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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↗
PubMed1999

The effects of lesions to the caudolateral neostriatum on sun compass based spatial learning in homing pigeons.

To better define the role of the avian caudolateral neostriatum (NCL) in spatial behavior, we used homing pigeons to explore the effects of NCL lesions on a sun compass based spatial learning task. Although NCL lesioned birds learned the task, they required more sessions to reach criterion than controls. NCL lesioned pigeons were also able to acquire a color discrimination task that was procedurally similar to the sun compass spatial learning task, but they made more errors than controls. Both the deficits observed in sun compass based spatial learning and color discrimination were correlated with the volume of lesion damage to dorsal rather than ventral portions of NCL. Overall, these findings suggest that the role of NCL in homing pigeon navigation from distant unfamiliar locations is not related to a bird's ability to learn stimulus-direction associations using a sun compass. However NCL does appear involved in a pigeon's ability to perform at least some behaviors common to both the color discrimination and the sun compass based spatial learning tasks.

Animals↗
PubMed2000

Increased incidence of HFE C282Y mutations in patients with iron overload and hepatocellular carcinoma developed in non-cirrhotic liver.

BACKGROUND/AIMS: Histological and biochemical iron overload has been reported in non-tumoral liver of most patients presenting an hepatocellular carcinoma (HCC) developed in non-cirrhotic liver (NCL). The aim of our study was to investigate HFE mutations in patients with HCC in NCL. METHODS: Thirty-five patients with HCC in NCL were included either retrospectively or prospectively. Clinical data, iron and viral status, and HFE gene mutations were compared between groups with (I+, n = 19) or without histological iron overload (I-, n = 16). RESULTS: Twenty per cent of patients were HBV or HCV positive. Fifty-four per cent had hepatocytic iron overload at histology. Mean hepatic iron concentration was 100.2 +/- 14.6 micromol/g in I+ versus 23.2 +/- 2.1 micromol/g in I- (p<0.001). Among the 19 I+ patients, eight mutations were found: two C282Y/C282Y, three C282Y/WT, two C282Y/H63D and one H63D/H63D. None of these mutations was found in the I- group. There was no significant difference concerning the H63D heterozygous mutation between I+ or I- patients. CONCLUSIONS: In patients with HCC in NCL, HBV and HCV markers are rare (20%), and mild iron overload is frequent (54%). In patients with HCC in NCL and iron overload, C282Y mutations are frequent (36.8% of cases) and significantly increased (p<0.009) compared to HCC in NCL without iron overload; these mutations are mostly heterozygous. H63D heterozygosity is not associated with liver iron overload. Because of the small size of the series, HFE C282Y mutation should be investigated on a larger scale in patients with HCC in NCL with iron overload in order to confirm this association.

Aged↗
PubMed1999

Normal ascorbic acid in cerebrospinal fluid of patients with infantile neuronal ceroid-lipofuscinosis.

Neuronal ceroid-lipofuscinoses (NCL) are a group of neurodegenerative disorders. There is much evidence for a role of peroxidation processes in the pathogenesis of NCL, although this would certainly be indirect. Reduced total antioxidant activity of cerebrospinal fluid (CSF) has been reported in NCL. Since ascorbic acid represents a major antioxidant in CSF, we have now determined this parameter in CSF of two patients with the infantile form of NCL (Santavuori-Haltia disease). However, the ascorbic acid values obtained (103.6 and 181.3 microM) are comparable with control values from the literature as well as with those measured in groups of children with neurologic/psychiatric diseases other than NCL (mean +/- standard deviation: 137.1+/-41.3 microM), with suspected (but excluded) meningitis (124.1+/-34.0 microM) and acute lymphoblastic leukemia (131.7+/-17.0 microM). Our results indicate that CSF ascorbic acid concentrations are not affected by peroxidation processes in infantile NCL, but reveal a sharply decreased ascorbic acid concentration in one of the non-NCL patients, possibly associated with his convulsions and/or his anticonvulsant therapy.

Ascorbic Acid↗
PubMed1997

Neuronal ceroid lipofuscinoses in Scandinavia. Epidemiology and clinical pictures.

