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PubMed1989

Analysis of dolichyl pyrophosphoryl oligosaccharides in purified storage cytosomes from ovine ceroid-lipofuscinosis.

Ovine ceroid-lipofuscinosis is an inherited neurodegenerative disorder characterised by the accumulation of storage cytosomes in brain and visceral organs. Phosphorylated dolichol-containing compounds, largely in the form of dolichyl pyrophosphoryl oligosaccharides, have been shown to constitute 1-2% of the dry weight of storage cytosomes isolated from brain and pancreas, and 0.5 and 0.1% respectively of storage cytosomes isolated from liver and kidney. The carbohydrate portion of these glyconjugates in storage cytosomes isolated from brain, pancreas and liver consisted of a series of oligosaccharides of composition Man2-9GlcNAc2, with Man5-8GlcNAc2 predominating. The concentrations of dolichyl pyrophosphoryl oligosaccharides in storage cytosomes from ovine ceroid-lipofuscinosis are much higher than has been reported for endoplasmic reticulum, their normal functional location.

Animals↗
PubMed1990

Batten disease (Spielmeyer-Vogt disease, juvenile onset neuronal ceroid-lipofuscinosis) gene (CLN3) maps to human chromosome 16.

The ceroid-lipofuscinoses are a group of inherited neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in neurons and other cell types. The underlying biochemical defect is unknown. Batten disease (Spielmeyer-Vogt disease, juvenile onset neuronal ceroid-lipofuscinosis) displays autosomal recessive inheritance. Genetic linkage studies were undertaken to determine the chromosomal location of the Batten disease mutation (CLN3). Following identification of linkage to the haptoglobin locus, linkage analysis has been carried out in 42 families by using DNA markers for loci on the long arm of human chromosome 16. The maximal lod score between Batten disease and the locus D16S148 calculated for combined sexes is 6.05 at a recombination fraction theta = 0.00. Multilocus analysis using five loci indicated the most likely order to be HP-D16S151-D16S150-CLN3-D16S148-D16S147. The maximal location score for CLN3 was 48 (equivalent to a lod score of 10.4) in that interval within this fixed marker map.

Chromosome Mapping↗
PubMed1990

Infantile neuronal ceroid-lipofuscinosis is not an allelic form of Batten disease: exclusion of chromosome 16 region with linkage analyses.

Infantile neuronal ceroid-lipofuscinosis (CLN1) is the form of neuronal ceroid-lipofuscinoses (NCL) with the earliest onset of symptoms. The locus of the most common form of these disorders, juvenile NCL (CLN3), has been mapped to chromosome 16. We report here linkage data of the same region in Finnish CLN1 families. Our results indicate that CLN1 is not allelic with CLN3 but represents a different locus, which is not located within about 70 cM in chromosome 16.

Alleles↗
PubMed1991

Infantile neuronal ceroid lipofuscinosis (CLN1): linkage disequilibrium in the Finnish population and evidence that variant late infantile form (variant CLN2) represents a nonallelic locus.

Two forms of neuronal ceroid lipofuscinosis (CLN) are enriched in the Finnish population: the infantile form (CLN1), which is the most common progressive encephalopathy of small children, and the variant late infantile form (variant CLN2), which is a rare, atypical form of neuronal ceroid lipofuscinosis. We recently established the linkage of the infantile form (CLN1) to the short arm of chromosome 1 close to the anchor marker D1S7. Here we demonstrate a linkage disequilibrium of CLN1 chromosomes using the two closest markers, DIS62 and L-MYC at the short arm of chromosome 1 (P less than 0.0025). The results of linkage analyses in Finnish variant CLN2 families using the markers linked to CLN1 revealed an exclusion; i.e., this form of CLN is caused by a locus different from that of CLN1. This finding was confirmed with the result of the M-test for heterogeneity. The genealogical data collected further support the molecular genetic findings and provide evidence that the mutation causing CLN1 in Finland is very old, whereas the mutation causing the variant CLN2 could be a result of a younger, i.e., more recent founder effect.

Alleles↗
PubMed2006

Functional biology of the neuronal ceroid lipofuscinoses (NCL) proteins.

