Krabbe Globoid Cell Research Articles

Kunihiko Suzuki and sphingolipidoses

Kunihiko Suzuki is a neurologist by training whose research accomplishments range widely from basic research in brain lipids, their metabolism to genetic disorders involving the nervous system. Among them are identification of the enzymatic defect, the pathogenetic mechanism, and animal models of Krabbe's globoid cell leukodystrophy, the chemical and molecular pathologies of many glycosphingolipidoses, discovery of the abnormal accumulation of very long chain fatty acids in adrenoleukodystrophy, and elucidation of the complex metabolic interrelationship among sphingolipids with extensive use of the gene targeting technology. This reflections and perspectives highlight his accomplishments briefly.

Krabbe Globoid Cell Leukodystrophy: Electron Microscopy Shows Characteristic Inclusions in Eccrine Sweat Glands

Evidence for storage in eccrine sweat glands from skin biopsies of 7 patients with Krabbe globoid cell leukodystrophy is demonstrated. Clear cells showed characteristic free or intravacuolar inclusions containing needle-like and splinter-shaped structures with sometimes clearly outlined paracrystalline-like geometric configurations. These inclusions were very similar to those observed in the characteristic globoid cells found in the central nervous system and in Schwann cells of cutaneous, conjunctival and peripheral nerves. This finding suggests that the storage is not restricted to the nervous system. The diagnostic value of skin biopsy in Krabbe globoid cell leukodystrophy is emphasized.

Fatty Acid Composition of Human Myelin Proteolipid Protein in Peroxisomal Disorders

Myelin proteolipid protein (PLP) is an acylated protein which contains approximately 2 mol of ester-bound fatty acids. In this study, the amount and composition of fatty acids covalently bound to human myelin PLP were determined during development and in peroxisomal disorders. Palmitic, oleic, and stearic acids accounted for most of the PLP acyl chains. However, in contrast to PLP in other species, human PLP contains relatively more very long chain fatty acids (VLCFA). The fatty acid composition remained essentially unchanged between 1 day and 74 years of age. The total amount of fatty acid bound to PLP was not altered in any of the pathological cases examined. However, in the peroxisomal disorder adrenoleukodystrophy, the proportions of saturated and, to a lesser extent, monounsaturated VLCFA bound to PLP were increased at the expense of oleic acid. Smaller, but significant, changes were observed in adrenomyeloneuropathy. The reduction in the levels of oleic acid was also observed in two other peroxisomal disorders, the cerebrohepatorenal (Zellweger) syndrome and neonatal adrenoleukodystrophy, as well as in the lysosomal disorder Krabbe globoid cell leukodystrophy. However, in these disorders, the decrease in oleic acid occurred at the expense of stearic acid, and not VLCFA. The results indicate that, although a characteristic PLP fatty acid pattern is normally maintained, changes in the acyl chain pool can ultimately be reflected in the fatty acid composition of the protein. The altered PLP-acyl chain pattern in peroxisomal disorders may contribute to the pathophysiology of these devastating disorders.

A case of krabbe’s leukodystrophy without globoid cells

Krabbe's globoid cell leukodystrophy is a rare hereditary progressive neurological disease of infants, in which there is deficient activity of galactosylceramide beta-galactosidase. The pathological hallmark is the presence of multinucleated globoid cells in the white matter associated with severe myelin depletion and gliosis. We report a second case where galactosylceramide beta-galactosidase deficiency was proven but no globoid cells were found in the brain. Symptoms began within the first 10 months of life and a deficiency of galactosylceramide beta-galactosidase activity was demonstrated in peripheral blood leukocytes and skin fibroblasts. The child survived till 8 yrs 7 mths. The reason for the absence of globoid cells is not clear but may be related to different effects of the gene mutation on the four substrates or possibly the interaction of sphingolipid activator protein-2.

Intracerebral paraventricular hyperdensities: A new CT sign in Krabbe globoid cell leukodystrophy

Computer-assisted tomographic (CT) scanning showed intracranial paraventricular calcification in two out of six patients with enzymatically and/or histologically confirmed Krabbe globoid cell leukodystrophy (GLD) 1-5 months after the onset of symptoms of the disease.