The epidemiology of neuronal ceroid lipofuscinoses (NCL) in Scandinavia was studied. For juvenile NCL 40 Swedish living patients were identified. The corresponding number for Finland was 61, for Norway 28, for Denmark 16 and for Iceland three. The prevalence of juvenile NCL was thus 4.6, 12.2, 6.5, 3.1 and 11 per million inhabitants in Sweden, Finland, Norway, Denmark, and Iceland, respectively. For calculating incidence the years 1976-85 were used. The incidence was 2.2 per 100,000 live births in Sweden, 4.8 in Finland, 3.7 in Norway, 2.0 in Denmark, and 7.0 in Iceland. Late infantile NCL was found in five Swedish children, including one variant form, CLN5. This gives a prevalence of about 0.6 per million. In Finland 13 cases gave a prevalence of 2.6 per million with the variant form in 80% of cases. In Norway, three children corresponded to a prevalence of 0.7 per million and one case in Iceland to 3.8 per million. No Danish cases were reported. As for infantile NCL, sixteen Swedish cases have been diagnosed during the 27-year period 1968-95, six are presently alive. This gives an estimated prevalence of 0.7 per million and an incidence of 0.6 per 100,000. The prevalence and incidence of infantile NCL in Finland were 5.4 per million and 5 per 100,000, respectively. The prevalence in Norway was 0.2 per million inhabitants. The variability of onset, clinical course and symptoms in the Swedish cases of juvenile and infantile NCL were analysed.

Adolescent↗
PubMed1983

High levels of brain dolichols in neuronal ceroid-lipofuscinosis and senescence.

Dolichols as unesterified alcohols were identified as significant components of lipid extracts from storage cytosomes isolated post-mortem from the brains of patients with the infantile, late infantile, and juvenile types of neuronal ceroid-lipofuscinosis (NCL). Very small amounts of dolichols were present in the corresponding subcellular fractions of non-NCL brains. The nuclear fraction from NCL cerebral cortex contained the highest dolichol content expressed per milligram protein or lipid, whereas the crude mitochondrial fraction was the richest in normal brain. Highly significant elevations of dolichol levels were found in human cerebral cortex of patients with NCL and Alzheimer's disease compared with age-matched controls, but the levels were normal in Pick's disease. In human non-NCL cerebral cortex, dolichols increased from 16 micrograms/g at age 5 to over 200 at age 81. Rat cerebral cortex showed a similar progressive increase in dolichol content with age. The high dolichol values in NCL, Alzheimer's disease, and senescence appears to be related to the increase of lipofuscin in brain. This is the first time a uniform biochemical abnormality has been found in all childhood forms of NCL, but the enzyme defect is still unidentified. It may lie on pathways where dolichols and retinyl compounds are recycled in Golgi membranes and derived organelles during the biosynthesis of glycoproteins.

Adolescent↗
PubMed1986

Radioimmunoassay for the carboxy-terminal cross-linking domain of type IV (basement membrane) procollagen in body fluids. Characterization and application to collagen type IV metabolism in fibrotic liver disease.

The carboxy-terminal cross-linking domain (NCl) of type IV procollagen was isolated from human placenta and used for the production of polyclonal and monoclonal antibodies. Purity of the antigen and specificity of the antibodies were verified by Western blotting and radioimmunoassays. A radioimmunoassay was developed using rabbit antiserum. Intra- and interassay coefficients of variation were 4.7% and 5.8%, respectively; recovery of NCl added to serum and bile was 95-105%. NCl concentration in sera of healthy volunteers was 6 +/- 2.9 ng/ml (mean +/- 2.5 SD) and was elevated up to 18 ng in sera of patients with autoimmune or metastatic tumor disease and up to 240 ng in sera of patients with fibrogenic liver disease. Substantial amounts of antigen were also found in bile, urine, and ascites. 67% of serum antigens eluted from an agarose A5M column with an apparent molecular weight of 60 kD and 23% with a molecular weight of 90 and 150 kD, well below the molecular weight of type IV procollagen (550 kD). Serum NCl is apparently derived from the degradation of basement membrane collagen. The time course of NCl concentrations in sera of patients with fibrogenic liver disease showed no correlation with the serum concentration of the amino-terminal procollagen type III peptide, a marker of hepatic collagen biosynthesis. A decline of serum NCl levels along with elevated serum procollagen type III peptides apparently indicates bad prognosis in fibrogenic liver disease. The radioimmunoassay for NCl is a useful tool for studying type IV collagen metabolism in conditions causing remodeling or breakdown of basement membranes.