Neuronal ceroid lipofucinoses (NCLs) are a group of severe neurodegenerative disorders characterized by accumulation of autofluorescent ceroid lipopigment in patients' cells. The different forms of NCL share many similar pathological features but result from mutations in different genes. The genes affected in NCLs encode both soluble and transmembrane proteins and are localized to ER or to the endosomes/lysosomes. Due to selective vulnerability of the central nervous system in the NCL disorders, the corresponding proteins are proposed to have important, tissue specific roles in the brain. The pathological similarities of the different NCLs have led not only to the grouping of these disorders but also to suggestion that the NCL proteins function in the same biological pathway. Despite extensive research, including the development of several model organisms for NCLs and establishment of high-throughput techniques, the precise biological function of many of the NCL proteins has remained elusive. The aim of this review is to summarize the current knowledge of the functions, or proposed functions, of the different NCL proteins.

Aminopeptidases↗
PubMed2005

Behavioral assessment in mouse models of neuronal ceroid lipofuscinosis using a light-cued T-maze.

Learning impairment is a common feature of the neuronal ceroid lipofuscinoses (NCL), a family of lysosomal storage disorders associated with progressive neurodegeneration. Murine models for the neuronal ceroid lipofuscinoses include the well-characterized motor neuron degeneration (mnd/mnd) model for one variant of late infantile NCL (CLN8), and the more recently generated models for the infantile (CLN1) and juvenile (CLN3) forms of NCL. To determine whether these mouse models exhibit behavioral deficits analogous to the learning impairment characteristic of the human disorders, the performance of these animals on an associative learning task was assessed. The abilities of affected and normal control mice to associate a light stimulus with a food reward were evaluated in 14-16-week-old animals using a T-maze. Normal mice were able to reach a criterion for having learned to make the association within a mean of 9.4 trials. The CLN8 and CLN3 mice, on the other hand, required means of 26.2 and 27.5 trials, respectively, to reach the same performance criterion (p<0.05), whereas none of the CLN1 mice were able to reach the criterion within a limit of 30 trials. The poor performance of the mutant mice did not appear to result from impaired retinal function; mice of all three strains exhibited retinal electrophysiological responses to dim light flashes and displayed robust pupillary light reflexes. Associative learning deficits appear to be an early disease phenotype in the NCL mouse models that will be useful for assessing the efficacy of therapeutic interventions such as gene or stem cell therapies.

Analysis of Variance↗
PubMed2005

Progressively reduced synaptic vesicle pool size in cultured neurons derived from neuronal ceroid lipofuscinosis-1 knockout mice.

The neuronal ceroid lipofuscinoses are a newly-recognized group of lysosomal storage disorders in which neurodegeneration predominates. The pathophysiological basis for this is unknown. In the current paper, we sought to determine whether neurons that lack the enzyme responsible for the infantile form of neuronal ceroid lipofuscinosis (INCL) display abnormalities in culture that could be related to the clinical disorder. Electrophysiological and fluorescent dye studies were performed using cortical neuronal cultures established from postnatal day 2 palmitoyl-protein thioesterase-1 (Ppt1) knockout mice. We found a 30% reduction in synaptic vesicle number per bouton that was progressive with time in culture as well as an elevation in lysosomal pH, whereas a number of passive and active membrane properties of the neurons were normal. The reduction in vesicle pool size was also reflected in a decrease in the frequency of miniature synaptic currents. The progressive and gradual decline in vesicle numbers and miniature event frequency we observed here may be an early indicator of synapse degeneration, in keeping with observations during competitive stimulation at the neuromuscular junction or age-related synapse elimination recently reported by others. PPT1 did not colocalize with synaptic vesicle or synapse markers, suggesting that lysosomal dysfunction leads indirectly to the synaptic abnormalities. We conclude that from an early age, neurons deficient in PPT1 enzyme activity display intrinsically abnormal properties that could potentially explain key features of the clinical disease, such as myoclonus and seizures.

Animals↗
PubMed2005

CNS-directed AAV2-mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis.

The neuronal ceroid lipofuscinoses (Batten disease) are a group of inherited neurodegenerative diseases characterized by the progressive intralysosomal accumulation of autofluorescent material in many cells, visual defects, seizures, cognitive deficits, and premature death. Infantile neuronal ceroid lipofuscinosis (INCL) has the earliest onset ( approximately 1.5 years of age) and is caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). Currently there is no effective treatment for children with INCL. In this study, newborn PPT1-deficient mice received two (cortex), four (cortex and hippocampus), or six (cortex, hippocampus, and cerebellum) bilateral intracranial injections of AAV2-PPT1. The AAV-treated animals had localized increases in PPT1 activity, decreased autofluorescent material, improved histologic parameters, and increased brain mass. In addition, the treated animals had dose-dependent improvements in a battery of behavioral tests and improved interictal electroencephalographic tracings. However, there was neither a significant decrease in seizure frequency nor an increase in longevity even in INCL animals receiving six injections. These data suggest that early treatment of INCL using gene transfer techniques can be efficacious. However, higher levels or a broader distribution of PPT1 expression, or both, will be required for more complete correction of this neurodegenerative disease.

