Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Classical late-infantile neuronal ceroid lipofuscinosis (LINCL; CLN2) is an inherited neurodegenerative disorder of childhood characterized by seizures, loss of vision, and progressive motor and mental deterioration. The hallmark of this disease is the accumulation of enlarged, secondary lysosomes packed with curvilinear bodies in cells of affected individuals. The biochemical basis of LINCL remains unknown and there is no treatment effective in delaying the progression of this fatal disorder. During a genome-wide search using a set of highly polymorphic markers and 15 affected individuals from 7 multi-affected families, we obtained evidence for linkage of the LINCL gene CLN2 with markers on chromosome 11p15.5. We then genotyped patients and all available family members, including 8 single-affected families, for markers spanning 15 cM of 11p15.5. We obtained a maximum two-point LOD score of 6.16 at 0 = 0.00 at the marker locus D11S2362. Multipoint analysis yielded a maximum LOD score of 6.90 localized to the same marker. Using haplotype analysis, we localized CLN2 to a minimum candidate region of 11 cM flanked by marker loci D11S4046 on the telomeric side and D11S1996 on the centromeric side. Additionally, we present data suggesting that the gene underlying a variant LINCL subtype found in Costa Rica maps to the region defined by the CLN6 locus on chromosome 15q21-23. The mapping of these two LINCL loci provides a genetic basis for understanding the clinical heterogeneity observed in this group of diseases.
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PMID:Chromosomal localization of two genes underlying late-infantile neuronal ceroid lipofuscinosis. 1073 26

The CLN6 gene that causes variant late-infantile neuronal ceroid lipofuscinosis (vLINCL), a recessively inherited neurodegenerative disease that features blindness, seizures, and cognitive decline, maps to 15q21-23. We have used multiallele markers spanning this approximately 4-Mb candidate interval to reveal a core haplotype, shared in Costa Rican families with vLINCL but not in a Venezuelan kindred, that highlighted a region likely to contain the CLN6 defect. Systematic comparison of genes from the minimal region uncovered a novel candidate, FLJ20561, that exhibited DNA sequence changes specific to the different disease chromosomes: a G-->T transversion in exon 3, introducing a stop codon on the Costa Rican haplotype, and a codon deletion in exon 5, eliminating a conserved tyrosine residue on the Venezuelan chromosome. Furthermore, sequencing of the murine homologue in the nclf mouse, which manifests recessive NCL-like disease, disclosed a third lesion-an extra base pair in exon 4, producing a frameshift truncation on the nclf chromosome. Thus, the novel approximately 36-kD CLN6-gene product augments an intriguing set of unrelated membrane-spanning proteins, whose deficiency causes NCL in mouse and man.
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PMID:Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. 1179 Dec 7

The neuronal ceroid-lipofuscinoses (NCL) are the most common group of progressive neurodegenerative diseases in children, with an incidence as high as one in 12,500 live births. The main features of this disease are failure of psychomotor development, impaired vision, seizures, and premature death. Many biochemical and physiological studies have been initiated to determine the cellular defect underlying the disease, although only a few traits have been truly associated with the disorders. One of the paradox's of the NCL-diseases is the characteristic accumulation of autofluorescent hydrophobic material in the lysosomes of neurons and other cell types. However, the accumulation of this lysosomal storage material, which no doubt contributes to the neurologic disease, does not apparently lead to disease outside the CNS, and how these cellular alterations relate to the neurodegeneration in NCLs is unknown. Mutations have been identified in six distinct genes/proteins, namely CLN1, which encodes PPT1, a protein thiolesterase; CLN2, which encodes TPP1, a serine protease; and CLN3, CLN5, CLN6, and CLN8, which encode novel transmembrane proteins. Mutation in any one of these CLN-proteins results in a distinct type of NCL-disease. However, there are many shared similarities in the pathology of these diseases. The most obvious connection between PPT1, TPP1, CLN3, CLN5, CLN6, and CLN8 is their subcellular localization. To date, three of the four proteins whose subcellular localization has been confirmed, namely PPT1, TPP1, and CLN3, reside in the lysosome. We review the function of the CLN-proteins and discuss the possibility that a disruption in a common biological process leads to an NCL-disease.
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PMID:The neuronal ceroid lipofuscinoses: mutations in different proteins result in similar disease. 1202 57

