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PubMed1989

Muscle-eye-brain disease (MEB)

Clinical features of a rare congenital myopathy, muscle-eye-brain (MEB) disease, are described in 19 patients. The pedigree data suggest an autosomal recessive inheritance. The patients presented with congenital hypotonia and muscle weakness. Serum CK was elevated, EMG was myopathic and muscle biopsy showed slight or moderate changes compatible with muscular dystrophy. Ophthalmological findings included severe visual failure and uncontrolled eye movements associated with severe myopia. The flash VEPs were exceptionally high, whereas non-corneal ERG was unrecordable. The EEG showed progressive abnormalities after the age of 6 months. Psychomotor development was slow during the first years of life, and mental retardation was severe. Most patients began to deteriorate around age 5 years. This change included spasticity and joint contractures. CT scans showed ventricular dilatations and abnormally low white matter density in several patients. Spasticity, high VEPs and ocular manifestations differentiate MEB from the Fukuyama type congenital muscular dystrophy.

Adolescent↗
PubMed1994

Identification of a metalloprotease from Alzheimer's disease brain able to degrade the beta-amyloid precursor protein and generate amyloidogenic fragments.

A 4.2-kDa polypeptide termed beta protein (A beta) accumulates in senile plaques and blood vessels in Alzheimer's disease and Down's syndrome. It is widely believed that A beta is the product of the posttranslational processing of a larger precursor protein, the beta amyloid precursor protein (APP). The proteolytic processes involved in the generation of the A beta are virtually unknown. Here the purification and characterization of a protease from Alzheimer's disease brain capable of cleaving a 10 amino acid synthetic substrate flanking the N terminus of A beta at the Met-Asp bond are described. Most importantly, the purified protease degrades human recombinant APP and generates a 15-kDa amyloidogenic fragment. The protease requires the presence of a reducing agent for its activity. Its pH optimum is around physiological pH, while the enzyme is inactive at acidic pH (below pH 5.0) and basic pH (over pH 7.6). The enzyme is inhibited by N-ethylmaleimide, (hydroxymercuri)benzoate, 1.10-phenanthroline, EDTA, and EGTA. Phenylmethanesulfonyl fluoride has no effect on its activity. This protease is devoid of caseinolytic or gelatinase activities, as well as activities against cathepsin B and cathepsin L substrates. Sequence analysis reveals high homology to the rat metallopeptidase EC 3.4.24.15, a protease involved in neuropeptide processing.

Alzheimer Disease↗
PubMedDate not supplied

Cerebrospinal fluid and plasma concentration of soluble intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and endothelial leukocyte adhesion molecule in patients with acute ischemic brain disease.

BACKGROUND: Leukocyte migration into the ischemic area is a complex process, controlled by adhesion molecules (AM) in leukocytes and endothelium, by migratory capacity of leukocytes and the presence of hemotaxic agents in the tissue. In this research it was supposed that in the blood and cerebrospinal fluid (CSF) of patients in the acute phase of ischemic brain disease (IBD) there were relevant changes in the concentration of soluble AM (sICAM-1, sVCAM-1 and sE-selectin), that could have been the indicators of the intensity of damaging processes in central nervous system (CNS). METHODS: The study included 45 IBD patients, 15 with transient ischemic attack (TIA), 15 with reversible ischemic attack (RIA), and 15 with brain infarction (BI), of both sexes, mean age 66 +/- 7. Control group consisted of 15 patients with radicular lesions of discal origin, subjected to diagnostic radiculography, without the signs of interruption in the passage of CSF. Changes of selected biochemical parameters were determined in all patients in frame 72 hours since the occurrence of an ischemic episode. Concentrations of soluble AM were determined in plasma and CSF by ELISA. Total number of leukocytes (TNL) in peripheral blood was determined by hematological analyzer. RESULTS: The results showed that during the first 72 hrs of IBD significant increases occurred in TNL and that the increase was progressive compared to the severeness of the disease. Significant increase of soluble AM concentration was shown in plasma of IBD patients. The increase was highest in BI, somewhat lower in RIA and the lowest in TIA patients compared to the control. In CSF concentrations of sICAM-1, sVCAM-1 and sE-selectin demonstrated similar increasing trend as in plasma. CONCLUSION: TNL, as well as the soluble AM concentrations in plasma and CSF, were increased during the acute IBD phase and progressive in relation to the severeness of the disease, so that they might have been the indicators of CNS inflammatory reaction intensity. Furthermore, the results indicated their role in IBD pathogenesis and offered the possibility of researching the application of antagonists and/or activity modulators of some of them in IBD therapy.

