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

Northern epilepsy is an autosomal recessive childhood onset epilepsy syndrome, clinically characterized by generalized tonic-clonic seizures with onset at 5 to 10 years of age and subsequent slowly progressive mental deterioration. The patients may reach 50 or 60 years of age. A mutation responsible for the disease has recently been identified in a novel gene on chromosome 8p23, encoding a putative membrane protein with an unknown function. The present study, based on three autopsied patients, is the first neuropathological analysis of the disease, and showed intraneuronal accumulation of cytoplasmic autofluorescent granules. The granules were strongly stained by the Luxol fast blue, periodic acid-Schiff, and Sudan black B methods in paraffin sections, and were immunoreactive for subunit c of the mitochondrial ATP synthase and sphingolipid activator proteins A and D. The intraneuronal storage was highly selective: the third layer of the isocortex and the hippocampal CA2, CA3, and CA4 sectors were severely affected, while other layers of the isocortex, the CA1 sector, and the cerebellar cortex were only minimally involved. The membrane-bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. Western blotting and N-terminal sequence analysis of purified storage material identified subunit c as the major component. These findings establish Northern epilepsy as a new form of neuronal ceroid-lipofuscinosis with an exceptionally protracted course.
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PMID:Northern epilepsy: a novel form of neuronal ceroid-lipofuscinosis. 1076 41

Cathepsin D-deficient (CD-/-) mice have been shown to manifest seizures and become blind near the terminal stage [approximately postnatal day (P) 26]. We therefore examined the morphological, immunocytochemical, and biochemical features of CNS tissues of these mice. By electron microscopy, autophagosome/autolysosome-like bodies containing part of the cytoplasm, granular osmiophilic deposits, and fingerprint profiles were demonstrated in the neuronal perikarya of CD-/- mouse brains after P20. Autophagosomes and granular osmiophilic deposits were detected in neurons at P0 but were few in number, whereas they increased in the neuronal perikarya within days after birth. Some large-sized neurons having autophagosome/autolysosome-like bodies in the perikarya appeared in the CNS tissues, especially in the thalamic region and the cerebral cortex, at P17. These lysosomal bodies occupied the perikarya of almost all neurons in CD-/- mouse brains obtained from P23 until the terminal stage. Because these neurons exhibited autofluorescence, it was considered that ceroid lipofuscin may accumulate in lysosomal structures of CD-/- neurons. Subunit c of mitochondrial ATP synthase was found to accumulate in the lysosomes of neurons, although the activity of tripeptidyl peptidase-I significantly increased in the brain. Moreover, neurons near the terminal stage were often shrunken and possessed irregular nuclei through which small dense chromatin masses were scattered. These results suggest that the CNS neurons in CD-/- mice show a new form of lysosomal accumulation disease with a phenotype resembling neuronal ceroid lipofuscinosis.
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PMID:Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. 1099 34

Northern epilepsy, or progressive epilepsy with mental retardation (EPMR), is an autosomal recessive disorder characterized by normal early development, onset of generalized tonic-clonic seizures between the ages of 5 and 10 years, and subsequent progressive mental retardation. The seizures increase in frequency until puberty after which the epileptic activity starts to decline. Mental retardation begins 2-5 years after the onset of seizures and continues through adulthood. Neuropathological findings have shown that EPMR is a new member (CLN8) of the neuronal ceroid lipofuscinosis (NCL) group of neurodegenerative disorders. The CLN8 gene was identified recently. It encodes a 286 amino acid putative transmembrane protein with no homology to previously known proteins. Subsequently, the homologous mouse gene (Cln8) was sequenced and localized to the region of the mouse genome linked to motor neuron degeneration, mouse mnd. Mnd is a naturally occurring mouse mutant with intracellular autofluorescent inclusions similar to those seen in human CLN8. A mutation in mnd mouse DNA was identified, indicating that mnd is a murine model for CLN8.
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PMID:Northern epilepsy, a new member of the NCL family. 1107 27

Neuronal ceroid lipofuscinoses are a group of rare neurodegenerative disorders that are characterised by an accumulation of autofluorescent lipopigments in neurons and extraneuronal tissues. We report on a 4-year-old boy who presented with an acute onset of seizures followed by rapid psychomotor deterioration, ataxia, and visual failure. Photic stimulation at 1 to 3 Hz elicited discrete spike and wave discharges in the electroencephalogram, which were diminished at a higher frequency of stimulation. The electroretinogram was extinct. Magnetic resonance imaging of the brain showed generalised cerebral and cerebellar atrophy. Electron microscopic examination of lymphocytes and samples of muscle and skin revealed characteristic curvilinear inclusion bodies. To our knowledge, this is the first case of late infantile neuronal ceroid lipofuscinosis to be reported in a Hong Kong Chinese patient.
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PMID:Classic late infantile neuronal ceroid lipofuscinosis in a Chinese patient. 1140 82