Animals↗
PubMed1984

Suction biopsy of rectal mucosa in the diagnosis of infantile and juvenile types of neuronal ceroid lipofuscinoses.

Rectal mucosa obtained by suction biopsy from 17 patients with infantile-type neuronal ceroid lipofuscinosis (NCL) and from 31 patients with juvenile-type NCL was studied histologically and electron microscopically. In specimens from both types of NCL the lamina propria of the mucosa contained abundant large macrophages, demonstrating positive histochemical reactions for ceroid and lipofuscin. On electron microscopy the macrophages were shown to be filled with cytosomes containing the storage material. In infantile NCL the storage material was amorphous and granular, with only occasional short membranous structures. In juvenile NCL the storage material formed approximately equal amounts of curvilinear profiles and fingerprint profiles. Typical inclusions were found in the capillary endothelial cells, Schwann cells, and smooth cells as well as in macrophages in both types of NCL. In two patients juvenile NCL was diagnosed from the biopsy before the appearance of any neurologic symptoms. It is concluded that morphologic investigation of the easily obtained rectal suction biopsy specimen is a reliable diagnostic method in these types of NCL. It is also useful in screening non-symptomatic patients at risk for NCL and in follow-up studies, when necessary.

Age Factors↗
PubMed2001

Neuronal ceroid lipofuscinoses: classification and diagnosis.

The neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative disorders characterized by accumulation of ceroid lipopigment in lysosomes in various tissues and organs. The childhood forms of the NCLs represent the most common neurogenetic disorders of childhood and are inherited in an autosomal-recessive mode. The adult form of NCL is rare and shows either an autosomal-recessive or autosomal dominant mode of inheritance. Currently, five genes associated with various childhood forms of NCLs, designated CLN1, CLN2, CLN3, CLN5, and CLN8, have been isolated and characterized. Two of these genes, CLN1 and CLN2, encode lysosomal enzymes: palmitoyl protein thioesterase 1 (PPT1) and tripetidyl peptidase 1 (TPP1), respectively. CLN3, CLN5, and CLN8 encode proteins of predicted transmembrane topology, whose function has not been characterized yet. Two other genes, CLN6 and CLN7, have been assigned recently to small chromosomal regions. Gene(s) associated with the adult form of NCLs (CLN4) are at present unknown. This study summarizes the current classification and new diagnostic criteria of NCLs based on clinicopathological, biochemical, and molecular genetic data. Material includes 159 probands with NCL (37 CLNI, 72 classical CLN2, 10 variant LINCL, and 40 CLN3) collected at the New York State Institute for Basic Research in Developmental Disabilities (IBR) as well as a comprehensive review of the literature. The results of our study indicate that although only biochemical and molecular genetic studies allow for definitive diagnosis, ultrastructural studies of the biopsy material are still very useful. Thus, although treatments for NCLs are not available at present, the diagnosis has become better defined.

Adolescent↗
PubMed2001

Cellular pathology and pathogenic aspects of neuronal ceroid lipofuscinoses.

Lysosomal accumulation of autofluorescent, ceroid lipopigment material in various tissues and organs is a common feature of the neuronal ceroid lipofuscinoses (NCLs). However, recent clinicopathologic and genetic studies have evidenced that NCLs encompass a group of highly heterogeneous disorders. In five of the eight NCL variants distinguished at present, genes associated with the disease process have been isolated and characterized (CLN1, CLN2, CLN3, CLN5, CLN8). Only products of two of these genes, CLN 1 and CLN2, have structural and functional properties of lysosomal enzymes. Nevertheless, according to the nature of the material accumulated in the lysosomes, NCLs in humans as well as natural animal models of these disorders can be divided into two major groups: those characterized by the prominent storage of saposins A and D, and those showing the predominance of subunit c of mitochondrial ATP synthase accumulation. Thus, taking into account the chemical character of the major component of the storage material, NCLs can be classified currently as proteinoses. Of importance, although lysosomal storage material accumulates in NCL subjects in various organs, only brain tissue shows severe dysfunction and cell death, another common feature of the NCL disease process. However, the relation between the genetic defects associated with the NCL forms, the accumulation of storage material, and tissue damage is still unknown. This chapter introduces the reader to the complex pathogenesis of NCLs and summarizes our current knowledge of the potential consequences of the genetic defects of NCL-associated proteins on the biology of the cell.

