acid-phosphatase and Tuberous-Sclerosis

Focal cortical dysplasia (FCD) is a localized malformation of cortical development and is the commonest cause of severe childhood epilepsy in surgical practice. Children with FCD are severely disabled by their epilepsy, presenting with frequent seizures early in life. The commonest form of FCD in children is characterized by the presence of an abnormal population of cells, known as balloon cells. Similar pathological changes are seen in the cortical malformations that characterize patients with tuberous sclerosis complex (TSC). However, the cellular and molecular mechanisms that underlie the malformations of FCD and TSC are not well understood. We provide evidence for a defect in autophagy in FCD and TSC. We have found that balloon cells contain vacuoles that include components of the autophagy pathway. Specifically, we show that balloon cells contain prominent lysosomes by electron microscopy, immunohistochemistry for LAMP1 and LAMP2, LysoTracker labelling and enzyme histochemistry for acid phosphatase. Furthermore, we found that balloon cells contain components of the ATG pathway and that there is cytoplasmic accumulation of the regulator of autophagy, DOR. Most importantly we found that there is abnormal accumulation of the autophagy cargo protein, p62. We show that this defect in autophagy can be, in part, reversed in vitro by inhibition of the mammalian target of rapamycin (mTOR) suggesting that abnormal activation of mTOR may contribute directly to a defect in autophagy in FCD and TSC.

Topics: Acid Phosphatase; Adaptor Proteins, Signal Transducing; Autophagy; Brain; Brain Diseases; Cells, Cultured; Child; Cytoplasm; Epilepsy; Humans; Immunohistochemistry; Lysosomal Membrane Proteins; Lysosomal-Associated Membrane Protein 2; Lysosomes; Malformations of Cortical Development; Malformations of Cortical Development, Group I; Sequestosome-1 Protein; Tissue Banks; TOR Serine-Threonine Kinases; Tuberous Sclerosis

5 serum protein polymorphic systems (haptoglobin, alkaline phosphatase, group-specific (Gc) proteins, beta2-glycoprotein 1 and leucine aminopeptidase) and 6 red-cell polymorphisms (adenosine deaminase, adenylate kinase, phosphoglucomutase, glutamic-pyruvic transaminase, phosphogluconate dehydrogenase and acid phosphatase) have been investigated in 54 subjects with tuberous sclerosis. The frequencies of all systems were compared with those of a control sample drawn from a similar mentally retarded population and abnormal distributions were detected in the haptoglobin and Gc system. Quantitative estimation of the serum levels of the Gc protein failed to detect any inter-group differences. Data on the deviations from the Hardy-Weinberg equlibrium, Haldane's Log ratio test between groups, and gene frequencies of both test and control groups are given. It is suggested that selection by mortality is the possible causation for the abnormal distribution of the Gc phenotypes, but the haptoglobin phenotype distribution requires further investigation with care being taken in the selection of control subjects.

Topics: Acid Phosphatase; Adenosine; Adult; Alanine Transaminase; Alkaline Phosphatase; Aminohydrolases; Blood Proteins; Erythrocytes; Female; Gene Frequency; Glycoproteins; Haptoglobins; Humans; Intellectual Disability; Leucyl Aminopeptidase; Male; Phenotype; Phosphoglucomutase; Phosphogluconate Dehydrogenase; Phosphotransferases; Polymorphism, Genetic; Tuberous Sclerosis

Topics: Acid Phosphatase; Brain; Cerebrosides; Diffuse Cerebral Sclerosis of Schilder; Electrons; Microscopy; Microscopy, Electron; Myelin Sheath; Pathology; Phagocytosis; Rats; Research; Spleen; Tuberous Sclerosis; White Matter

Topics: Acid Phosphatase; Child; Diffuse Cerebral Sclerosis of Schilder; Glycogen Storage Disease; Humans; Leukodystrophy, Metachromatic; Mucopolysaccharidosis I; Niemann-Pick Diseases; Sulfatases; Tuberous Sclerosis; Urine

Topics: Acid Phosphatase; Aspartate Aminotransferases; Brain; Chromatography; Diffuse Cerebral Sclerosis of Schilder; Glucosephosphate Dehydrogenase; Humans; Infant; Infant, Newborn; L-Lactate Dehydrogenase; Leukodystrophy, Globoid Cell; Lipids; Neurochemistry; Neuroglia; Phospholipids; Tuberous Sclerosis

Topics: Acid Phosphatase; Child; Diffuse Cerebral Sclerosis of Schilder; Electrons; Humans; L-Lactate Dehydrogenase; Leukodystrophy, Globoid Cell; Microscopy; Microscopy, Electron; Oxidoreductases; Tuberous Sclerosis

Topics: Acid Phosphatase; Adolescent; Alkaline Phosphatase; Aminohydrolases; Brain; Carotenoids; Child; Chondroitin; Diffuse Cerebral Sclerosis of Schilder; Gangliosides; Glucosyltransferases; Histocytochemistry; Humans; Infant; Kidney; Lipid Metabolism; Liver; Metabolic Diseases; Mucopolysaccharidosis I; Phosphotransferases; Rats; Research; Sulfatases; Sulfates; Sulfur Isotopes; Tuberous Sclerosis