The neuronal ceroid lipofuscinoses (NCL), also known as Batten disease, are a group of inherited severe neurodegenerative disorders primarily affecting children. They are characterised by the accumulation of autofluorescent storage material in many cells. Children suffer from visual failure, seizures, progressive physical and mental decline and premature death, associated with the loss of cortical neurones. Six genes have been identified that cause human NCL (CLN1, CLN2, CLN3, CLN5, CLN6, CLN8), and approximately 150 mutations have been described. The majority of mutations result in a characteristic disease course for each gene. However, mutations associated with later disease onset or a more protracted disease course have also been described. At least seven common mutations exist, either with a world-wide distribution or associated with families from specific countries. All mutations are described in the NCL Mutation Database (http://www.uc.ac.uk/ncl).
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PMID:The genetic spectrum of human neuronal ceroid-lipofuscinoses. 1499 39

The neuronal ceroid lipofuscinoses (NCL) are worldwide the most common lysosomal storage disorders of childhood. Clinical features often include progressive visual impairment, seizures, psychomotor deterioration, dementia, and premature death. Most NCL cases are caused by mutations in the CLN1, CLN2 and CLN3 genes, which play an essential role in lysosomal protein degradation. Laboratory diagnostics for a patient suspected of NCL should start with enzyme analysis in the case of INCL and LINCL and investigation of lymphocyte vacuolisation for JNCL. Diagnosis at the protein level is not available for JNCL, but CLN3 mutation analysis is possible. The carrier status of healthy relatives in families with known mutations in either CLN1, CLN2, CLN3 or CLN6 can be determined with certainty by mutation analysis.
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PMID:[From gene to disease; from CLN1, CLN2 and CLN3 to neuronal ceroid lipofuscinosis]. 1573 38

Neuronal ceroid lipofuscinoses (NCLs) are the most common neurodegenerative childhood-onset disorders characterized by autosomal recessive inheritance, epileptic seizures, progressive psychomotor deterioration, visual failure, and premature death. At least seven subtypes of childhood-onset NCLs have been identified of which the late-infantile-onset forms (LINCLs) are genetically the most heterogeneous with four underlying genes identified. A variant form of LINCL (vLINCL) present in Turkish patients has been considered a distinct clinical and genetic entity (CLN7). However, we recently showed that mutations in the CLN8 gene account for a subset of Turkish vLINCL. Toward identifying the CLN7 gene we here screened the known NCL loci for homozygosity in nine Turkish vLINCL families. These loci were excluded in seven families that are likely to represent the 'true' Turkish vLINCL. In two families, we identified two novel homozygous mutations in the CLN6 gene: an intronic base substitution (c.542+5G>T) affecting the splicing of the transcript and a nonsense mutation (c.663C>G) creating a stop codon at tyrosine 221. These data indicate that CLN6 mutations, in addition to those of CLN8, should be considered a diagnostic alternative in Turkish vLINCL patients. The genetic background of the 'true' Turkish vLINCL, CLN7, remains to be defined.
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PMID:Two novel CLN6 mutations in variant late-infantile neuronal ceroid lipofuscinosis patients of Turkish origin. 1599 15

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are fatal inherited lysosomal storage diseases of children characterized by increasing blindness, seizures and profound neurodegeneration but the mechanisms leading to these pathological changes remain unclear. Sheep with a CLN6 form that have a human-like brain and disease progression are invaluable for studying pathogenesis. A study of preclinical pathology in these sheep revealed localized glial activation at only 12 days of age, particularly in cortical regions that subsequently degenerate. This has been extended by examining fetal tissue from 60 days of gestation onwards. A striking feature was the presence of reactive astrocytes and the hypertrophy and proliferation of perivascular cells noted within the developing white matter of the cerebral cortex 40 days before birth. Astrocytic activation was evident within the cortical gray matter 20 days before birth, and was confined to the superficial laminae 12 days after birth. Clusters of activated microglia were detected in upper neocortical gray matter laminae shortly after birth. Neuronal development in affected sheep was undisturbed at these early ages. This prenatal activation of non-neuronal cells within the affected brain indicates the onset of pathogenesis during brain development and that an ordered sequence of glial activation precedes neurodegeneration.
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PMID:Activation of non-neuronal cells within the prenatal developing brain of sheep with neuronal ceroid lipofuscinosis. 1676 50

