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PubMed1999

Ovine ceroid lipofuscinosis (OCL6): postulated mechanism of neurodegeneration.

It is proposed that ceroid lipofuscinosis in Southhampshire sheep (OCLSouthhampshire) be also known as OCL6 as it is syntenic with CLN6 of humans. Histopathological studies show a severe and progressive neurodegeneration of the cerebral cortex which sometimes appears to have a laminar pattern and which is accompanied by a severe midcortical astrocytosis. Other studies have shown that fibroblasts maintained in tissue culture have abnormal regulation of ATP synthase. If this was reflected in neurons, then selective neuron death is likely to be the result of energy-linked excitotoxicity of neurons receiving abundant glutamate input. Increased sensitivity of the NMDA receptor due to inefficient repolarization of the neuron membrane would allow increased cellular uptake of calcium, increased formation of free radicals, and neuron death. The general hypothesis, as developed for other chronic neurodegenerative diseases, is partly based on application of various drugs that block or mediate parts of the pathway involved. The same approach could be used to help test the hypothesis in OCL6 lambs and if successful some of the drugs might have therapeutic potential. As patterns of neurodegeneration are similar in various other forms of ceroid lipofuscinosis accumulating subunit c of mitochondrial ATP synthase, the model may have more general application than merely to CLN6.

Age Factors↗
PubMed1989

Comparison of the clinical courses in patients with juvenile neuronal ceroid lipofuscinosis receiving antioxidant treatment and those without antioxidant treatment.

Juvenile neuronal ceroid-lipofuscinosis (JNCL) is a progressive encephalopathy characterized by a neural and extraneural accumulation of ceroid and lipofuscin like storage cytosomes and by an autosomal recessive inheritance. It begins with a gradual loss of vision at the age of 4-7 years and is accompanied by epilepsy, a loss of motor function, and a progressive dementia (Santavuori 1988). We have studied 26 Finnish JNCL patients treated with vitamins E, B2, B6 and sodium selenite (antioxidant treatment) by using a JNCL disease specific scoring system introduced by Kohlschütter et al. (1988). Scores were given for the problems of vision, intellect, language, motor function, as well as epilepsy, and compared with the data of 17 German JNCL patients not treated with antioxidants (Kohlschütter et al. 1988). Loss of vision began at the same time among the Finnish and the German JNCL patients. However, loss of intellectual, language, and motor functions and total blindness occurred later among the group of Finnish JNCL patients treated with antioxidants. Courses of the epileptic seizures were rather heterogenous and slightly favouring the Finnish patients. This study supports the theory that antioxidant treatment retards JNCL disease. The study design, however, contains many possible biases, so that the results must be interpreted cautiously.

Antioxidants↗
PubMed1985

Disease-specific electrophysiological findings in adult ceroid-lipofuscinosis (Kufs disease).

Two adults with mild dementia and a history of memory loss and disequilibrium were seen in the eye clinic following complaints of acuity loss in the 20/30-20/70 (Snellen) range. Results from the fundus examination of one patient were entirely normal; the other showed minimal vascular attenuation and optic atrophy. Electrophysiology was remarkable: (1) Photopic ERG b-waves were reduced, delayed, and showed pronounced oscillations. (2) EOG 'light-rise' potentials were absent or very small. (3) Binocular pattern-VER signals showed addition of the monocular signal. Scotopic ERG signals were normal. Brain biopsy and microscopy showed intercellular, autofluorescent ceroid deposits which provided a clear diagnosis of Kufs disease. Histology of model animal retinal cells show ceroid deposits in cell classes implicated by the human retinal signals. The cluster of electrophysiological results point toward early changes in the pigment epithelium and inner plexiform layer cells as a means of noninvasive diagnosis.

Adult↗
PubMed1990

Topographic heterogeneity of amyloid B-protein epitopes in brains with various forms of neuronal ceroid lipofuscinoses suggesting defective processing of amyloid precursor protein.