Adult↗
PubMed1977

[Effects of morphine on the single unit activity of nucleus dorsal raphe].

Effects of morphine were studied in 36 gallamine triethiodide immobilized adult cats under light N2O anesthesia. Single units were recorded from the nucleus dorsal raphe using a stainless steel microelectrode. Dorsal raphe neurons were divided into two types; one was a clock-like (CL) neuron which was typically slow in rate, rhythmic and stable throughout recording time, and the other was a non-clock like (NCL) neuron which was relatively irregular in pattern as compared with CL neuron. Out of 36 neurons recorded in this experiment, 13 were CL neurons and 23 were NCL neurons. Mean discharge rates (spikes per sec) of CL neuron and NCL neuron were 2.84 (range of 2.01 approximately 3.68) and 4.11 (range of 0.10 approximately 35.09), respectively. None of the 13 CL neurons responded to the nociceptive (pinch and/or brdaykinin) and non-nociceptive (hair bending and/or tapping) stimuli. On the contrary, out of 23 NCL neurons, 13 responded to both nociceptive and non-nociceptive stimuli, 4 were responsive to only non-nociceptive stimuli and 6 were not responsive to these stimuli. Receptive fields of NCL neurons were wide with various somatic modalities. The latency for bradykinin (3 microgram) was 6.46 +/- 0.77 sec. Effects of morphine were examined in 6 CL neurons and 12 NCL neurons. After morphine, no nociceptive neuron responded to nociceptive stimuli, although there was no appreciable change in the responsiveness to non-nociceptive stimuli. Firing frequency and pattern of all CL neurons were unaffected by morphine. Out of 12 NCL neurons, 7 were unaffected in firing frequency and 5 were decreased after morphine.

Action Potentials↗
PubMed1993

A novel tissue-specific calpain species expressed predominantly in the stomach comprises two alternative splicing products with and without Ca(2+)-binding domain.

Our previous studies have demonstrated that, in addition to the conventional mu- and m-calpains ubiquitously expressed in tissues, a muscle-specific calpain comprising a novel member of the large subunit family (p94 or nCL-1, which stands for novel Calpain Large subunit) exists in muscle cells. To clarify the physiological function of nCL-1, we screened cDNA libraries of various rat tissues for other tissue-specific calpains and, as a result, discovered a novel member of the calpain large subunit family. RNA blot analysis showed that the mRNA is expressed predominantly in the stomach. Isolated cDNA clones could be structurally divided into two groups, whose 5'-halves of about 1.1 kilobase pairs were identical, but whose 3'-halves bore no similarity at all. This suggests generation by an alternative splicing mechanism, which was proved by genomic DNA cloning. Open reading frames were found encoding 703 and 381 amino acid residues with calculated molecular masses of 79,554 and 42,591 for nCL-2 and -2', respectively. The deduced amino acid sequence of nCL-2 is very similar to those of other calpain large subunits and can be aligned without significant insertions or deletions, suggesting that nCL-2 should possess cysteine protease activity and calcium binding ability. nCL-2' is identical to the N-terminal half of nCL-2 and, thus, contains only the cysteine protease domain but not the calcium binding domain. Possible roles of the calpain family are discussed based on these findings.

Alternative Splicing↗
PubMed1988

Clinico-pathological variability in the childhood neuronal ceroid-lipofuscinoses and new observations on glycoprotein abnormalities.

Our 86 cases of neuronal ceroid-lipofuscinosis (NCL) included 7 children with the infantile variant, 28 with the late infantile variant, and 51 with the juvenile variant. Thirty-one cases were drawn from a NCL registry and were not evaluated personally by the authors. Another 30 cases from the registry were not included because of inadequate data. The clinical course was subacute in most children with the infantile and late infantile variants and chronic in the juvenile variant. Sixteen of 86 cases (19%) were considered to be atypical clinically [3/7 (43%) with the infantile variant, 3/28 (11%) with the late infantile variant, and 10/51 (20%) with the juvenile variant]. Clinical variability among and between families was most striking in the juvenile variant. Pathological investigations of skin, buffy coat and/or brain showed atypical and/or more than one type of cytoplasmic inclusions in 10/50 (20%) of late infantile and juvenile variants. All of the children with the infantile variant had granular, osmiophilic profile in tissues. Biochemical studies on the glycoproteins of cultured fibroblasts in three cases of juvenile NCL showed that there was a higher proportion of one size class of N-linked oligosaccharides and a higher proportion of mannose-containing glycoproteins in NCL than in control cells. This supports previous lectin histochemical studies of glycoconjugates in skin of juvenile NCL [Wisniewski and Szumanska, 1986] and suggests that there may be defects in the processing of N-linked oligosaccharides in the glycoproteins of juvenile NCL.

