Classification and Natural History of the Neuronal Ceroid Lipofuscinoses

Mink, Jonathan W.; Augustine, Erika F.; Adams, Heather; Marshall, Frederick J.; Kwon, Jennifer M.

doi:10.1177/0883073813494268

Cited by 113 publications

(114 citation statements)

References 41 publications

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“…Among the various subtypes of NCL, the accumulated materials have characteristic ultrastructural appearances often referred to as GRODs (granular osmiophilic deposits) or as fingerprint, curvilinear, or rectilinear profiles [2]. The clinical manifestations of the NCLs include progressive visual impairment, declining cognitive and motor functions, seizures, generalized brain atrophy and premature death [3]. NCL-causing mutations were first identified in PPT1 and CLN3 and reported in 1995 [4,5].…”

Section: Introductionmentioning

confidence: 99%

Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5

Gilliam

Kolicheski

Johnson

et al. 2015

Molecular Genetics and Metabolism

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We studied a recessive, progressive neurodegenerative disease occurring in Golden Retriever siblings with an onset of signs at 15 months of age. As the disease progressed these signs included ataxia, anxiety, pacing and circling, tremors, aggression, visual impairment and localized and generalized seizures. A whole genome sequence, generated with DNA from one affected dog, contained a plausibly causal homozygous mutation: CLN5:c.934_935delAG. This mutation was predicted to produce a frameshift and premature termination codon and encode a protein variant, CLN5:p.E312Vfs*6, which would lack 39 C-terminal amino acids. Eighteen DNA samples from the Golden Retriever family members were genotyped at CLN5:c.934_935delAG. Three clinically affected dogs were homozygous for the deletion allele; whereas, the clinically normal family members were either heterozygotes (n = 11) or homozygous for the reference allele (n = 4). Among archived Golden Retrievers DNA samples with incomplete clinical records that were also genotyped at the CLN5:c.934_935delAG variant, 1053 of 1062 were homozygous for the reference allele, 8 were heterozygotes and one was a deletion-allele homozygote. When contacted, the owner of this homozygote indicated that their dog had been euthanized because of a neurologic disease that progressed similarly to that of the affected Golden Retriever siblings. We have collected and stored semen from a heterozygous Golden Retriever, thereby preserving an opportunity for us or others to establish a colony of CLN5-deficient dogs.

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Section: Introductionmentioning

confidence: 99%

Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5

Gilliam

Kolicheski

Johnson

et al. 2015

Molecular Genetics and Metabolism

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“…The lysosome is an important cellular organelle involved in the breakdown of macromolecules that can be transported back into the cytoplasm (de Duve, 2005). In NCL, mutations in genes involved in lysosomal function lead to the accumulation of autofluorescent storage material known as lipopigment within lysosomes (Mink et al, 2013). The abnormal accumulation of lipopigment within neurons may lead to eventual neuronal death (Bartsch et al, 2013; Katz et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Progressive retinal degeneration and accumulation of autofluorescent lipopigments in Progranulin deficient mice

et al. 2014

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Prior investigations have shown that patients with neuronal ceroid lipofuscinosis (NCL) develop neurodegeneration characterized by vision loss, motor dysfunction, seizures, and often early death. Neuropathological analysis of patients with NCL shows accumulation of intracellular autofluorescent storage material, lipopigment, throughout neurons in the central nervous system including in the retina. A recent study of a sibling pair with adult onset NCL and retinal degeneration showed linkage to the region of the progranulin (GRN) locus and a homozygous mutation was demonstrated in GRN. In particular, the sibling pair with a mutation in GRN developed retinal degeneration and optic atrophy. This locus for this form of adult onset neuronal ceroid lipofuscinosis was designated neuronal ceroid lipofuscinosis-11 (CLN11). Based on these clinical observations, we wished to determine whether Grn-null mice develop accumulation of autofluorescent particles and retinal degeneration. Retinas of both wild-type and Progranulin deficient mice were examined by immunostaining and autofluorescence. Accumulation of autofluorescent material was present in Progranulin deficient mice at 12 months. Degeneration of multiple classes of neurons including photoreceptors and retinal ganglion cells was noted in mice at 12 and 18 months. Our data shows that Grn −/− mice develop degenerative pathology similar to features of human CLN11.

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“…CLN2 disease has an onset of around 2 years old and death usually occurs before adolescence [20], yet the zebrafish model has visible phenotypes from 2 dpf (smaller brain and eye, curved body and larger yolk) and dies by 7 dpf [16]. This early onset may be due to the precocious zebrafish development, the fact that it develops ex-ovo, or because TPP1 expression is upregulated earlier in the zebrafish than in humans.…”

Section: Cln2 Diseasementioning

confidence: 99%

New Zebrafish Models of Neurodegeneration

Martín-Jiménez

Campanella

Russell

2015

Curr Neurol Neurosci Rep

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In modern biomedicine the increasing need to develop experimental models to further our understanding of disease conditions and delineate innovative treatments has found in the zebrafish (Danio rerio) an experimental model, and indeed a valuable asset, to close the gap between in vitro and in vivo assays. Translation of ideas at a faster pace is vital in the field of neurodegeneration, with the attempt to slow or prevent the dramatic impact on society's welfare being an essential priority. Our research group has pioneered the use of zebrafish to contribute to the quest for faster and improved understanding and treatment of neurodegeneration in concert with, and inspired by, many others who have primed the study of the zebrafish to understand and search for a cure for disorders of the nervous system. Aware of the many advantages this vertebrate model holds, here we present an update on the recent zebrafish models available to study neurodegeneration with the goal of stimulating further interest and increasing the number of diseases and applications for which they can be exploited.We shall do so by citing and commenting on recent break-throughs made possible via zebrafish, highlighting their benefits for the testing of therapeutics and dissecting of disease mechanisms.

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Classification and Natural History of the Neuronal Ceroid Lipofuscinoses

Cited by 113 publications

References 41 publications

Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5

Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5

Progressive retinal degeneration and accumulation of autofluorescent lipopigments in Progranulin deficient mice

New Zebrafish Models of Neurodegeneration

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