Globoid cell leukodystrophy: distinguishing early-onset from late-onset disease using a brain MR imaging scoring method.
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BACKGROUND AND PURPOSE: Our purpose was to determine the characteristic MR features of early-onset (before age 2 years) versus late-onset (after age 2 years) globoid cell leukodystrophy (GLD). METHODS: Thirty-four brain MR images in 22 patients with GLD were reviewed. A severity score (0 to 32), based on a point system derived from the location and extent of disease and the presence of focal and/or global atrophy, was calculated for each examination. RESULTS: Of the 22 patients, three were asymptomatic and 19 were symptomatic. Ten patients had early-onset disease, whereas nine had late-onset disease. MR images of all patients showed abnormalities. In the early-onset group (n = 10; mean maximum MR score, 8.1; range, 3-18), 90% had pyramidal tract involvement, 80% had cerebellar white matter involvement, 70% had deep gray matter involvement, 60% had posterior corpus callosal involvement, 50% had parietooccipital white matter involvement, and 40% had cerebral atrophy. Serial MR imaging in four of these patients revealed progressive disease. In the late-onset group (n = 9; mean maximum MR score, 5.6; range, 4-10), 100% had pyramidal tract involvement, 100% had parietooccipital white matter involvement, 89% had posterior corpus callosal involvement, and none had cerebellar white matter involvement, deep gray matter involvement, or cerebral atrophy. Serial MR imaging in one patient with late-onset GLD did not reveal any change. A spectrum of findings was observed in the three patients who were asymptomatic. CONCLUSION: Cerebellar white matter and deep gray matter involvement are present only in early-onset GLD. Pyramidal tract involvement is a characteristic finding in both early- and late-onset GLD. This scoring method for brain MR observations will assist in the objective assessment of the impact of hematopoietic stem cell transplantation in patients with GLD. (+info)
Optic nerve enlargement in Krabbe's disease.
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We report imaging and gross pathologic findings from two cases of Krabbe disease in which there was marked enlargement of the intracranial optic nerves. Numerous globoid cells were observed in the optic nerves at autopsy in one case. Krabbe disease should be included in the differential diagnosis of children with enlargement of the optic nerves. (+info)
Inhibition of cytokinesis by a lipid metabolite, psychosine.
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Although a number of cellular components of cytokinesis have been identified, little is known about the detailed mechanisms underlying this process. Here, we report that the lipid metabolite psychosine (galactosylsphingosine), derived from galactosylceramide, induced formation of multinuclear cells from a variety of nonadherent and adherent cells due to inhibition of cytokinesis. When psychosine was added to the human myelomonocyte cell line U937, which was the most sensitive among the cell lines tested, cleavage furrow formed either incompletely or almost completely. However, abnormal contractile movement was detected in which the cellular contents of one of the hemispheres of the contracting cell were transferred into its counterpart. Finally, the cleavage furrow disappeared and cytokinesis was reversed. Psychosine treatment also induced giant clots of actin filaments in the cells that probably consisted of small vacuoles with filamentous structures, suggesting that psychosine affected actin reorganization. These observations could account for the formation of multinuclear globoid cells in the brains of patients with globoid cell leukodystrophy, a neurological disorder characterized by the accumulation of psychosine due to galactosylceramidase deficiency. (+info)
MR imaging and proton MR spectroscopy in adult Krabbe disease.
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We present the MR imaging findings in four patients (two pairs of siblings from two unrelated families) with adult Krabbe disease. In the first family, clinical presentation mimicked familial spastic paraplegia. Their MR images showed selective, increased signal intensity on T2-weighted sequences along the corticospinal tracts, most prominently in the proband and barely detectable in her brother. Proton MR spectroscopy showed increased choline and myo-inositol in the affected white matter. In the second family, the clinical presentation differed in that the signs of pyramidal tract involvement were asymmetrical, with concomitant asymmetry on MR images in one. In adults, Krabbe disease may present on MR imaging with selective pyramidal fiber involvement. (+info)
Globoid cell leukodystrophy: the first case with antemortem diagnosis in Japan.