A 5-year-old boy presented with frequent absences. Speech began to regress. He became ataxic, barely able to walk. Studies with Xe-133 and hexamethylpropylene amine oxime single-photon emission computed tomography revealed sharply decreased cerebral blood flow, especially in the occipital area. Landau-Kleffner syndrome was suspected but a sleep electroencephalogram showed few abnormalities. He was started on clorazepate and diltiazem. A skin biopsy to rule out possible CLN2 revealed, instead of the predicted curvilinear profiles, granular osmiophilic deposits, consistent with infantile neuronal ceroid lipofuscinosis (CLN1). The family reported increased seizure frequency and consulted with a colleague, who advised them to resume valproate and discontinue diltiazem. The boy died shortly thereafter. Decreased cerebral blood flow is a new finding in CLN1 with delayed onset. Calcium-channel blockers improve cerebral blood flow and perhaps delay clinical regression.
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PMID:Impaired temporo-occipital blood flow in an atypical CLN1 case with late infantile onset and granular osmiophilic deposits. 1158 94

PPT1 and PPT2 encode two lysosomal thioesterases that catalyze the hydrolysis of long chain fatty acyl CoAs. In addition to this function, PPT1 (palmitoyl-protein thioesterase 1) hydrolyzes fatty acids from modified cysteine residues in proteins that are undergoing degradation in the lysosome. PPT1 deficiency in humans causes a neurodegenerative disorder, infantile neuronal ceroid lipofuscinosis (also known as infantile Batten disease). In the current work, we engineered disruptions in the PPT1 and PPT2 genes to create "knockout" mice that were deficient in either enzyme. Both lines of mice were viable and fertile. However, both lines developed spasticity (a "clasping" phenotype) at a median age of 21 wk and 29 wk, respectively. Motor abnormalities progressed in the PPT1 knockout mice, leading to death by 10 mo of age. In contrast, the majority of PPT2 mice were alive at 12 mo. Myoclonic jerking and seizures were prominent in the PPT1 mice. Autofluorescent storage material was striking throughout the brains of both strains of mice. Neuronal loss and apoptosis were particularly prominent in PPT1-deficient brains. These studies provide a mouse model for infantile neuronal ceroid lipofuscinosis and further suggest that PPT2 serves a role in the brain that is not carried out by PPT1.
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PMID:Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. 1171 24

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

We describe the first three cases of classical, late-infantile, neuronal ceroid lipofuscinosis from Russia. All of the patients had seizures, myoclonia, cognitive deterioration, cerebellar and pyramidal signs and also optic atrophy. Parkinsonian features were observed in one case. Electroencephalogram, evoked potentials, fundoscopy and magnetic resonance imaging (MRI) findings were characteristic for classical, late-infantile, neuronal ceroid lipofuscinosis. There was also evidence of hypointensity of the thalami in T2-weighted MRI in one patient, which was not reported earlier. Nerve conduction velocity was slowed in one case. All patients were found to have significantly reduced tripeptidyl peptidase 1 activity. All patients were homozygous for g3670 C-->T (Arg208Stop) mutation. We presume that this mutation is common in Russia.
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PMID:The first three Russian cases of classical, late-infantile, neuronal ceroid lipofuscinosis. 1236 3

We examined 26 individuals with clinical and electron microscopic signs of late infantile neuronal ceroid lipofuscinosis (LINCL). In 22 cases, we found both pathogenic alleles. Sixteen patients exclusively carried either one or a combination of the two common mutations R208X and IVS5-1G > C. In the remaining cases, four missense mutations could be detected, of which R127Q, N286S, and T353P represent novel, previously not described alleles. A clinical performance score was developed by rating motor, visual, and verbal functions and the incidence of cerebral seizures in 3-month intervals during the course of the disease. A Total Disability Score was derived by summing up the single scores for motor, visual, and verbal functions. The 16 individuals with the two common mutations were grouped together (referred to as standard patients), and the 5th, 50th, and 95th centiles were calculated and graphically depicted over time. The scores for motor function and language ability dropped earliest and progressed very similarly in the standard patients. The performance curves of two children with the N286S mutation slightly diverged from the 95th centile. However, the performance curves of one patient with atypical LINCL carrying the R127Q mutation fell far beyond the 95th centile. The presented performance rating clearly and quantitatively delineates the disease course of the LINCL patients and hence offers a useful tool for clinical evaluation of future therapeutic interventions. In addition, the described performance score system can be applied to other types of neuronal ceroid lipofuscinoses and could be adapted to various other neurodegenerative diseases of childhood.
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PMID:Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations. 1237 36


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