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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical and biochemical findings in a male subject with progressive encephalopathy and peripheral neuropathy are presented. Early development was normal. At age 3.5 years, he had seizures associated with fever. Subsequently, there was progressive neurologic deterioration. A CT brain scan at age 4 years, 2 months demonstrated multiple areas of variable density in the white matter. There was mild slowing of nerve conduction velocities and a sural nerve biopsy revealed segmental demyelinative neuropathy. Metachromatic leukodystrophy was suspected, but arylsulfatase A activity in leukocytes and fibroblasts was in the normal range. The cerebroside sulfate loading test on intact cultured fibroblasts showed attenuated hydrolysis leading to a tentative diagnosis of cerebroside sulfatase activator deficiency. However, the attenuated response of proband fibroblasts was not normalized by supplementation with activator in a reproducible manner, and urine showed hyperexcretion rather than deficiency of activator. Ultimately, an assay for galactosylceramide beta-galactosidase activity established a deficiency of this enzyme leading to the diagnosis of late-onset Krabbe disease.
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PMID:Late-onset Krabbe disease initially diagnosed as cerebroside sulfatase activator deficiency. 290 3

The properties and distribution of beta-galactosidase were studied in the mouse brain using the artificial substrate methylumbelliferyl-beta-galactoside. Enzyme activities were compared between an audiogenic seizure-susceptible mouse strain (DBA/2) and three non-susceptible strains of mice (BALB/c, C3H/He and Swiss A2G). At all ages, DBA/2 mice have significantly lower beta-galactosidase activity compared with the three other mouse strains: this is attributed to the different alleles present at the Bgs locus. The low activity of beta-galactosidase is also evident when the natural substrate GMl-ganglioside is hydrolyzed. In contrast to this low GMl-ganglioside-beta-galactosidase activity, there is no difference in the activity of the second form of acid beta-galactosidase, galactosylceramidase, in DBA/2 mice at 7 and 14 days. However, at 21 and 28 days the activity is significantly lower in DBA/2 mice compared with the other strains of mice. These results on beta-galactosidase activity in the brain of seizure-susceptible and non-susceptible mice are discussed in relation to published levels of GMl-ganglioside and galactosylceramide present in the developing mouse brain.
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PMID:Substrate specificity and distribution of acid beta-galactosidase activities in seizure-susceptible and non-susceptible strains of mice. 643 23

Early infantile Krabbe disease is a progressive neurodegenerative disease caused by deficiency of lysosomal enzyme galactocerebroside beta-galactosidase, with onset before the age of 6 months. We present serial clinical, radiological and neurophysiological findings of a patient with early infantile Krabbe disease, presenting at the third day of life with hypotonia, macrocephaly and neonatal seizures. The patient had a deceptively normal initial magnetic resonance imaging examination at the age of 3 months, with progression of the white matter disease over the following 9 months, showing a clinical picture of profound hypotonia with pyramidal and pseudobulbar signs, as well as mild optic atrophy. Assay of galactocerebroside beta-galactosidase activity in leukocyte culture disclosed a marked deficiency of the enzyme (0.00 nmol/mg protein per h with normal values > 0.7 nmol/mg protein per h), thus confirming the diagnosis of Krabbe disease. Nerve conduction velocity and evoked potential studies, as well as the electroencephalogram, were abnormal at the age of 6 months, while serial neurophysiological studies at the age of 12 and 18 months demonstrated the progressive nature of the disease.
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PMID:Early infantile Krabbe disease: deceptively normal magnetic resonance imaging and serial neurophysiological studies. 940 97

We have cross-bred twitcher mice (galactosylceramidase deficiency) and acid beta-galactosidase knockout mice (G(M1) gangliosidosis) and found that the acid beta-galactosidase gene dosage exerts an unexpected and paradoxical influence on the twitcher phenotype. Twitcher mice with an additional complete deficiency of acid beta-galactosidase have the mildest phenotype with the longest lifespan and nearly rescued CNS pathology. In contrast, twitcher mice with a single functional acid beta-galactosidase gene have the most severe disease with the shortest lifespan, despite the fact that G(M1) gangliosidosis carrier mice with an otherwise normal genetic background are phenotypically normal. A significant proportion of these galc(-/-), bgal(+/-) mice clinically develop additional extreme hyper-reactivity and generalized seizures not seen in any other genotypes. Consistent with the clinical seizures, widespread neuronal degeneration is present in the galc(-/-), bgal(+/-) mice, most prominently in the CA3 region of the hippocampus. The double knockout mice show a massive accumulation of lactosylceramide in all tissues. The brain inexplicably contains only a half-normal amount of galactosylceramide, which may account for the mild clinical and pathological phenotype. On the other hand, brain psychosine level is increased in all twitcher mice, but galc(-/-), bgal(+/-) mice show a significantly higher level than other genotypes. The reduced galactosylceramide in the brain of the double knockout mice and the significantly higher psychosine in the brain of the galc(-/-), bgal(+/-) mice cannot readily be explained from the genotypes of these mice. These observations are contrary to the expected outcome of Mendelian autosomal recessive single gene disorders and may also be interpreted as that the acid beta-galactosidase gene functions as a modifier gene for the phenotypic expression of genetic galactosylceramidase deficiency.
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PMID:Paradoxical influence of acid beta-galactosidase gene dosage on phenotype of the twitcher mouse (genetic galactosylceramidase deficiency). 1086 Dec 97

