Neuronal ceroid lipofuscinoses : research update. (2001 Feb)
neuronal ceroid lipofuscinoses : research update . This study describes the phenotype / genotype analysis of 159 probands with neuronal ceroid lipofuscinosis ( 37 CLN1 , 72 classic CLN2 , 10 variant lincl , and 40 CLN3 ) collected at the New York state institute for basic research in developmental disabilities ( IBR ) . phenotype / genotype comparison showed that mutations in the CLN1 gene were associated with different phenotypes : infantile , late infantile , and juvenile . Two common mutations ( 223A C and 451C T ) were found in 26 of 37 CLN1 subjects ( 64 of alleles examined ) . A nonsense point mutation , 451C T , was the most common in CLN1 subjects with infantile onset at 0 2 years , accounting for 50 of alleles studied . A missense point mutation , 223A C , was the most common among CLN1 subjects with juvenile onset older than 4 years , accounting for 45 of alleles examined . twenty one other CLN1 mutations were identified in 4 of 37 subjects with infantile onset , 6 of 37 with late infantile onset , and 6 of 37 with juvenile onset . All CLN1 probands were palmitoyl protein thioesterase ( PPT ) deficient and showed granular osmiophilic deposits ( GROD ) at the electron microscopic ( EM ) level . In the group of classic CLN2 ( 72 probands ) , two common mutations were found : an intronic 3556g C transversion in the invariant …

Human forms of neuronal ceroid lipofuscinosis ( batten disease ) : consensus on diagnostic criteria , hamburg 1992. (1993 Oct)
human forms of neuronal ceroid lipofuscinosis ( batten disease ) : consensus on diagnostic criteria , hamburg 1992 .

Delayed classic and protracted phenotypes of compound heterozygous juvenile neuronal ceroid lipofuscinosis. (1999 Feb)
delayed classic and protracted phenotypes of compound heterozygous juvenile neuronal ceroid lipofuscinosis . objective : To correlate the phenotypes with the genotypes of 10 finnish juvenile neuronal ceroid lipofuscinosis ( JNCL ; late onset batten disease ) patients who all are compound heterozygotes for the major 1 . 02 kb deletion in the CLN3 gene . methods : The mutations on the non 1 . 02 kb deletion chromosomes were screened in 6 patients ; in the other 4 patients the mutations were known ( one affecting a splice site , two missense mutations , and one deletion of exons 10 through 13 ) . clinical features were examined , and MRI , MRS , somatosensory evoked magnetic field ( SEF ) , and overnight polysomnography ( PSG ) studies were performed . results : A novel deletion of exons 10 through 13 was found in 6 patients belonging to three families . In the patients carrying the deletions of exons 10 through 13 the clinical course of the disease was fairly similar . variation was greatest in the time course to blindness . In these patients the mental and motor decline was slower than in classic JNCL , but more severe than in the two patients with missense mutations in exons 11 and 13 . MRI showed brain atrophy in 4 patients . One patient had hyperintense periventricular white matter , otherwise brain signal intensities were normal . SEFs were enhanced in patients older than 14 years , whereas …

Neuronal ceroid lipofuscinosis : a common pathway ? The neuronal ceroid lipofuscinoses are pediatric neurodegenerative diseases with common clinical features. (2007 Jan)
neuronal ceroid lipofuscinosis : a common pathway ? The neuronal ceroid lipofuscinoses are pediatric neurodegenerative diseases with common clinical features . Of the nine clinical variants ( CLN1 CLN9 ) , six have been genetically identified . Most variants manifest cell death and dysregulated sphingolipid metabolism , suggesting the proteins defective in these disorders may interact along one pathway . NCL patient derived cell lines exhibit cell growth and apoptotic defects that reverse following transfection with the wild type gene . The membrane bound proteins CLN3 , CLN6 , and CLN8 complement each other , as do CLN1 and CLN2 proteins , with respect to growth and apoptosis . The CLN2 protein also corrects growth and apoptosis in CLN3 , CLN6 , and CLN8 deficient cell lines . neither CLN1 deficient nor CLN2 deficient growth defects are corrected by CLN3 , CLN6 , and CLN8 proteins . CLN2 , CLN3 , CLN6 , and CLN8 proteins co immunoprecipitate and co localize to early and / or recycling endosomes and lipid rafts . additionally , cln2p and cln1p co immunoprecipitate . The work presented supports interactions between NCL proteins occurring at multiple points along one pathway .