Adolescent↗
PubMed1988

Clinical and biochemical studies of Japanese neuronal ceroid-lipofuscinosis.

We studied clinical manifestations of Japanese patients with neuronal ceroid-lipofuscinosis (NCL). The onset of the disease and initial symptoms were almost identical to those reported previously in Caucasians. Japanese patients with NCL were not significantly clinically different from Caucasian cases. An atypical case NCL associated with a deficiency of diaminobenzidine peroxidase activity was also presented. Pathogenesis of NCL was studied on the basis of urine dolichol excretion, autofluorescent compounds in urine, thiol protease activities and protein analysis in tissues of NCL patients. Possible biochemical abnormalities in NCL are discussed.

Adolescent↗
PubMed1988

Reconsideration of the classification of the neuronal ceroid-lipofuscinoses.

Neuronal ceroid-lipofuscinoses (NCL) represent diseases of different types. Each variety of NCL may have its own clinical course, genetics, pathogenesis, and treatment. Four disorders are presently accepted as examples of NCL. These include the chronic juvenile or Batten type, the acute late infantile or Bielschowsky type, the chronic or subacute adult Kufs type, and the acute infantile or Santavuori-Haltia type. Seventy patients with clinical and pathological features of NCL have been studied over 20 years; 62 of these fit into one of the above categories, but 8 are atypical and present nosologic problems. Recognized as examples of atypical NCL are 1) chronic congenital or Norman-Wood type, 2) acute adult or Zeman-Dyken type, 3) acute childhood or Bielschowsky variant, 4) chronic childhood (Edathodu-Dyken) type, with pervasiveness, 5) chronic infantile (Dyken) type with autism, and 6) chronic juvenile (Dyken) type with ataxia. It is proposed that our present classification of NCL be based on differentiating clinical dynamics and characteristics, age-of-onset, and morphological and pathological criteria. Although genetic characteristics are now recognized, these are of autosomal recessive or autosomal dominant type. No differentiating biochemical differences have been established to aid in the nosology of these diseases.

Adult↗
PubMed1995

Pigment variant of neuronal ceroid-lipofuscinosis.

A 6-year-old girl had progressive ataxia, and visual disturbances resulting in blindness. She died in her sleep at age 22 years. She shared with her sister and paternal relatives bilateral pes cavus deformities and impaired deep-tendon reflexes which suggested Charcot-Marie-Tooth disease. Her sister, who also had both polyneuropathy and a progressive central nervous system (CNS) disease, did not have pigmentary retinopathy. At autopsy, the patient was found to have neuronal ceroid-lipofuscinosis (NCL) marked by intraneuronal accumulation of autofluorescent granular lipopigments in ballooned perikarya and conspicuous extraneuronal pigmentation of subcortical grey matter, but without axonal spheroids. These findings indicate a pigment variant of NCL and represent one of very few patients recorded. The ultrastructure of the intraneuronal pigments was uniformly granular, while that of the extraneuronal pigments found within processes of the neuropil and glial perikarya was more variegated. In addition to those patients with the pigment variant of NCL, described earlier by Jakob and Kolkmann [1973: Acta Neuropathol (Berl) 26:225-236], and Jervis and Pullarkat [1978: Neurology 28:500-503], our patient shared clinical symptoms with those described in a family afflicted with polyneuropathy and NCL by Wisniewski et al. [1987: J Child Neurol 2:33-41]. Currently, it is unclear whether they have similar atypical forms of juvenile NCL (JNCL). We conclude that the spectrum of pigment variants in lysosomal diseases is heterogeneous: only few and recently described patients have had NCL, while others most likely had other forms of lipidosis.