We report three children, each of whom seemed to have a primary mitochondrial disorder at presentation but was eventually diagnosed with an extramitochondrial inherited metabolic disease. The first patient presented at 6 months with developmental delay. Magnetic resonance imaging showed an abnormal signal in the white matter, and magnetic resonance spectroscopy showed elevated lactate peaks. A muscle biopsy showed complex IV deficiency, but leukocyte measurement of galactosylceramide beta-galactosidase activity was markedly diminished, consistent with Krabbe's disease. The second patient presented at birth with seizures and later had developmental delays. There was brain atrophy on neuroimaging. Serum and cerebrospinal fluid lactate levels were elevated. She had persistently elevated urine thiosulfate, which was diagnostic for molybdenum cofactor deficiency. The third child presented at 2 months with seizures and hypotonia. Magnetic resonance imaging showed an abnormal signal in the basal ganglia and surrounding white matter, whereas magnetic resonance spectroscopy showed elevated lactate peaks. A brain biopsy was diagnostic for Alexander's disease. These cases and others in the literature suggest that lactic acid elevation in the central nervous system can be found in a number of extramitochondrial neurologic diseases. Such diseases would constitute a third category of lactic acidosis.
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PMID:Lactic acid elevation in extramitochondrial childhood neurodegenerative diseases. 1157 6

The twitcher mouse is well known as a naturally occurring authentic mouse model of human globoid cell leukodystrophy (GLD; Krabbe disease) due to genetic deficiency of lysosomal galactosylceramidase. The twitcher mice used most commonly are on the C57BL/6J background. We generated twitcher mice that were on the mixed background of C57BL/6J and 129SvEv, the standard strain for production of targeted mutations. Twitcher mice on the mixed background were smaller and had a shorter lifespan than were those on the C57BL/6J background. Many twitcher mice on the mixed background developed generalized seizures around 30 days that were never seen in twitcher mice on the C57BL/6J background. Neuropathologically, although the degree of the typical demyelination with infiltration of macrophages was similar in the central and peripheral nervous systems, in both strains, marked neuronal cell death was observed only in twitcher mice on the mixed background. In the hippocampus, the neuronal cell death occurred prominently in the CA3 region in contrast to the relatively well-preserved CA1 and CA2 areas. This neuropathology has never been seen in twitcher mice on the C57BL/6J background. Biochemically, the brain of twitcher mice on the mixed background showed much greater accumulation of lactosylceramide. Genetic background must be carefully taken into consideration when phenotype of mutant mice is evaluated, particularly because most targeted mutants are initially on a mixed genetic background and gradually moved to a pure background. These findings also suggest an intriguing possibility of important function of some sphingolipids in the hippocampal neuronal organization and maintenance.
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PMID:Genetic background markedly influences vulnerability of the hippocampal neuronal organization in the "twitcher" mouse model of globoid cell leukodystrophy. 1526 20

Krabbe disease is a rare, recessively inherited degenerative disorder of myelin, caused by a deficiency of the lysosomal enzyme galactocerebroside beta-galactosidase. Ninety-five percent of cases begin in early infancy, typically presenting with irritability, hypertonicity, tonic spasms, visual loss with optic atrophy, and occasionally seizures. In 5% of cases, symptoms begin late, between 15 months and 10 years, usually presenting with spastic paralyses, cerebellar ataxia, visual failure, and peripheral neuropathy. Seizures occasionally develop months to years after symptom onset. In a review of 50 such cases from the world literature, in only two did seizures signal the onset. This report describes an 18-month-old male with late-onset Krabbe disease who is the first such reported patient presenting with myoclonic seizures, an epileptic encephalopathy normally thought to reflect gray matter disease.
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PMID:Myoclonic seizures in Krabbe disease: a unique presentation in late-onset type. 1687 17