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A Japanese boy was diagnosed as globoid cell leukodystrophy on the basis of a marked decrease in the galactocerebroside beta-galactosidase activity in the leukocytes and the serum when one year and two months old. At autopsy when 1 year and 10 months, microscopic findings were characteristic for those of globoid cell leukodystrophy. Galactocerebroside beta-galactosidase activities of leukocytes and sera of his father and mother were found to be half those of control subjects, thus it suggested the parents being heterozygotes of the disease. (+info)
Electroencephalographic findings in a case of globoid cell leukodystrophy.
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An increased slow wave pattern of the EEG basic waves without epileptogenic discharges was observed in an early stage of a case of Krabbe's disease. In the later stage of the illness, spikes and sharp waves were mixed with. The peculiar runs of fast activity which were described by Kliemann et al. (1969) were not observed during the course of our patient. (+info)
Identification of a molecular target of psychosine and its role in globoid cell formation.
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Globoid cell leukodystrophy (GLD) is characterized histopathologically by apoptosis of oligodendrocytes, progressive demyelination, and the existence of large, multinuclear (globoid) cells derived from perivascular microglia. The glycosphingolipid, psychosine (d-galactosyl-beta-1,1' sphingosine), accumulates to micromolar levels in GLD patients who lack the degradative enzyme galactosyl ceramidase. Here we document that an orphan G protein-coupled receptor, T cell death-associated gene 8, is a specific psychosine receptor. Treatment of cultured cells expressing this receptor with psychosine or structurally related glycosphingolipids results in the formation of globoid, multinuclear cells. Our discovery of a molecular target for psychosine suggests a mechanism for the globoid cell histology characteristic of GLD, provides a tool with which to explore the disjunction of mitosis and cytokinesis in cell cultures, and provides a platform for developing a medicinal chemistry for psychosine. (+info)
Quantification of cellular acid sphingomyelinase and galactocerebroside beta-galactosidase activities by electrospray ionization mass spectrometry.
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BACKGROUND: Diagnosis of Niemann-Pick (A and B) and Krabbe diseases is achieved by measurement of the lysosomal enzymes acid sphingomyelinase (ASM) and galactocerebroside beta-galactosidase (GCG), respectively. Conventional assays use radiolabeled or fluorescent substrates and do not allow simultaneous determination of two or more enzymes in the sample. METHODS: We developed a sensitive and specific method to assay ASM and GCG in skin fibroblast homogenates using biotinylated substrate conjugates. The products were purified by bioaffinity capture on streptavidin-agarose beads and, following release, were analyzed by electrospray ionization mass spectrometry. Quantification was achieved using stable-isotope-labeled internal standards that were chemically identical to the products of the enzymatic reactions. RESULTS: The method demonstrated excellent linearity of ASM and GCG enzymatic product formation with the amount of cellular protein and incubation time. The range of ASM activities in fibroblast lysates from six healthy patients was 39-70 nmol. mg(-1). h(-1) compared with 3.7-5.1 nmol. mg(-1). h(-1) in cell lysates from two patients affected with Niemann-Pick A disease. The GCG activities toward the corresponding substrate conjugate were 4.0-6.8 nmol. mg(-1). h(-1) in cell lysates from healthy patients compared with 0.1-0.2 nmol. mg(-1). h(-1) in cell lysates from two patients affected with Krabbe disease. The amounts of substrate conjugates needed per analysis were 15 nmol (14 microg) for both ASM and GCG. CONCLUSIONS: Electrospray mass spectrometry combined with the use of biotinylated substrate conjugates and bioaffinity purification represents a new approach for the diagnosis of lysosomal storage diseases as demonstrated for Niemann-Pick A and Krabbe diseases. No radioactive substrates are used, and the method uses a single instrumental platform to determine both ASM and GCG in one cell sample. (+info)