Neuronal Ceroid Lipofuscinosis in 3 Australian Shepherd Littermates

O’Brien, Dennis P.; Katz, Martin L.

doi:10.1111/j.1939-1676.2008.0079.x

Cited by 25 publications

(26 citation statements)

References 22 publications

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“…Genomic DNA was extracted from the rehydrated tissue as previously described [5, 7]. The same procedure was used to extract DNA from a paraffin block containing tissue from an unrelated NCL-affected Australian Shepherd described previously in [4]. Additional canine DNA samples were obtained from the University of Missouri Canine DNA Repository (http://www.caninegeneticdiseases.net/).…”

Section: Methodsmentioning

confidence: 99%

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A Missense Mutation in Canine CLN6 in an Australian Shepherd with Neuronal Ceroid Lipofuscinosis

Katz

Farias

Sanders

et al. 2010

BioMed Research International

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The childhood neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative diseases that are progressive and ultimately fatal. An Australian Shepherd that exhibited a progressive neurological disorder with signs similar to human NCL was evaluated. The cerebral cortex, cerebellum, and retina were found to contain massive accumulations of autofluorescent inclusions characteristic of the NCLs. Nucleotide sequence analysis of DNA from the affected dog identified a T to C variant (c.829T>C) in exon 7 of CLN6. Mutations in the human ortholog underlie a late-infantile form of NCL in humans. The T-to-C transition results in a tryptophan to arginine amino acid change in the predicted protein sequence. Tryptophans occur at homologous positions in the CLN6 proteins from all 13 other vertebrates evaluated. The c.829T>C transition is a strong candidate for the causative mutation in this NCL-affected dog. Dogs with this mutation could serve as a model for the analogous human disorder.

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Section: Methodsmentioning

confidence: 99%

“…These mutations all occur in orthologs of genes that contain mutations responsible for specific forms of human NCL or a similar disorder. We previously identified NCL in a family of Australian Shepherds [4]. Only paraffin-embedded tissues were available from these dogs, and no genetic analyses were undertaken.…”

Section: Introductionmentioning

confidence: 99%

A Missense Mutation in Canine CLN6 in an Australian Shepherd with Neuronal Ceroid Lipofuscinosis

Katz

Farias

Sanders

et al. 2010

BioMed Research International

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“…Naturally-occurring NCLs have been identified in several larger animal species, including dogs (Awano et al 2006a; Awano et al 2006b; Bond et al 2013; Farias et al 2011; Katz et al 2005; Katz et al 2011; O’Brien and Katz 2008; Palmer et al 2011; Sanders et al 2010). Among the canine NCLs is a form of the disease in Dachshunds which results from a null mutation in TPP1 that encodes the lysosomal enzyme tripeptidyl-peptidase-1 (TPP1) (Awano et al 2006b).…”

Section: Introductionmentioning

confidence: 99%

Pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis

Whiting¹,

Narfström²,

Yao³

et al. 2013

Experimental Eye Research

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Late-infantile neuronal ceroid lipofuscinosis (CLN2) is a hereditary neurological disorder characterized by progressive retinal degeneration and vision loss, cognitive and motor decline, seizures, and pronounced brain atrophy. The progressive loss of neurological functions eventually leads to death, usually by the early teenage years. Utilizing a canine model of CLN2, therapeutic studies to inhibit the brain and retinal degenerations are currently under way. Using this dog model, studies were undertaken to compare quantitative assessments of the pupillary light reflex (PLR) and electroretinography (ERG) as tools for evaluating the effects of the disease on retinal function. The PLR and ERG were recorded in normal and CLN2-affected Dachshunds at 2 month intervals between the ages of 4 and 10 months. Using custom instrumentation for quantitative PLR assessments, a series of white light stimuli of varying intensity was used to elicit pupil constriction, and pupil images were recorded using continuous infrared illumination and an infrared-sensitive camera. Electroretinography was used to evaluate retinal function in the same dogs. As the disease progressed, affected dogs exhibited progressive and profound declines in ERG amplitudes under both scotopic and photopic conditions. With low intensity light stimuli, CLN2 was also accompanied by progressive deficits in the PLR. Changes in the PLR to dim light stimuli included significant deficits in latency, constriction velocity, constriction amplitude, and redilation velocity. However, despite the almost complete loss of detectable ERG responses by disease end stage, the PLR to bright stimuli was well preserved throughout the disease progression. These findings demonstrate that the PLR is much more sensitive than the ERG in detecting residual retinal function in animal models of retinal degenerative disease. The preservation of the PLR in dogs with profoundly depressed ERGs correlates with a preservation of visually-mediated behavior even late in the disease progression. Quantitative analysis of the PLR has potential as a biomarker in animal models of retinal degenerative diseases and in evaluating the efficacy of therapeutic interventions in preserving retinal function.

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“…10 Subunit c of mitochondrial adenosine triphosphate synthase (SCMAS) is the main storage material in the diseases caused by the mutations in CLN2, CLN3, CLN5, CLN6, CLN7, CLN8, and CLCN7, whereas the accumulation of saposins (A and D) is recognized in some subtypes of NCL (those affected by mutations in CLN1 and CLN10). 10 Clinical and pathological features of the disease have been reported in several animal species, such as dogs, 1,2,13,14,18,19,22,23,26,28 cats, 16,21 sheep, 5,12,24,25 cattle, 6,8,11 goats, 4 horses, 9,31 and nonhuman primates. 29 Even in the veterinary field, mutations of causative genes have been identified: CLN5, 5 CLN6, 24,25 and CL10 30 in sheep; CLN5 in cattle 8 ; and CLN2 (TPP1), 1 CLN5, 18 CLN8, 13 and CLN10 (CTSD) 2 in dogs.…”

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confidence: 99%

Clinical and Pathologic Features of Neuronal Ceroid-Lipofuscinosis in a Ferret (Mustela putorius furo)

et al. 2011

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Clinical and pathologic features of neuronal ceroid-lipofuscinosis in a 4-month-old ferret are reported. Clinical signs including neurological symptoms appeared at 3 months of age and progressed rapidly. By magnetic resonance imaging, severe cerebral atrophy was recognized. Histopathologically, there was severe neuronal loss and diffuse astrogliosis with macrophage accumulations; lesions were found predominantly in the cerebral cortex. Intracytoplasmic pigments were observed in surviving neurons and macrophages throughout the brain. The pigments were intensely positive for periodic acid-Schiff, Luxol fast blue, and Sudan black B and exhibited a green autofluorescence. Electron microscopic examination revealed the accumulation of electron-dense granular material within lysosomes of neurons and macrophages. Immunohistochemically, a large number of saposin-positive granules accumulated in the neuronal cells, astrocytes, and macrophages of the lesions, but significant immunoreactivity for subunit c of mitochondrial adenosine triphosphate synthase was not observed. Based on these findings, the animal was diagnosed as affected by neuronal ceroid-lipofuscinosis.

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Neuronal Ceroid Lipofuscinosis in 3 Australian Shepherd Littermates

Cited by 25 publications

References 22 publications

A Missense Mutation in Canine CLN6 in an Australian Shepherd with Neuronal Ceroid Lipofuscinosis

A Missense Mutation in Canine CLN6 in an Australian Shepherd with Neuronal Ceroid Lipofuscinosis

Pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis

Clinical and Pathologic Features of Neuronal Ceroid-Lipofuscinosis in a Ferret (Mustela putorius furo)

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