Adolescent↗
PubMed1987

Early infantile form of neuronal ceroid lipofuscinosis. Four Dutch cases and review of the literature.

In this paper four Dutch cases of early infantile neuronal ceroid lipofuscinosis (NCL) are described, all being boys. NCL is a group of diseases morphologically characterized by accumulation of autofluorescent ceroid lipofuscin-like pigment. Psychomotor deterioration, impairment of vision, and epileptic manifestations are the major clinical features. Onset in early infantile age is rare. We reviewed 71 cases reported in the literature, and compared the symptoms and signs with the findings in our patients. Psychomotor deterioration, visual impairment and myoclonic jerks are often observed early in the disease. Eventually, every patient shows psychomotor deterioration. The outcome is always lethal, usually within a few years. Special attention is paid to diagnostic procedures.

Child↗
PubMed1982

Ultrastructure and visceral distribution of lipopigments in infantile neuronal ceroid-lipofuscinosis.

After an uneventful psychomotor development, a Jordanian boy developed increasing blindness, deafness, myoclonic jerks, tetraspasticity and dementia beginning at the age of 8 months and finally resulting in coma during which he died at the age of 3 years and 4 months. Two of his older siblings had possibly suffered from the same disease, but one of them had died in the Near East without adequate diagnosis. Autopsy revealed infantile neuronal ceroid-lipofuscinosis (NCL). Lipopigments showing typical autofluorescence and PAS staining granules were abundant in the markedly atrophic brain and numerous visceral organs, especially in cells of the reticulo-endothelial system, intestinal tunica propria, the bone marrow and hepatic von Kupffer cells. Ubiquitous accumulation of these NCL-typical lipopigments were found in adventitial mesenchymal cells of small vessels, particularly in lungs, liver and lymphatic organs. Lipopigments had accreted to a lesser degree in podocytes of renal glomerula and Sertoli cells, and in striated muscle fibers only around nuclei. Lymphocytes, smooth muscle cells and stratified epithelial cells did not contain lipopigments. The ultrastructure of the membrane-surrounded osmiophilic cytosomes consisted predominantly of finely granular lipofuscin although short membranous profiles were occasionally embedded within this granular matrix. These morphological findings emphasize the diagnostic importance of lymph node, rectal and bone marrow biopsies and, to a lesser degree, of liver biopsy in infantile neuronal ceroid-lipofuscinosis. The nosology of infantile NCL, independent of the ethnic background, was further clarified by our studies on ultrastructure and visceral distribution of these lipopigments. Morphological damage to parenchymal cells of visceral organs, contrary to the widespread loss of cortical neurons in the brain could not be demonstrated.

Bone Marrow↗
PubMed1988

Neuronal ceroid-lipofuscinoses in childhood.

Neuronal Childhood types of ceroid-lipofuscinoses (NCL) are reviewed. All three main types, infantile, late infantile and juvenile, are progressive encephalopathies characterized by neural and extraneural accumulation of ceroid- and lipofuscin like storage cytosomes. The pathogenesis of NCL is unknown. A disturbance of the peroxidation of polyunsaturated fatty acids and a defect in the processing and turn-over of the glycoproteins in the lysosomal membrane are those hypotheses which have been most widely investigated. Reduced membrane lipids and reduced membrane fluidity have recently been detected. Prenatal diagnosis, based on the characteristic ultrastructural findings, is possible in all types.

Brain↗
PubMed1998

Photoparoxysmal response in late infantile neuronal ceroid-lipofuscinosis.

A patient presented with rapid developmental regression whose MRI findings suggested a leukodystrophy, but nerve, muscle, skin, and bone marrow biopsies were unrevealing. A characteristic photoparoxysmal response on electroencephalogram provided an important clue for the correct diagnosis of late infantile neuronal ceroid-lipofuscinosis, which was confirmed later with electron microscope examination of a brain biopsy. In patients with rapid neurologic deterioration, diagnosis of neuronal ceroid-lipofuscinosis should be considered and an electroencephalogram should be performed using photic stimulation to look for characteristic findings.