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are recessively inherited neurodegenerative disorders that affect humans and other animals, characterised by brain atrophy and the accumulation of lysosome derived fluorescent storage bodies in neurons and most other cells. Common clinical signs include blindness, ataxia, dementia, seizures and premature death. The associated genes for six different human forms have been identified (CLN1, CLN2, CLN3, CLN5, CLN6 and CLN8), and three other human forms suggested (CLNs 4, 7 and 9). A form of NCL in Australian Devon cattle is caused by a single base duplication (c.662dupG) in bovine CLN5. This mutation causes a frame-shift and premature termination (p.Arg221GlyfsX6) which is predicted to result in a severely truncated protein, analogous to disease causing mutations in human Finnish late infantile variant NCL (CLN5), and a simple genetic diagnostic test has been developed. The symptoms and disease course in cattle also matches CLN5. Only one initiation site was found in the bovine gene, equivalent to the third of four possible initiation sites in the human gene. As cattle are anatomically and physiologically similar to humans with a human-like central nervous system and easy to maintain and breed, they provide a valuable alternative model for CLN5 studies.
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PMID:Neuronal ceroid lipofuscinosis in Devon cattle is caused by a single base duplication (c.662dupG) in the bovine CLN5 gene. 1693 76

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are a group of fatal recessively inherited neurodegenerative diseases of humans and animals characterised by common clinical signs and pathology. These include blindness, ataxia, dementia, behavioural changes, seizures, brain and retinal atrophy and accumulation of fluorescent lysosome derived organelles in most cells. A number of different variants have been suggested and seven different causative genes identified in humans (CLN1, CLN2, CLN3, CLN5, CLN6, CLN8 and CTSD). Animal models have played a central role in the investigation of this group of diseases and are extremely valuable for developing a better understanding of the disease mechanisms and possible therapeutic approaches. Ovine models include flocks of affected New Zealand South Hampshires and Borderdales and Australian Merinos. The ovine CLN6 gene has been sequenced in a representative selection of these sheep. These investigations unveiled the mutation responsible for the disease in Merino sheep (c.184C>T; p.Arg62Cys) and three common ovine allelic variants (c.56A>G, c.822G>A and c.933_934insCT). Linkage analysis established that CLN6 is the gene most likely to cause NCL in affected South Hampshire sheep, which do not have the c.184C>T mutation but show reduced expression of CLN6 mRNA in a range of tissues as determined by real-time PCR. Lack of linkage precludes CLN6 as a candidate for NCL in Borderdale sheep.
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PMID:A missense mutation (c.184C>T) in ovine CLN6 causes neuronal ceroid lipofuscinosis in Merino sheep whereas affected South Hampshire sheep have reduced levels of CLN6 mRNA. 1704 13

The late-infantile-onset forms are the most genetically heterogeneous group among the autosomal recessively inherited neurodegenerative disorders, the neuronal ceroid lipofuscinoses (NCLs). The Turkish variant was initially considered to be a distinct genetic entity, with clinical presentation similar to that of other forms of late-infantile-onset NCL (LINCL), including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death. However, Turkish variant LINCL was recently found to be genetically heterogeneous, because mutations in two genes, CLN6 and CLN8, were identified to underlie the disease phenotype in a subset of patients. After a genomewide scan with single-nucleotide-polymorphism markers and homozygosity mapping in nine Turkish families and one Indian family, not linked to any of the known NCL loci, we mapped a novel variant LINCL locus to chromosome 4q28.1-q28.2 in five families. We identified six different mutations in the MFSD8 gene (previously denoted "MGC33302"), which encodes a novel polytopic 518-amino acid membrane protein that belongs to the major facilitator superfamily of transporter proteins. MFSD8 is expressed ubiquitously, with several alternatively spliced variants. Like the majority of the previously identified NCL proteins, MFSD8 localizes mainly to the lysosomal compartment. However, the function of MFSD8 remains to be elucidated. Analysis of the genome-scan data suggests the existence of at least three more genes in the remaining five families, further corroborating the great genetic heterogeneity of LINCLs.
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PMID:The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter. 1756 70


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