Variant late infantile ceroid lipofuscinoses associated with novel mutations in CLN6

In all patients, multifocal myoclonic jerks and seizures were a key feature, but myoclonic seizures were an early and prominent sign in the teenage/adult form only. Conversely, the childhood-onset form was characterized by initial and severe cognitive impairment coupled with electroretinogram and EEG attenuation. Cortical hyperexcitability, shown by the PPR and enlarged somatosensory evoked potentials, was a universal feature.

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“…The mutations have been previously described, 5,10,11 with the exception of a novel mutation in patient 7.…”

Section: Resultsmentioning

confidence: 98%

Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations

et al. 2015

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“…This insertion results in a frameshift followed by 25 novel amino acids and a premature stop codon [11]. Human mutations in CLN6 have been found in seven different exons, all resulting in similar pathological features [16] – providing no pattern in severity of disease symptoms and age of onset making it difficult to pinpoint domains that are critical for proper protein function [8], [10], [13], [15], [16], [69]. Access to these reliable, well validated animal models of vLINCL will allow scientists to better understand both the genotype/phenotype relationship of these mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, not all NCL animal models exhibit the same degree of retinal degeneration and visual loss, indicating that some compensation may be made at different levels, with convergent pathways that eventually result in neuronal loss [76]. This is further evident in NCL patients, since not all patients display the same levels of degeneration [8], [10], [13], [15], [16], [69].…”

Section: Discussionmentioning

confidence: 99%

“…The most common mutation in CLN6, which leads to vLINCL, results from the insertion of an additional cytosine at base pair 307 in exon 4, leading to a frameshift and premature stop codon. vLINCL disease onset occurs between 18 months and eight years of age, with symptoms of motor delay, vision loss, dystharthia, and ataxia followed by premature death during the second decade of life [16], [17].…”

Section: Introductionmentioning

confidence: 99%

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A Murine Model of Variant Late Infantile Ceroid Lipofuscinosis Recapitulates Behavioral and Pathological Phenotypes of Human Disease

et al. 2013

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Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6nclf) mouse line to validate its utility for translational research. We demonstrate that this Cln6nclf mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6nclf mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics.

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“…It is now recognized that mutations in all genes are distributed across many countries, albeit with higher incidence in some ethnic groups due to founder effects. Among the many recognized variants of NCL human forms (recent reviews in [3,6,11]), eight causal genes have been identified: CLN10/CTSD [12][13][14], CLN1/PPT1 [3,6,[15][16][17][18], CLN2/TPP1 [6,[18][19][20][21], CLN3 [22][23][24][25], CLN5 [26][27][28][29][30], CLN6 [31][32][33][34], CLN7/ MFSD8 [35][36][37][38][39], CLN8 [40][41][42]. The genes CLCN6 [43], and CLCN7 [44], and possibly SGSH [45], may also contribute to rare forms of NCL.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

Kohan¹,

Cismondi²,

Oller-Ramírez³

et al. 2011

CPB

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The Neuronal Ceroid Lipofuscinoses (NCLs) are lysosomal storage diseases (LSDs) affecting the central nervous system (CNS), with generally with recessive inheritance. They are characterized by pathological lipofuscin-like material accumulating in cells. The clinical phenotypes at all onset ages show progressive loss of vision, decreasing cognitive and motor skills, epileptic seizures and premature death, with dementia without visual loss prominent in the rarer adult forms. Eight causal genes, CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, CLN8, with more than 269 mutations and 49 polymorphisms (http://www.ucl.ac.uk/ncl) have been described. Other NCL genes are hypothesized, including CLN4 and CLN9; CLCN6, CLCN7 and possibly SGSH are under study. Some therapeutic strategies applied to other LSDs with significant systemic involvement would not be effective in NCLs due to the necessity of passing the blood brain barrier to prevent the neurodegeneration, repair or restore the CNS functionality. There are therapies for the NCLs currently at preclinical stages and under phase 1 trials to establish safety in affected children. These approaches involve enzyme replacement, gene therapy, neural stem cell replacement, immune therapy and other pharmacological approaches. In the next decade, progress in the understanding of the natural history and the biochemical and molecular cascade of events relevant to the pathogenesis of these diseases in humans and animal models will be required to achieve significant therapeutic advances.

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Variant late infantile ceroid lipofuscinoses associated with novel mutations in CLN6

Cited by 43 publications

References 18 publications

Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations

Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations

A Murine Model of Variant Late Infantile Ceroid Lipofuscinosis Recapitulates Behavioral and Pathological Phenotypes of Human Disease

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

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