Biopsy↗
PubMed2004

Neuronal ceroid lipofuscinosis: a clinicopathological study.

We report the clinical, electrophysiological, radiological and morphological features in a series of 12 patients of histopathologically confirmed cases (infantile, juvenile and adult onset) of neuronal ceroid lipofuscinosis (NCL) observed from 1979 to 1998 at National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore (South India). The commonest type of NCL was juvenile (n = 8, 67%) while infantile and adult forms were two each (n = 2, 16.8%). The age at presentation ranged from 2 to 45 years (mean--12.6, 14.3 years; median--7 years; M:F ratio of 2:1). Four patients (33%) had positive family history and five patients had history of consanguineous parentage (41.6%). The commonest presenting symptoms were regression of milestones (83.3%) and/or seizures, myoclonus (83.8%) followed by involuntary choreiform movements (50%), visual loss (41.6%), ataxia (33.3%) and abnormal behaviour (16.6%). Neuro-ophthalmological abnormalities like optic atrophy (50%), macular degeneration (33.3%) and retinitis pigmentosa (8.3%) were seen in two thirds. Nerve conduction studies (n = 4) revealed abnormalities in two, suggestive of sensorimotor neuropathy. Scalp EEG (n = 9) showed slowing of background activity (BGA) of varying degrees with paroxysmal bursts of seizure discharges in majority. Cranial CT scan (n = 4) revealed varying degrees of diffuse atrophy. Diagnostic brain biopsy was carried out in 11 and brain was examined at autopsy in 1 case. Histological examination revealed characteristic PAS and Luxol Fast Blue (LFB) positive, autofluorescent (AF) intracellular ceroid material, both in neurons and astrocytes in the grey matter. Electron microscopy (n = 5) revealed curvilinear (n = 4), lamellar (n = 2) and electron dense (n = 2) inclusions in neurons, astrocytes and vascular endothelial cells. To conclude, this neurodegenerative disease had varied but characteristic clinical presentations and required histopathological confirmation of diagnosis.

Adolescent↗
PubMed1999

The neuronal ceroid-lipofuscinoses (Batten disease): a new class of lysosomal storage diseases.

The neuronal ceroid-lipofuscinoses (Batten disease) are a group of severe neurodegenerative disorders characterized clinically by visual loss, seizures and psychomotor degeneration, and pathologically by loss of neurons and lysosomal accumulation of autofluorescent storage material resembling ageing pigment. To date, eight genetic loci have been identified (CLN1-8). Four CLN genes have been isolated (CLN1, CLN2, CLN3 and CLN5) and their gene products have been characterized. CLN1 is a lysosomal palmitoyl-protein thioesterase (PPT) and CLN2 is a lysosomal pepstatin-insensitive peptidase. CLN3 and CLN5 are proteins with multiple membrane-spanning regions and have no homologies to other proteins that would suggest their function. The CLN3 protein is associated with lysosomal membranes and the intracellular location of the CLN5 protein is unknown. Therefore, there is ample evidence that the neuronal ceroid-lipofuscinoses represent a new class of lysosomal storage disorders.

Animals↗
PubMed1998

CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis.

The neuronal ceroid lipofuscinoses (NCLs) represent a group of common recessive inherited neurodegenerative disorders of childhood, with an incidence of 1:12,500 live births. They are characterized by accumulation of autofluorescent lipopigments in various tissues. Several forms of NCLs have been identified, based on age at onset, progression of disease, neurophysiological and histopathological findings and separate genetic loci. All types of NCL cause progressive visual and mental decline, motor disturbance, epilepsy and behavioral changes, and lead to premature death. One of the subtypes, Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCL; MIM256731) affects children at 4-7 years of age. The first symptom is motor clumsiness, followed by progressive visual failure, mental and motor deterioration and later by myoclonia and seizures. We have previously reported linkage for vLINCL on chromosome 13 (ref. 5) and constructed a long-range physical map over the region. Here, we report the positional cloning of a novel gene, CLN5, underlying this severe neurological disorder. The gene encodes a putative transmembrane protein which shows no homology to previously reported proteins. Sequence analysis of DNA samples from patients with three different haplotypes revealed three mutations; one deletion, one nonsense and one missense mutation, suggesting that mutations in this gene are responsible for vLINCL.

Amino Acid Sequence↗