To verify our hypothesis of defective protease inhibitor domains that are encoded by abnormal processing of amyloid precursor protein (APP) in brains of patients with neuronal ceroid lipofuscinoses (NCL), immunohistochemical and cytochemical studies were performed with monoclonal antibodies (mAbs) directed against various domains of APP. For the studies, 22 autopsy brains were used: 12 with different forms of NCL, and 10 control brains. The staining procedure for the avidin-biotin complex (ABC) technique and the postembedding gold-labelled procedure for electron microscopy (EM) were employed. Of all mAbs used for the study, only mAbs generated against amyloid B-protein bound to neural tissue were affected with NCL. The strongest immunostaining of neurons and of some reactive glial cells was found in brains with the juvenile form of NCL. Only in the infantile form of the disease were some neurons overloaded with storage material weakly immunoreactive. In brains of patients with the adult form of NCL, immunoreactivity was found in affected neurons and in extracellularly deposited material of senile plaques. The results of EM study showed that the immunoreactivity was restricted to lysosomal cytosomes in neural tissue with any form of NCL selectively localized on the curvilinear and fingerprint proteinaceous component of ceroid lipofuscin. Studies performed on control aging brains and Alzheimer's disease (AD) brains confirmed previous observations of immunoreactivity being found diffusely in the protein component of some neurons containing lipopigment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Lectin histochemistry in brains with juvenile form of neuronal ceroid-lipofuscinosis (Batten disease).

Defective utilization of dolichols in the synthesis of glycoprotein leads to an accumulation of the storage, pigment "ceroid" lipofuscin, containing high-mannose-type glycoconjugates, in brains affected by neuronal ceroid-lipofuscinoses (NCL). We have employed lectin histochemistry to study the distribution of such compounds and the composition of other glycoconjugates in brains of patients with a juvenile form of the disease (JNCL). Concanavalin A detected the high-mannose glycoconjugates in all neurons of brains with JNCL, in lipofuscin-containing neurons of aging brains and in some neurons of age-matched control brains. Three other lectins (soybean agglutinin, Peanut agglutinin and Ulex europaeus agglutinin-I) recognized sugar moieties in neurons containing lipofuscin in patients only with JNCL and not in age-matched or aging brains. The results led to the conclusion, that the binding pattern of these three lectins may differentiate between storage materials of NCL and aging brains.

Adolescent↗
PubMed1977

So-called neuronal ceroid-lipofuscinosis. Histochemical study with evidence of extractibility of the stored material.

Histochemical study of so-called neuronal ceroid-lipofuscinoses (NCL) showed that the stored material is extractable in the unfixed state especially with alkalized or acidified chloroform-methanol mixtures when compared with other solvents. The extractability was strongly reduced or almost abolished by fixation with formaldehyde. Identical results were obtained with the type one storage material (see Elleder, 1977) in all late infantile cases and in a juvenile case studied, in which, contrary to the infantile form, the stored material displayed a significantly higher degree of extractability. As far as the extractability of the type two storage material is concerned insufficient data have been accumulated, but it seems that it does not differ significantly from the first one. In the control group of lipopigments ceroid was found to be much more extractable under identical conditions than matured lipofuscin which was almost entirely resistant to all extraction procedures. The significance of the results is discussed.

Adolescent↗
PubMed1995

Neuronal ceroid lipofuscinosis in the Polish Owczarek Nizinny (PON) dog. A retinal study.

Visual dysfunction and neurological symptoms were found in Polish Owczarek Nizinny (PON) dogs. Two dogs were examined, one at 2 years of age and the other one at 4 years. The oldest dog was totally blind. The 2-year-old dog developed mental disturbances and the 4-year-old dog became severely ataxic. Ophthalmoscopical findings were retinal hyper-reflectivity, attenuation of the retinal vessels and the presence of greyish to brown spots in the fundus. Electrophysiological and ultrastructural studies were performed in the 2-year-old dog. Scotopic ERG responses were absent, whereas 30 Hz cone flicker responses were recordable, although with an amplitude reduced to about 30% of the normal level. A slow negative potential replaced the c-wave, indicating a dysfunction of the RPE. Intracellular inclusions with a granular appearance or containing membranous fingerprint-like or curvilinear profiles, resembling ceroid, were found in different retinal cells. The RPE cells in the central areas were charged with autofluorescent material having similar structure, Photoreceptor degeneration was most severe in the central areas, corresponding to the RPE changes. It appears than the PON dog may provide a new animal model for neuronal ceroid lipofuscinosis.