Urinary sediment dolichol excretion in patients with batten disease and other neurodegenerative and storage disorders. (1985 May)
urinary sediment dolichol excretion in patients with batten disease and other neurodegenerative and storage disorders . nonesterified dolichols have been measured in the urinary sediment of 20 patients with the late infantile and juvenile forms of neuronal ceroid lipofuscinosis ( batten disease ) , in 15 patients with other storage and neurodegenerative disorders and in 10 control subjects . dolichols were measured by a high performance liquid chromatographic method and were related to urinary creatinine concentration . The levels of dolichols in batten disease were not significantly elevated when compared to the normal subjects or to patients with other neurodegenerative disorders . The highest levels seen were in two patients with mucopolysaccharidosis types II and IV , respectively . measurement of dolichols in urinary sediment is of little value in the diagnosis of batten disease or in furthering our understanding of the underlying primary defect .

Abnormal cathepsin B activity in batten disease. (1989 Mar)
abnormal cathepsin B activity in batten disease . fibroblasts cultured from patients with various forms of neuronal ceroid lipofuscinosis ( NCL ; batten disease ) showed variably decreasing cathepsin B activity with increasing passage number and months in culture in the presence of fetal calf serum . cathepsin H activity and that of a wide range of lysosomal hydrolases was unaffected by these conditions . cathepsin B activity was assayed either colorimetrically ( N alpha benzoyl DL Arg beta naphthylamide ; BANA ) , fluorimetrically ( Z Arg Arg methylcoumarin ) , or autoradiographically , following nadodso4 12 . 5 polyacrylamide gel electrophoresis ( 125 Tyr Ala Lys Arg ch2cl ) and was found to be lysosomal in localization . fractionation of disrupted fibroblasts on a percoll gradient showed evidence of abnormally buoyant lysosomes in some NCL patients , and these tended to be low in cathepsin B but rich in other lysosomal hydrolases . Our data do not support a primary defect in cathepsin B as the basic defect in NCL . however , a possible explanation for various studies implicating a protease defect in NCL is that cathepsin B was highly sensitive to inactivation by peroxides and aldehydes . Thus hydrogen peroxide ( 0 . 3 mM ) or 4 hydroxynonenal ( 1 nM ) inactivated cathepsin B without inhibiting cathepsin H or lysosomal hydrolases such as alpha L fucosidase . since peroxides and 4 hydroxynonenal have been shown to accumulate in NCL tissue ( despite apparently normal …

Neuronal ceroid lipofuscinosis. (1984 Mar)
neuronal ceroid lipofuscinosis . diagnosis from peripheral blood smear . neuronal ceroid lipofuscinosis ( NCL ) , or batten Vogt s disease , is a disorder of young children who manifest visual , neurologic , and mental problems . The ophthalmologist can provide helpful diagnostic information by examining the fundus and performing an electroretinogram . In addition , diagnostic markers can be identified by examining circulating lymphocytes from a peripheral blood specimen with light and electron microscopy .

Clinical and magnetic resonance imaging findings in batten disease : analysis of the major mutation ( 1. (1997 Dec)
clinical and magnetic resonance imaging findings in batten disease : analysis of the major mutation ( 1 . 02 kb deletion ) . A total of 36 patients with batten disease ( juvenile onset neuronal ceroid lipofuscinosis ) , homozygous or heterozygous for the major mutation , a 1 . 02 kb deletion , in the CLN3 gene , were studied to relate their genotype to their clinical phenotype . The onset of visual failure and epilepsy was highly concordant in both groups . great inter and intrafamilial heterogeneity was demonstrated in the development of mental and physical handicap and in magnetic resonance imaging findings among both homozygous and heterozygous patients . The 1 . 02 kb deletion in homozygous form was always associated with mental and physical handicap , whereas the heterozygous phenotype could be extremely benign without affecting the intellectual level of the patient . Our data suggest that genetic background , modifying genes , and environmental factors all influence the final phenotype of batten disease .

