were submitted for histologic examination. Histopathologic findings included a markedly reduced expression of calbindin D28K and inositol triphosphate receptor 1 by Purkinje cells, with only mild signs of neuronal degeneration. Results of pedigree analysis suggested an autosomal recessive mode of inheritance. Candidate-gene analysis via mRNA sequencing for 2 of the affected puppies revealed no genetic variants that could be causally associated with the observed abnormalities.

CLINICAL RELEVANCE Findings for the dogs of this report suggested the existence of a hereditary form of ataxia in Norwegian Buhunds with histologic characteristics suggestive of Purkinje cell dysfunction. The presence of hereditary ataxia in this breed must be considered both in clinical settings and for breeding strategies.

Contributor Notes

Address correspondence to Dr. Mari (lorenzo.mari@aht.org.uk).