Acute Disease↗
PubMed2002

Deficiency of alpha-dystroglycan in muscle-eye-brain disease.

Alpha-dystroglycan is a component of the dystrophin-glycoprotein-complex, which is the major mechanism of attachment between the cytoskeleton and the extracellular matrix. Muscle-eye-brain disease (MEB) is an autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities and lissencephaly. We recently found that MEB is caused by mutations in the protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase (POMGnT1) gene. POMGnT1 is a glycosylation enzyme that participates in the synthesis of O-mannosyl glycan, a modification that is rare in mammals but is known to be a laminin-binding ligand of alpha-dystroglycan. Here we report a selective deficiency of alpha-dystroglycan in MEB patients. This finding suggests that alpha-dystroglycan is a potential target of POMGnT1 and that altered glycosylation of alpha-dystroglycan may play a critical role in the pathomechanism of MEB and some forms of muscular dystrophy.

Child↗
PubMedDate not supplied

Muscle and brain disease: an update.

A number of syndromes included under this rubric are considered, and their main features discussed. The congenital muscular dystrophy of the Fukuyama type as it occurs in Japan and in the western world are almost certainly the same condition. The muscle disorder is associated with cerebral lesions which may be due to an arrest of neural migration or to demyelination. Muscle, eye and brain disease, or Santavuori's syndrome, shows ocular abnormalities, as well as those of the muscle and brain, as does the Walker-Warburg syndrome. In the latter disorder the cerebral lesions tend to be more severe, and it is more rapidly fatal. The manifestations of all these syndromes undoubtedly overlap, but there has been controversy on the question of their identity. Are they separate entities, or are they different expressions of a similar genetic disorder? The genes for all these conditions will have to be isolated to see if the different phenotypes are alleles of the same gene, or not. Some of the arguments, for and against, are presented.

Brain Damage, Chronic↗
PubMed2007

Breaches of the pial basement membrane and disappearance of the glia limitans during development underlie the cortical lamination defect in the mouse model of muscle-eye-brain disease.

Neuronal overmigration is the underlying cellular mechanism of cerebral cortical malformations in syndromes of congenital muscular dystrophies caused by defects in O-mannosyl glycosylation. Overmigration involves multiple developmental abnormalities in the brain surface basement membrane, Cajal-Retzius cells, and radial glia. We tested the hypothesis that breaches in basement membrane and the underlying glia limitans are the key initial events of the cellular pathomechanisms by carrying out a detailed developmental study with a mouse model of muscle-eye-brain disease, mice deficient in O-mannose beta31,2-N-acetylglucosaminyltransferase 1 (POMGnT1). The pial basement membrane was normal in the knockout mouse at E11.5. It was breached during rapid cerebral cortical expansion at E13.5. Radial glial endfeet, which comprise glia limitans, grew out of the neural boundary. Neurons moved out of the neural boundary through these breaches. The overgrown radial glia and emigrated neurons disrupted the overlying pia mater. The overmigrated neurons did not participate in cortical plate (CP) development; rather they formed a diffuse cell zone (DCZ) outside the original cortical boundary. Together, the DCZ and the CP formed the knockout cerebral cortex, with disappearance of the basement membrane and the glia limitans. These results suggest that disappearance of the basement membrane and the glia limitans at the cerebral cortical surface during development underlies cortical lamination defects in congenital muscular dystrophies and a cellular mechanism of cortical malformation distinct from that of the reeler mouse, double cortex syndrome, and periventricular heterotopia.

Animals↗
PubMed2006

Carriers and patients with muscle-eye-brain disease can be rapidly diagnosed by enzymatic analysis of fibroblasts and lymphoblasts.