Structure of the CLN3 gene and predicted structure , location and function of CLN3 protein. (1997 Aug)
structure of the CLN3 gene and predicted structure , location and function of CLN3 protein . The genomic sequence of the human CLN3 gene , which is defective in juvenile onset neuronal ceroid lipofuscinosis ( batten disease ) is being delineated using a variety of methods . A saccharomyces cerevisiae gene , YHC3 ( for yeast homologue to human CLN3 ) , which is highly similar to the human disease gene , has been identified by computer aided homology searching . topology predictions indicate the CLN3 protein contains six transmembrane segments . Most similarity between the human and yeast proteins lies either in the transmembrane segments or along one face of the predicted protein structure .

Strategy for mutation detection in CLN3 : characterisation of two finnish mutations. (1997 Aug)
strategy for mutation detection in CLN3 : characterisation of two finnish mutations . A strategy for detection of mutations in CLN3 , the gene for batten disease or juvenile onset neuronal ceroid lipofuscinosis , has been devised using a technique which detects conformation polymorphisms and direct sequencing of genomic DNA fragments . We define two mutations found uniquely in finnish patients , one a large deletion ( 2 . 8 kb ) , the other a point mutation affecting the 5 splice donor site of an intron .

Mapping the gene for juvenile onset neuronal ceroid lipofuscinosis to chromosome 16 by linkage analysis. (1992 Jul)
mapping the gene for juvenile onset neuronal ceroid lipofuscinosis to chromosome 16 by linkage analysis . The ceroid lipofuscinoses are a group of inherited neurodegenerative disorders characterised by the accumulation of autofluorescent lipopigment in neurones and other cell types . The underlying biochemical defect is unknown . juvenile onset neuronal ceroid lipofuscinosis ( batten disease ; spielmeyer Vogt disease ) is an autosomal recessive trait . linkage studies were undertaken to determine the location of the batten disease ( CLN3 ) mutation . studies were carried out on 205 members of 42 families in which there were 76 affected individuals . families originated from 7 north european countries and canada . serum samples from 23 families , including a total of 48 affected children , were tested for a set of classical markers . A positive lod score was found with the haptoglobin ( Hp ) system . The combined male and female maximum lod score was 3 . 00 at theta 0 . 00 and theta 0 . 26 , respectively . This provided an indication of localisation to the long arm of chromosome 16 . linkage analysis was then carried out in 42 families using DNA markers for loci on human chromosome 16 . The maximal lod score between batten disease and the locus d16s148 calculated for combined sexes was 6 . 05 . No recombinants were observed . multilocus analysis using 5 loci indicated the most likely order to be HP d16s151 d16s150 CLN3 d16s148 d16s147 . …

Different patterns of hydrophobic protein storage in different forms of neuronal ceroid lipofuscinosis ( NCL , batten disease ). (1997 Aug)
different patterns of hydrophobic protein storage in different forms of neuronal ceroid lipofuscinosis ( NCL , batten disease ) . since the discovery of mitochondrial ATP synthase subunit c storage in different forms of neuronal ceroid lipofuscinosis ( NCL , batten disease ) , it has been found that other hydrophobic proteins also accumulate in different forms . costorage of subunit c of vacuolar atpase is observed in mnd / mnd mice and in english setters , border collies and tibetan terriers . A small amount is stored in the ovine disease and none in the human late infantile disease . It is a storage body matrix component . An additional 8 kDa component immunoreactive to vacuolar atpase subunit c antibodies is found in brain derived storage bodies . The sphingolipid activator proteins , SAPs A and D , are stored in the human infantile disease and a form in miniature schnauzer dogs , but neither of the c subunits are . these results suggest two classes of NCL , the subunit c storing diseases , related by a series of lesions in a subunit c turnover pathway , and the SAP storing diseases .