Animals↗
PubMed1988

Electrophysiological findings of neuronal ceroid lipofuscinosis in heterozygotes.

Nineteen obligate heterozygotes, 8 individuals at risk of being heterozygote, and 10 patients afflicted with four different forms of neuronal ceroid lipofuscinosis were examined electrophysiologically. The group of obligate heterozygotes was compared to age-matched control groups. Statistically significant differences were found between scotopic b-wave amplitudes, P-ERG amplitudes, and EOG light peaks of the obligate carriers of the juvenile type and the control subjects. The photopic L-ERGs and the latencies of the VEPs were mostly within the normal range. The findings represent the first evidence of functional ophthalmological changes in obligate carriers of neuronal ceroid lipofuscinosis and demonstrate that heterozygotes with certain hereditary autosomal recessive diseases may manifest subtle functional signs.

Adolescent↗
PubMed2007

[Adult-onset neuronal ceroid lipofuscinosis].

Neuronal ceroid lipofuscinoses are a heterogenous group of genetic progressive neurodegenerative disorders. Curative therapeutic strategies are not known. These are largely diseases of childhood; adult-onset forms are rare and poorly characterized. The classical adult variant is CLN4 (Kufs' disease), in which autosomal-recessive and autosomal dominant forms are known. Furthermore the "classic infantile" CLN1, caused by a deficiency of the enzyme palmitoylprotein-thioesterase, may be of adult onset Neuronal ceroid lipofuscinoses in adulthood are multifaceted diseases. Their clinical picture is mainly characterized by progressive dementia, seizures, and extrapyramidal motor symptoms. In contrast to the infantile forms, visual loss is an uncommon feature that appears only in adult CLN1 but not CLN4, which may be helpful in clinical differential diagnosis.

Adult↗
PubMed1999

Characterization and chromosomal mapping of a mouse ortholog of the late-infantile ceroid-lipofuscinosis gene CLN2.

Late-infantile ceroid-lipofuscinosis (CLN2) is an autosomal recessively inherited, neurodegenerative disease in humans. The CLN2 locus has been mapped to Chromosome (Chr) 11p15, and its sequence and genomic organization have recently been reported. In the present study, the cDNA sequence, exon/intron organization, and chromosomal localization of a mouse ortholog of the CLN2 gene are described. The mouse cDNA contains an open reading frame that predicts a protein product of 562 amino acids. The mouse and human coding regions are 86% and 88% identical at the nucleic acid and amino acid levels, respectively. One less codon appears in the mouse cDNA when compared with the human ortholog. The mouse gene (Cln2) spans more than 6 kb and consists of 13 exons separated by introns ranging in size from 111 to 1259 bp. Length polymorphism in an (AC)(n) microsatellite in intron 3 of the mouse Cln2 gene was used to perform segregation analysis with The Jackson Laboratory DNA Panel Mapping Resource. On the basis of this analysis, the Cln2 gene was localized to a region of mouse Chr 7 that corresponds to human Chr 11p15. Characterization of the mouse Cln2 gene will facilitate generation of a mouse model for late-infantile ceroid-lipofuscinosis by gene targeting and identification of functionally important regions of the Cln2 protein.

Amino Acid Sequence↗
PubMed2001

Distribution and development of CLN2 protein, the late-infantile neuronal ceroid lipofuscinosis gene product.