Globoid-cell Leukodystrophy (GLD; Krabbe's disease) is a rapidly progressing inherited demyelinating disease caused by a deficiency of the lysosomal enzyme Galactosylceramidase (GALC). Deficiency of GALC leads to altered catabolism of galactosylceramide and the cytotoxic lipid, galactosylsphingosine (psychosine). This leads to a rapidly progressive fatal disease with spasticity, cognitive disability and seizures. The murine model of GLD (Twitcher; GALC-/-) lacks the same enzyme and has similar clinical features. The deficiency of GALC leads to oligodendrocyte death, profound neuroinflammation, and the influx of activated macrophages into the CNS. We showed previously that keratinocyte chemoattractant factor (KC) is highly elevated in the CNS of untreated Twitcher mice and significantly decreases after receiving a relatively effective therapy (bone marrow transplantation combined with gene therapy). The action of KC is mediated through the CXCR2 receptor and is a potent chemoattractant for macrophages and microglia. KC is also involved in oligodendrocyte migration and proliferation. Based on the commonalities between the disease presentation and the functions of KC, we hypothesized that KC and/or CXCR2 contribute to the pathogenesis of GLD. Interestingly, the course of the disease is not significantly altered in KC- or CXCR2-deficient Twitcher mice. There is also no alteration in inflammation or demyelination patterns in these mice. Furthermore, transplantation of CXCR2-deficient bone marrow does not alter the progression of the disease as it does in other models of demyelination. This study highlights the role of multiple redundant cytokines and growth factors in the pathogenesis of GLD.
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PMID:Central nervous system pathology progresses independently of KC and CXCR2 in globoid-cell leukodystrophy. 2375 34

Globoid cell leukodystrophy (GLD) is a neurological disease caused by deficiency of the lysosomal enzyme galactosylceramidase (GALC). In the absence of GALC, the cytotoxic glycosphingolipid, psychosine (psy), accumulates in the nervous system. Psychosine accumulation preferentially affects oligodendrocytes, leading to progressive demyelination and infiltration of activated monocytes/macrophages into the CNS. GLD is characterized by motor defects, cognitive deficits, seizures, and death by 2-5 years of age. It has been hypothesized that psychosine accumulation, primarily within lipid rafts, results in the pathogenic cascade in GLD. However, the mechanism of psychosine toxicity has yet to be elucidated. Therefore, we synthesized the enantiomer of psychosine (ent-psy) to use as a probe to distinguish between protein-psy (stereo-specific enantioselective) or membrane-psy (stereo-insensitive nonenantioselective) interactions. The enantiomer of psychosine has equal or greater toxicity compared with psy, suggesting that psy exerts its toxicity through a nonenantioselective mechanism. Finally, in this study we demonstrate that psy and ent-psy localize to lipid rafts, perturb natural and artificial membrane integrity, and inhibit protein Kinase C translocation to the plasma membrane. Although other mechanisms may play a role in disease, these data strongly suggest that psy exerts its effects primarily through membrane perturbation rather than through specific protein-psy interactions.
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PMID:Psychosine, the cytotoxic sphingolipid that accumulates in globoid cell leukodystrophy, alters membrane architecture. 2400 12

Krabbe disease (globoid cell leukodystrophy, GLD) is an inherited disease caused by a deficiency in the lysosomal enzyme galactocerebrosidase (GALC). The major galactosylated lipid degraded by GALC is galactosylceramide. However, GALC is also responsible for the degradation of galactosylsphingosine (psychosine), a highly cytotoxic glycolipid. It has been hypothesized that GALC-deficiency leads to psychosine accumulation that preferentially kills oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. Krabbe disease has traditionally been considered a white matter disease characterized by the loss and disorganization of myelin, infiltration of multinucleated monocytes/macrophages (globoid cells) and lymphocytes, and dysregulation of pro-inflammatory cytokines and chemokines. However, new studies have revealed unexpected neuronal deficiencies. Infantile Krabbe disease is believed to be the most common and aggressive form. However, juvenile and adult onset forms have been described. Children affected with infantile Krabbe disease present with motor dysfunction, cognitive decline, intractable seizures, and premature death between two to five years of age. Murine, canine, and primate models of GALC deficiency have been described and have played an important role in our understanding of this invariably fatal disease. Although there is no cure for Krabbe disease, hematopoietic stem cell transplantation can slow the progression of disease. Recent pre-clinical data indicate that simulataneously targeting multiple pathogenic mechanisms greatly increases efficacy in the murine model of Krabbe disease. A better understanding of the underlying pathogenesis will identify new therapeutic targets that may further increase efficacy.
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PMID:Insights into the Pathogenesis and Treatment of Krabbe Disease. 2749 Dec 17


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