The value of positron emission tomography in the diagnosis and monitoring of late infantile and juvenile lipopigment storage disorders ( … (1997 Aug)
The value of positron emission tomography in the diagnosis and monitoring of late infantile and juvenile lipopigment storage disorders ( so called batten or neuronal ceroid lipofuscinoses ) . positron emission tomography ( PET ) with 2 deoxy 2 18F fluoro D glucose provides a measure of functional brain activity , particularly in the dendritic field . In CLN3 ( juvenile neuronal ceroid lipofuscinosis or juvenile batten disease , with fingerprint inclusions ) hypometabolism slowly spreads from calcarine to anterior areas , sparing subcortical structures and brainstem . In CLN2 ( late infantile neuronal ceroid lipofuscinosis or jansky bielschowsky disease , with curvilinear inclusions ) degeneration is rapid with generalized cortical and subcortical hypometabolism . This is associated with rapidly progressive cerebral atrophy on anatomical neuroimaging . A 4 year old child with CLN2 scanned with PET 13 months after the clinical onset showed hypometabolism , severe in the thalamus and mild in cortical areas . three other patients with CLN2 had severe generalized hypometabolism and brain atrophy . longitudinal PET studies in CLN may provide key insights into degenerative processes .

Neuronal ceroid lipofuscinosis. (1994 Jul)
neuronal ceroid lipofuscinosis . report of 4 cases with study by rectal histochemistry , conjunctiva electron microscopy and necropsy The authors present the neuropathological and clinical findings of four cases of ceroid lipofuscinosis or batten s disease . In two cases the autopsy findings showed brain atrophy and nerve cells packed with cytoplasmic granules compatible with lipofuscin . One case was diagnosed by histochemical techniques in frozen sections of rectal biopsy which showed myoenteric ganglion cells with cytoplasmic acid phosphatase positive material as well as numerous macrophages filled with lipofuscin in the mucosae . The fourth case diagnosed by electron microscopy of conjunctival biopsy which showed cytoplasmic inclusions of membranous , curvilinear and fingerprint types .

Altered flurothyl seizure induction latency , phenotype , and subsequent mortality in a mouse model of juvenile neuronal ceroid lipofuscinosis … (2002 Oct)
altered flurothyl seizure induction latency , phenotype , and subsequent mortality in a mouse model of juvenile neuronal ceroid lipofuscinosis / batten disease . purpose : juvenile neuronal ceroid lipofuscinosis ( JNCL ) , or batten disease , is a pediatric neurodegenerative disease characterized by vision loss , seizure activity , cognitive decline , and premature death . discovery of the batten disease related gene , CLN3 , led to creation of a Cln3 protein deficient mouse model ( Cln3 / ) , which recapitulates some of the histopathologic characteristics of the human condition . We hypothesized that lack of Cln3 would alter seizure related behavioral parameters . methods : using flurothyl gas inhalation , we examined seizure induction latencies in Cln3 / mice and wildtype ( wt ) controls at time points that represent late neonatal , immature , mature , and aged time points . We examined latency to first myoclonic jerk ( LMJ ) , latency to loss of posture ( LOP ) , and subsequent mortality . results : Our results demonstrate an age dependent alteration of seizure induction latencies in Cln3 / . immature Cln / mice aged 35 42 days had an increased latency to both LMJ and LOP compared with age matched wt controls . there were no significant latency differences between Cln3 / and wt at other time points examined . mortality after generalized seizure was high in both Cln3 / and wt animals at late neonatal and immature developmental stages . …

Neuronal ceroid lipofuscinosis in the amaurotic retardate : electron microscopic confirmation. (1983 Feb)
neuronal ceroid lipofuscinosis in the amaurotic retardate : electron microscopic confirmation . The clinical features of two cases of blindness with pigmentary retinopathy in young retardates are presented . The diagnosis of neuronal ceroid lipofuscinosis ( batten s disease ) was suspected . This was confirmed in both cases by electron microscopic examination of blood and skin with demonstration of fingerprint and curvilinear inclusions . these inclusions are present in cells other than neurons ; circulating lymphocytes , smooth muscle cells and eccrine sweat glands suggesting a more widespread pathological process . Less invasive procedures namely venepuncture and skin biopsy may be preferred to brain and rectal biopsy in the absence of a practical biochemical analysis at the present time .