Expression of the late-infantile neuronal ceroid lipofuscinosis (LINCL) gene (CLN2) protein was investigated by immunoblotting and immunohistochemistry in human brains and visceral organs of control individuals and of patients with neuronal ceroid lipofuscinosis (NCL). Immunoblotting analyses showed reactivity in the cerebrum, liver, kidney, heart and colon of controls, whereas CLN2 protein was not detected in these organs in a LINCL patient. Immunohistochemistry showed that the reactivity of the protein was ubiquitous in extracerebral organs as well as within the CNS, apparently corresponding to widely distributed deposition of lipopigments in LINCL. The expression of CLN2 protein in the cerebral cortex increased with development, and reached adult level after the age of 2. This development of expression seemed to be related to the onset of LINCL at 2-4 years of age. We confirmed no immunoreactivity in two of three patients with LINCL, who were diagnosed clinicopathologically. One case showing combined ultrastructural morphology of fingerprint profiles and curvilinear bodies had intermediate reactivity, suggesting heterogeneity in clinical LINCL. Evaluation of the immunoreactivity of the CLN2 protein may be useful for characterization of a variant form.

Adolescent↗
PubMed1981

Superoxide dismutase, catalase and glutathione peroxidase in infantile, late infantile and juvenile neuronal ceroid-lipofuscinosis.

The neuronal ceroid-lipofuscinoses are characterized by a widespread deposit in the body of pigments believed to be end products of lipid peroxidation damaged organelles. CuZn superoxide dismutase, Mn superoxide dismutase, catalase and glutathione peroxidase, enzymes which conceivably might protect against lipid peroxidation, were investigated in blood cells from patients afflicted with infantile, late infantile and juvenile neuronal ceroid-lipofuscinosis. In some cases the enzymic activities were slightly lower than the activities of the controls, but no deficiencies which might be of etiolgical importance were revealed.

Adolescent↗
PubMed1981

Urinary levels of blood group A trisaccharide: observations in two siblings with neuronal ceroid lipofuscinosis.

A readily detectable carbohydrate in the urine of two siblings with neuronal ceroid lipofuscinosis was found to be the blood group A trisaccharide. One child expired before blood typing was done while the other sibling was AB. This latter child excreted greater amounts of the trisaccharide than a group of blood type A subjects with different diagnoses when all the subjects were receiving whole or skim milk by nasogastric feedings. While the relevance of this observation to neuronal ceroid lipofuscinosis is unknown, it has been shown that the trisaccharide may be a major urinary carbohydrate depending on diet and blood type.

ABO Blood-Group System↗
PubMed1990

Proteinase inhibitor alpha 1-antichymotrypsin has different expression in various forms of neuronal ceroid lipofuscinosis.

Defective proteolytic degradation is most widely maintained as the major pathogenetic factor in neuronal ceroid lipofuscinosis (NCL). The goal of the present study was to examine the expression in NCL brain tissue of one of the serine proteinase inhibitors, alpha 1-antichymotrypsin. Our study was based on previous findings of alpha 1-antichymotrypsin association with CNS amyloidoses related to amyloid beta protein deposits and our previous findings suggesting abnormal processing of amyloid beta-protein precursor (ABPP) in NCL brains. Immunocytochemical study was performed on formalin-fixed brain tissues collected from 15 NCL cases representing four different forms of the disorder and from 16 control cases comprising age-matched controls, older nondemented individuals, and Alzheimer disease cases. Our present study has shown that the expression of alpha 1-antichymotrypsin is generally higher in NCL cases than in control cases; however, it manifests in distinct variations of intensity and proportions of immunostained cells. The strongest immunoreactivity was found in the infantile form of NCL, which is characterized by a rapid clinical course and widespread tissue damage. We found no evidence of direct involvement of alpha 1-antichymotrypsin in either the ceroid lipopigment accumulation or the abnormal processing of ABPP in NCL. However, our findings may reflect the heterogeneity of the pathomechanism underlying this group of disorders and suggest that, similarly to blood circulation, alpha 1-antichymotrypsin can also represent an acute-phase protein in brain tissue.

Astrocytes↗
PubMed1993

Storage of saposins A and D in infantile neuronal ceroid-lipofuscinosis.

