Foamy cells with oligodendroglial phenotype in childhood ataxia with diffuse central nervous system hypomyelination syndrome.

Childhood ataxia with diffuse central nervous system hypomyelination syndrome (CACH) is a recently described leukodystrophy of unknown etiology. To characterize the neuropathological features and gain insight as to the pathogenesis of this disorder, we studied cerebral tissue from six patients with the CACH syndrome. Evaluation of toluidine blue-stained, semithin sections of white matter from CACH patients disclosed unusual cells with "foamy" cytoplasm, small round nuclei and fine chromatin. Electron microscopy (EM) revealed cells in the white matter with abundant cytoplasm containing many mitochondria and loosely clustered, membranous structures, but lacking the lysosomal structures seen in macrophages. Further analysis of tissue sections with antibodies and special stains demonstrated that the abnormal cells with abundant cytoplasm labeled with oligodendroglial markers, but did not react with macrophage or astrocytic markers. Double immunolabeling with macrophage and oligodendroglial markers clearly distinguished macrophages from the "foamy" oligodendroglial cells (FODCs). Proteolipid protein (PLP) mRNA in situ hybridization demonstrated PLP mRNA transcripts in a high proportion of oligodendrocytes in CACH patients compared to control patients, and PLP mRNA transcript signal in cells, morphologically consistent with FODCs. Normal and pathological brain control tissues did not contain FODCs. These neuropathological findings will be useful pathological identifiers of CACH, and may provide clues to the pathogenesis of this disorder.

CD11b/CD18-coated microspheres attach to E-selectin under flow.

Neutrophils can attach to E-selectin under flow. Proposed ligands for E-selectin carry SLe(x)-type glycans. The leukocyte beta2 integrins are glycosylated with SLe(x). Thus, we speculated that beta2 integrins could support attachment to E-selectin. To test this hypothesis, we coated 10-microm-diameter microspheres with purified CD11b/CD18 (alphaMbeta2) and investigated the adhesion of the resulting alphaMbeta2 microspheres to E-selectin. Under in vitro flow conditions, the alphaMbeta2 microspheres attached to Chinese hamster ovary cells expressing E-selectin (CHO-E) and 4-h interleukin-1beta-activated human umbilical vein endothelial cells (HUVEC). At a shear stress of 1.8 dynes/cm2, the attachment events were eliminated by pretreatment of the cellular monolayers with a mAb to E-selectin. alphaMbeta2 microspheres did not attach to untransfected CHO cells or unactivated HUVEC at 1.8 dynes/cm2. Taken together, the results strongly suggest that the CD11b/CD18-E-selectin bond has sufficient biophysical properties to mediate attachment of neutrophil-sized particles to E-selectin under flow.

Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease.

Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). This enzymatic defect results in the accumulation of the glycosphingolipid globotriaosylceramide (Gb(3); also referred to as ceramidetrihexoside) throughout the body. To investigate the effects of purified alpha-gal A, 10 patients with Fabry disease received a single i.v. infusion of one of five escalating dose levels of the enzyme. The objectives of this study were: (i) to evaluate the safety of administered alpha-gal A, (ii) to assess the pharmacokinetics of i.v.-administered alpha-gal A in plasma and liver, and (iii) to determine the effect of this replacement enzyme on hepatic, urine sediment and plasma concentrations of Gb(3). alpha-Gal A infusions were well tolerated in all patients. Immunohistochemical staining of liver tissue approximately 2 days after enzyme infusion identified alpha-gal A in several cell types, including sinusoidal endothelial cells, Kupffer cells, and hepatocytes, suggesting diffuse uptake via the mannose 6-phosphate receptor. The tissue half-life in the liver was greater than 24 hr. After the single dose of alpha-gal A, nine of the 10 patients had significantly reduced Gb(3) levels both in the liver and shed renal tubular epithelial cells in the urine sediment. These data demonstrate that single infusions of alpha-gal A prepared from transfected human fibroblasts are both safe and biochemically active in patients with Fabry disease. The degree of substrate reduction seen in the study is potentially clinically significant in view of the fact that Gb(3) burden in Fabry patients increases gradually over decades. Taken together, these results suggest that enzyme replacement is likely to be an effective therapy for patients with this metabolic disorder.

Mucolipidosis type IV: characteristic MRI findings.

OBJECTIVE: The objective of this study is to characterize the brain abnormalities on head MRI of patients with mucolipidosis type IV. BACKGROUND: Mucolipidosis type IV is an autosomal recessive lysosomal storage disease of unknown etiology. Patients develop corneal clouding, retinal degeneration, spastic quadriparesis, and mental retardation. Patients with this disorder have not been studied systematically. METHODS: We studied prospectively 15 consecutive patients with mucolipidosis type IV using cranial MRI. RESULTS: Fourteen patients with these typical clinical findings had a hypoplastic corpus callosum with absent rostrum and a dysplastic or absent splenium, signal abnormalities on T1-weighted head MRI images in the white matter, and increased ferritin deposition in the thalamus and basal ganglia. Atrophy of the cerebellum and cerebrum was observed in older patients, which may reflect disease progression. One patient with a mild clinical variant had a normal corpus callosum. CONCLUSION: Patients with mucolipidosis type IV have characteristic cranial MRI findings that suggest that this disorder causes both developmental and neurodegenerative abnormalities.

Quantitative analysis of cerebral vasculopathy in patients with Fabry disease.

OBJECTIVE: This study's purpose was to obtain a quantitative natural history of the cerebrovascular involvement in Fabry disease. BACKGROUND: Fabry disease is an X-linked recessive disorder due to alpha-galactosidase A deficiency. Progressive accumulation of ceramidetrihexoside within the intima and media of cerebral blood vessels causes ischemic lesions in the majority of affected patients. Determination of the natural history of the cerebral vasculopathy in Fabry disease is important to assess the effects of therapeutic intervention in this disorder. METHODS: A longitudinal MRI study of 50 patients who had a total of 129 MRI scans was performed. The burden of cerebrovascular disease was determined using direct linear measurement. RESULTS: On T2-weighted MRI scans, 32% of the patients had no lesions (mean age, 33 years), 16% had gray matter lesions only (mean age, 36 years), 26% had lesions in white matter only (mean age, 43 years), and 26% had lesions in white and gray matter (mean age, 47 years). Disease burden increased with age, but no patient younger than 26 had lesions on MRI. All patients older than 54 had cerebrovascular involvement. The distribution of MRI-detectable lesions was typical of a small-vessel disease. Only 37.5% of patients with cerebral lesions had neurologic symptoms. CONCLUSION: These findings provide a predictable outcome measure to assess the effect of molecular interventions on the cerebrovascular circulation in Fabry disease.