Genetic analysis of batten disease. (1993 Nov)
genetic analysis of batten disease . batten disease , or neuronal ceroid lipofuscinosis ( CLN ) comprises a group of inherited neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in neurones . The three main childhood varieties infantile ( CLN1 ) , late infantile ( CLN2 ) and juvenile ( CLN3 ) manifest autosomal recessive inheritance . The basic biochemical defect remains unknown . The strategy of positional cloning is being pursued to elucidate the molecular basis of batten disease . The infantile disease locus ( CLN1 ) has been mapped by linkage analysis to human chromosome 1p32 , and the juvenile disease locus ( CLN3 ) to human chromosome 16p12 . In each case marker loci in strong linkage disequilibrium with the disease loci have been identified . locus heterogeneity between classical late infantile CLN ( CLN2 ) and both CLN1 and CLN3 has been demonstrated . Work is in progress to clone CLN1 and CLN3 and to map CLN2 . identification of linked markers has provided a new approach to prenatal diagnosis . The methodology exists for positional cloning of these genes and elucidation of the molecular genetic basis of the ceroid lipofuscinoses .

Over expression of cln3p , the batten disease protein , inhibits pander induced apoptosis in neuroblastoma cells : further evidence … (2006 May)
Over expression of cln3p , the batten disease protein , inhibits pander induced apoptosis in neuroblastoma cells : further evidence that cln3p has anti apoptotic properties . juvenile neuronal ceroid lipofuscinosis ( JNCL ) or batten / spielmeyer Vogt sjogren disease ( OMIM 204200 ) is one of a group of nine clinically related inherited neurodegenerative disorders ( CLN1 9 ) . JNCL results from mutations in CLN3 on chromosome 16p12 . 1 . The neuronal loss in batten disease has been shown to be due to a combination of apoptosis and autophagy suggesting that cln3p , the defective protein , may have an anti neuronal death function . pander ( pancreatic derived factor ) is a novel cytokine that was recently cloned from pancreatic islet cells . pander is specifically expressed in the pancreatic islets , small intestine , testis , prostate , and neurons of the central nervous system , and has been demonstrated to induce apoptosis . In this study , we over expressed cln3p in SH SY5Y neuroblastoma cells and monitored the effects on pander induced apoptosis . cln3p significantly increased the survival rate of the SH SY5Y cells in this system . This study provides additional evidence that the function of cln3p is related to preventing neuronal apoptosis .

Early changes in gene expression in two models of batten disease. (2003 Mar)
early changes in gene expression in two models of batten disease . infantile and juvenile neuronal ceroid lipofuscinosis ( NCLs ) are progressive neurodegenerative disorders of childhood with distinct ages of clinical onset , but with a similar pathological outcome . infantile and juvenile NCL are inherited in an autosomal recessive manner due to mutations in the CLN1 and CLN3 genes , respectively . recently developed Cln1 and Cln3 knockout mouse models share similarities in pathology with the respective human disease . using oligonucleotide arrays we identified reproducible changes in gene expression in the brains of both 10 week old Cln1 and Cln3 knockout mice as compared to wild type controls , and confirmed changes in levels of several of the cognate proteins by immunoblotting . despite the similarities in pathology , the two mutations affect the expression of different , non overlapping sets of genes . The possible significance of these changes and the pathological mechanisms underlying NCL diseases are discussed .

Accumulation of the adenosine triphosphate synthase subunit C in the mnd mutant mouse. (1994 May)
accumulation of the adenosine triphosphate synthase subunit C in the mnd mutant mouse . A model for neuronal ceroid lipofuscinosis . The motor neuron degeneration ( mnd ) mutant mouse , initially described as an autosomal semidominant model of motor neuron disease , is characterized by progressive loss of motor activities and the accumulation of lipofuscin like material in the cytoplasm of neurons in many regions of the nervous system . The stored material is composed of granular , multilamellar , fingerprint , and curvilinear profiles and degenerating mitochondria . these inclusions are associated with the accumulation of subunit c of mitochondrial adenosine triphosphate synthase in an age dependent pattern . these abnormalities first appear in neurons of the thalamus , hippocampus , and cortex and eventually involve virtually all nerve cells , including those in the retina and enteric nervous system . This type of neuropathology and the presence of subunit c in neurons of mnd mutant mice are characteristic features of neuronal ceroid lipofuscinosis ( NCL ) . The murine disease resembles batten s disease , an autosomal recessive disorder and the most common NCL in humans . The mnd mouse should be of great value for investigations of the genetics of NCL , for studies designed to delineate the mechanism that lead to neuronal degeneration in these disorders , and for testing novel therapeutic approaches .