Enzyme Replacement with Liposomes Containing β-Galactosidase in Murine Krabbe's Globoid Cell Leukodystrophy

Enzyme replacement with liposomes containing β-galactosidase obtained from charonia lumpas was carried out in murine globoid cell leukodystrophy (OLD) . Charonia lumpas β-galactosidase was able to hydrolyze galactocerebroside and trapped into liposomes prepared from lecithin, cholesterol and sulfatide (molar ratio; 7: 2: 1) . Liposomes containing charonia lumpas β-galactosidase were successfully incorporated into the mouse tissues, 3H-galactocerebroside labeled liposomes were also incorporated into mouse liver, spleen and other tissues. The accumulation rate of 3H-galactocerebroside into Twitcher mice liver and spleen was almost 40 to 100 times higher than those of controls and degraded to 70 to 80% of accumulated radioactivity of 3H-galactocere-broside by single injection of liposomes containing charonia lumpas β-galactosidase. Results suggest that exogeneous enzyme trapped in liposomes can be useful for the correction of accumulated compound.

Isoelectric focusing of galactosylceramide beta-galactosylceramide beta-galactosidase in cultured skin fibroblasts of patients with Krabbe's globoid-cell leucodystrophy.

Isoelectric focusing of galactosylceramide beta-galactosylceramide beta-galactosidase in cultured skin fibroblasts of patients with Krabbe's globoid-cell leucodystrophy.

Krabbe's globoid cell leukodystrophy: deficiency of glactocerebrosidase in serum, leukocytes, and fibroblasts.

The activity of galactocerebroside beta-galactosidase was extremely low in serum, leukocytes, and cultured fibroblasts of patients with Krabbe's disease. Antemortem diagnosis is possible without organ biopsies. The parents of patients showed enzyme activities generally lower than that of normal controls. This finding provides supportive evidence that the deficient activity of galactocerebroside beta-galactosidase is the genetically determined enzymatic defect underlying the disease. Demonstration of this deficiency requires the use of the specific substrate, galactocerebroside. Assays carried out with synthetic, unnatural substrates, such as 4-methylumbelliferyl beta-galactoside, do not distinguish patients or heterozygous carriers from normal individuals.

Globoid cell leukodystrophy (Krabbe's disease): isolation of myelin with normal glycolipid composition

Myelin was isolated from the brain of a patient with Krabbe's globoid cell leukodystrophy at 0.4% of the normal yield. Despite the exceedingly low yield, the fraction appeared morphologically clean, and consisted mostly of well-preserved myelin lamellae and few contaminating structures. Total lipid and cholesterol were slightly lower than in normal myelin. Total phospholipid was normal, but the ratio of ethanolamine phospholipid to lecithin was reversed. Total galactolipid was normal, and consisted only of cerebroside and sulfatide in normal proportions. The only sugar in cerebroside and sulfatide was galactose. The fatty acid composition of cerebroside and sulfatide was essentially normal with no deficiency of long-chain fatty acids and only with a reversed ratio of C(24:0) to C(24:1) in cerebroside. These data appear to exclude the previous postulate that abnormally rapid breakdown of myelin occurs in this disorder as the result of the formation of chemically abnormal myelin, deficient in sulfatide.

Globoid cell leucodystrophy (Krabbe's disease): deficiency of galactocerebroside beta-galactosidase.

Profound deficiency of a specific enzyme, galactocerebroside beta-galactosidase, has been demonstrated in the brains, liver, and spleen of three patients with Krabbe's globoid cell leucodystrophy. The activity of this enzyme was normal in a variety of other cerebral diseases, including those with similarly devasted white matter. The lack of enzyme activity was not due to an inhibitor in the tissue, nor is it due to a shift in the pH optimum. The deficiency of galactocerebroside beta-galactosidase as the primary enzymatic defect can account for the morphological and biochemical characteristics of this disease better than the previously reported deficiency of cerebroside-sulfatide sulfotransferase.

Segmental demyelination of peripheral nerves in Krabbe's disease.

THE current literature contains many references to peripheral neuropathies in a variety of conditions1–4. This communication describes a peripheral neuropathy associated with Krabbe's globoid cell leucodystrophy which is a progressive heredofamilial neurological disorder of infancy, and is usually diagnosed by either brain biopsy or at necropsy by the demonstration of characteristic “globoid” cells in the white matter. Bachhawat et al.5 ave described a deficiency of cerebroside sulphotransferase in the brain of two cases. Clinical descriptions and details of investigations of a series of patients suffering from this rare condition are in preparation.

EEG findings in late infantile metachromatic and globoid cell leucodystrophy

The EEG findings in five verified cases of late infantile metachromatic leucodystrophy and five verified cases of Krabbe's globoid cell dystrophy are described. Serial recordings have been available in at least one case of each disease. As a rule the EEG was normal in the beginning of the disease, whereas a general tendency to slowing occurred in later stages, sometimes asymmetrical, often mixed with paroxysmal or epileptogenic activity. The EEG changes observed in this material are in no way specific for the diseases and do not contribute much to the differential diagnosis in degenerative diseases of the nervous system in children.