We have isolated storage cytosomes from brain tissue of patients with infantile neuronal ceroid-lipofuscinosis. The purified storage bodies were subjected to compositional analysis which revealed a high content of proteins, accounting for 43% of dry weight. Saposins A and D, also known as sphingolipid activator proteins (SAPs), were shown to constitute a major portion of the accumulated protein using gel electrophoresis and sequence analysis. This is the first time that saposins have been found to be stored in any form of neuronal ceroid-lipofuscinosis.

Adolescent↗
PubMed1986

Enrichment of high mannose-type glycans in nervous tissue glycoproteins in neuronal ceroid-lipofuscinosis.

In view of the hypothesis that a biochemical abnormality in the childhood forms of neuronal ceroid-lipofuscinosis may lie in the utilization of dolichols in glycoprotein synthesis, we analyzed the oligosaccharide structures of brain glycoproteins in infantile neuronal ceroid-lipofuscinosis (INCL). Lectin affinity chromatography of purified glycopeptides and of oligosaccharides prepared by hydrazinolysis showed an increase in high mannose-type glycopeptides and a decrease in tri- and tetra-antennary glycopeptides in INCL brain when compared with control brain. These changes were more pronounced in the storage cytosomes than in whole brain. Methylation analysis of the isolated glycopeptide fractions did not reveal differences in substitution patterns of the individual sugar residues between INCL and control brain. In INCL the core disaccharide of the O-glycosidically-linked oligosaccharides was sialylated to a higher degree than in control brain indicating that the structural changes were not confined only to N-glycosidically-linked carbohydrate chains. The observed structural changes in the carbohydrate chains of brain glycopeptides in INCL could be explained by a defect in the biosynthesis of glycoproteins. Alternatively, the changes may reflect the increased glial cell population in the degenerating brain. In fact, the elution profiles in lectin chromatography of oligosaccharides prepared from cultured rat glioma cells resembled those from INCL brain.

Adolescent↗
PubMed1979

On the ultrastructural diversity and essence of residual bodies in neuronal ceroid-lipofuscinosis.

In 4 patients with neuronal ceroid-lipofuscinoses (NCL) (3 patients with the junvenile type, 1 patient with the late infantile type), the ultrastructural spectrum of residual bodies in the central and peripheral nervous system presented curvilinear profiles in all cases and regions investigated and many more ultrastructural patterns within and beyond regions commonly accessible to biopsy, probably due to age dependence, local tissue and cellular biochemical factors. Sampling from basal ganglia especially yielded combined curvilinear-fingerpint bodies, from peripheral ganglia additional membranous bodies. Residual bodies in NCL were present in almost every cell type, similar to the distribution of regular lipofuscin. Although the classical subgroups of NCL contain electronmicroscopically well defined residual bodies, permitting distinction of the late infantile type from the juvenile type, the ultrastructural differences are more of a quantitative than of a qualitative nature. However, they are not pathognomonic. N.m.r. spectra of ceroid and lipofuscin support the concept of their biochemical similarity, and argue against the proposition that they contain a single major component.

Brain↗
PubMed1990

Storage protein in hereditary ceroid-lipofuscinosis contains S-methylated methionine.

Hereditary ceroid-lipofuscinoses are neurodegenerative disorders characterized by the accumulation in numerous tissues of a storage material with lipofuscin-like fluorescence properties. Investigations were undertaken to determine the chemical nature of this storage material isolated from the cerebral cortex of human subjects with the late infantile form of the disease. The storage material was mainly protein that consisted of a mixture of polypeptides ranging in apparent molecular weight from 13 to 67 kDa. Protein-bound fluorophores apparently were largely responsible for the autofluorescence of the storage bodies. The disease-related storage body protein was rich in S-methylmethionine [(3-amino-3-carboxypropyl) dimethyl sulfonium ion], an amino acid that does not normally occur in animal proteins. Methylation of proteins to form this unusual charged amino acid may impair proteolytic degradation or other aspects of protein metabolism, and account for the accumulation of protein-filled inclusions in cells of individuals with ceroid-lipofuscinoses. Similar amino acid modifications that block proteolysis could be involved in age pigment accumulation.

Amino Acids↗