We report a new fibroblast and lymphoblast based protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 enzymatic assay, which allows rapid and accurate diagnosis of carriers and patients with muscle-eye-brain type of congenital muscular dystrophy. Seven patients with genetically confirmed muscle-eye-brain disease were assayed for protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 enzyme activity. In three patients and their heterozygous parents, the assays were done on EBV-transformed lymphoblasts, in another three patients they were done on cultured fibroblasts and in the last patient on both fibroblasts and lymphoblasts. Cultured fibroblasts and lymphoblasts from the muscle-eye-brain patients showed a highly significant decrease in protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 activity relative to controls. The residual protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 level in fibroblasts (average 0.11 nmoles/h per mg) was about 13% of normal controls. The ratio of protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 activity to the activity of a glycosyltransferase control (N-acetylglucosaminyltransferase 1; GnT1) in fibroblasts was on average 0.006 in muscle-eye-brain patients and 0.045 in controls. The average residual protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 level in lymphoblasts was 15% of normal controls. The average ratio of protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1/GnT1 activity was 0.007 in muscle-eye-brain patients, 0.026 in heterozygous carriers and 0.046 in normal controls. Assay of protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 activity in fibroblasts and lymphoblasts from muscle-eye-brain carriers and patients provides a rapid and relatively simple diagnostic test for this disease and could be used as a screening test in carriers and patients with complex congenital muscular dystrophy.

Cells, Cultured↗
PubMedDate not supplied

Demonstrating immune-related antigens in Alzheimer's disease brain tissue.

Immune system associated markers have recently been reported in Alzheimer's disease (AD) brain. However, previous studies have not consistently revealed these antigens in the central nervous system. Immunohistochemistry of HLA-DR and other immune antigens (e.g., CD4+, IL-2R) in AD cortical tissue was compared using paraformaldehyde-fixed versus snap-frozen unfixed tissue. In addition, a free-floating immunohistochemistry method was contrasted with an on slide procedure. Even with an HLA-DR antibody known to work well on fixed tissue, unfixed tissue gave superior results. Free-floating immunohistochemistry also increased sensitivity. Where morphologic considerations are paramount, brief fixation with free-floating methods provides a reasonable alternative.

Alzheimer Disease↗
PubMed1998

Advanced glycation end products co-localized with astrocytes and microglial cells in Alzheimer's disease brain.

In the previous study [Takeda et al. (1996) Neurosci Lett 221: 17-21], we reported that the advanced glycation end products (AGEs) in the external space of neuronal perikarya (extraneuroperikaryal AGE deposits) were significantly abundant in the Alzheimer's brain. In this study, we investigated the spatial relationship of the extraneuroperikaryal AGE (carboxymethyllysine and pentosidine) deposits in astrocytes and microglial cells in the Alzheimer's disease brain using double immunolabelling for AGEs and astrocyte or microglial cell markers. Most of the extraneuroperikaryal AGE deposits were co-localized with glial fibrillary acidic protein-positive astrocytes. AGE deposit-bearing astrocytes also contained Gomori-positive granules. Furthermore, some of the extraneuroperikaryal AGE deposits were co-localized with microglial cells. These extraneuroperikaryal AGEs may activate astrocyte and microglia, and play a role in pathogenesis of Alzheimer's disease.

Aged↗
PubMed1999

Phospholipase pathway in Alzheimer's disease brains: decrease in Galphai in dorsolateral prefrontal cortex.

There is substantial evidence that G-protein-associated signaling pathways in the brain are altered in Alzheimer's disease (AD). Using quantitative immunoblotting we find a significant decrease in Galphai levels in every AD case examined compared to controls (mean Galphai level in AD was 43.5+/-7.4% of control). Galphao levels were slightly decreased, but Galphaq and betagamma were normal. Phospholipase C-beta1, but not gamma1, levels were also decreased. Total phospholipase C activity and ceramide levels were not changed. Thus, in AD, there is impairment in the Galphai-associated signaling pathway in neurons.

Aged↗