Cerebral Cortex↗
PubMed1999

Genetic heterogeneity of neuronal ceroid lipofuscinosis in The Netherlands.

An overview of patients in the Netherlands who are known to us with neuronal ceroid lipofuscinosis (NCL) is presented. Several CLN genes involved in NCL have been isolated or mapped. We have analyzed families with different types of NCL with polymorphic markers linked to CLN loci to investigate the genetic heterogeneity of NCL in the Netherlands. Haplotype analysis suggests that in addition to the CLN2 and CLN6 genes another gene is involved in at least one family with late infantile NCL in the Netherlands. The CLN2 and CLN6 loci have also been excluded in a family with protracted juvenile NCL.

Cyclins↗
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↗
PubMed1996

Recent advances in the molecular genetics of the neuronal ceroid lipofuscinoses.

Major advances in the molecular genetic analysis of the neuronal ceroid lipofuscinoses (NCL) have recently been made: the genes for two major types have been identified and the chromosomal location for a third defined. CLN1, the gene for infantile NCL (Santavuori-Haltia disease) encodes palmitoyl protein thioesterase (PPT). Most patients (75% of disease chromosomes) have the same point mutation. In contrast, CLN3, the gene for juvenile NCL (Batten or Spielmeyer-Vogt-Sjögren disease) is not a previously known gene, nor does its product display homology to any previously described proteins. The same 1 kb genomic deletion is present in the majority of patients (81% of disease chromosomes). CLN5, the gene for Finnish variant late infantile NCL, has been mapped to 13q and should be identified in the near future. The gene for late-infantile NCL (Jansky-Bielschowsky disease) has not yet been localized to a chromosome despite intensive research. It is likely that this type of NCL is caused by mutations in more than one gene each resulting in the same phenotype.

Chromosome Mapping↗
PubMed1977

Radiobromine labeled norcholesterol analogs. Synthesis and tissue distribution study in rats of bromine-82 labeled 6beta-bromomethyl-19-norcholest-5(10)-EN-38-OL.

6beta-Bromomethyl-19-norcholest-5(10)-en-3beta-ol (NCL-6-Br) was synthesized directly from cholest-5-ene-3beta,19-diol 19-toluene-p-sulfonate via homoallylic rearrangement with ammonium bromide or sodium bromide in acetonitrile. This method was applied to the radiolabeling of NCL-6-Br with bromine-82. Tissue distribution of bromine-82 labeled NCL-6-Br (NCL-6-Br-82) in rats was determined. The mean percent dose per gram uptake in adrenal at 24 and 120 h was 98 and 80 %/gm, respectively, which indicated a higher adrenal uptake as compared to iodine-131 labeled 19-iodocholest-5-en-3beta-ol (CL-19-I-131), but was at a lower level than that achieved with iodine-131 labeled 6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol (NCL-6-I-131). The ratio of radioactivity in the adrenal-to-liver concentration was also lower than that of CL-19-I-131 or NCL-6-I 131.

Adrenal Glands↗
PubMed1990

Altered amyloid beta-protein precursor processing in brains of patients with neuronal ceroid lipofuscinosis.

Our previous study disclosed strong immunostaining of brain tissue in neuronal ceroid lipofuscinosis (NCL) with antibodies against amyloid beta-protein and the presence of 31-kDa polypeptide in the storage material. In the present study, we investigated the immunoreactivity of the NCL brain tissue with anti-serum (anti-GID) raised against a synthetic peptide, based on the amyloid beta-protein precursor, with the 175-186 amino acid sequence. Immunocytochemistry was performed on autopsy brain material collected from 15 NCL cases, and from 8 age-matched normal controls. The results showed strong immunoreactivity of nerve cells in the NCL cases, which according to densitometry was 5 times more intense than in the control group (P less than 0.0001 by Student's t-test). Western blot analysis revealed that in protein fractions of NCL brain homogenates anti-GID recognized the protein band of 35 kDa. Thus our present and previously performed studies supplied for the first time data pointing to abnormal processing of amyloid beta-protein precursor in NCL. Moreover, the accumulation of both 31- and 35-kDa polypeptides that was demonstrated provides further support for postulated defective protein metabolism in this disorder.

Amyloid beta-Peptides↗