g(m2)-ganglioside and Leukodystrophy--Metachromatic

Lysosomal storage diseases are clinically heterogeneous with respect to their age of onset, progression of symptoms and the particular organs involved. Varying levels of residual enzyme activity, associated with different defective alleles that cause the respective diseases, are responsible in part for this clinical heterogeneity. In general, the higher the residual enzyme activity, the milder the phenotype. Enzyme activity in severe forms of disease is frequently zero, and in mild forms usually does not exceed approximately 5%. However, the correlation is not so strict as to allow prediction of the phenotype of individual patients. The molecular basis of the different levels of enzyme activity can only be revealed by biochemical investigations of the defective lysosomal proteins. Null alleles may be due to splice-site mutations or deletions. In the case of missense mutations, enzymes frequently fold incorrectly and are retained in the endoplasmic reticulum and subsequently degraded. As these enzymes do not reach the lysosome, they do not provide any functional residual activity. Residual enzyme activity is only observed in cases where the defective enzyme reaches the lysosome and has retained enzymatic activity. Patients carrying the same mutant alleles still show considerable phenotypic variability due to modifying genes and epigenetic factors. None of these has so far been elucidated. However, there are some indications that differences in splicing-factor machinery may influence the phenotypic expression of splice-site mutations and that hormonal modulation of secondary microglial activation in lipidosis may also influence the disease course.. Phenotypic variability is a frequent phenomenon in lysosomal storage diseases. Residual enzyme activity has been identified as one of the factors influencing the clinical outcome of disease; however, it is obvious that other genetic and epigenetic factors also affect phenotypic variability, particularly in patients with late onset disease.

Topics: Alleles; DNA, Recombinant; Endoplasmic Reticulum; G(M2) Ganglioside; Gangliosidoses, GM2; Gaucher Disease; Humans; Leukodystrophy, Metachromatic; Lysosomal Storage Diseases; Phenotype; Point Mutation; Tay-Sachs Disease

Most lysosomal storage disorders are known as pediatric diseases. In recent years late onset and adult forms of these disorders have been recognized. The adult form of a given lysosomal storage disorder differs from the childhood disease in several respects. Adult disorders are, with some exceptions, less common than the childhood diseases. The clinical picture is not only less severe, but often shows quite different clinical signs and symptoms than the early onset form. Metachromatic leucodystrophy, GM1 and GM2 gangliosidoses, Gaucher disease and aspartylglucosaminuria are presented as examples of lysosomal storage disorders manifesting as adult diseases. The differences of the early and late onset disorders are discussed in the light of recent results of molecular genetics, residual enzyme activity and pseudodeficiency.

Topics: Acetylglucosamine; Adult; Age of Onset; Aspartylglucosaminuria; G(M2) Ganglioside; Gangliosidoses; Gangliosidosis, GM1; Gaucher Disease; Humans; Leukodystrophy, Metachromatic

Topics: alpha-Galactosidase; Arylsulfatases; beta-Galactosidase; Cystine; Fabry Disease; G(M1) Ganglioside; G(M2) Ganglioside; Galactosylceramidase; Gangliosidoses; Genetic Carrier Screening; Glycoproteins; Heparitin Sulfate; Humans; Hydrolases; Isoelectric Focusing; Isoenzymes; Kinetics; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Lipid Metabolism, Inborn Errors; Lysosomes; Metabolism, Inborn Errors; Molecular Weight; Mucolipidoses; Niemann-Pick Diseases; Sphingolipidoses; Sphingomyelin Phosphodiesterase

Topics: Animals; Cattle; Enzyme Activation; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosidoses; Glucosylceramidase; Glycolipids; Glycosphingolipids; Hexosaminidases; Humans; Leukodystrophy, Metachromatic; Lysosomes; Mice; Protein Binding; Proteins; Rats; Substrate Specificity; Sulfatases

Topics: Adolescent; Adult; Animals; beta-Galactosidase; Cats; Cerebrovascular Disorders; Child, Preschool; Coronary Disease; Fabry Disease; Female; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosidoses; Gaucher Disease; Glycolipids; Hexosaminidases; Humans; Infant; Infant, Newborn; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Male; Sodium-Potassium-Exchanging ATPase; Vascular Resistance

Topics: G(M2) Ganglioside; Gangliosides; Glycoproteins; Humans; Leukodystrophy, Metachromatic; Liver; Niemann-Pick Diseases; Proteins; Saposins; Sphingolipid Activator Proteins; Sphingolipidoses

Topics: G(M1) Ganglioside; G(M2) Ganglioside; G(M3) Ganglioside; Gangliosidoses; Genetic Carrier Screening; Genetic Counseling; Glycoside Hydrolases; Humans; Leukodystrophy, Metachromatic; Lipidoses; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis III; Mucopolysaccharidosis IV; Mucopolysaccharidosis VI; Phenotype; Polymorphism, Genetic

Topics: Animals; Cats; Cattle; Disease Models, Animal; Dogs; G(M2) Ganglioside; Gangliosidoses; Gaucher Disease; Glycogen; Glycogen Storage Disease Type II; Glycopeptides; Humans; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Lipidoses; Lysosomes; Mannosidases; Metabolism, Inborn Errors; Mice; Niemann-Pick Diseases; Rabbits; Sphingolipids

Topics: alpha-Mannosidosis; Female; Fetal Diseases; G(M2) Ganglioside; Humans; Leukodystrophy, Metachromatic; Metabolism, Inborn Errors; Mucopolysaccharidoses; Pregnancy; Prenatal Diagnosis; Tay-Sachs Disease

Congenital glycolipidoses of the nervous system cause accumulation of various storage substances in cells. Methods of lipid and lectin histochemistry were used in an attempt for classification by known groups of diseases, on the basis of stored lipids. While conventional methods of lipid histochemistry enabled classification of accumulated substances only by lipid classes, lectin approaches provided additional information on sugar bonding points in cases of glycosphingolipidoses. For example, HPR-labelled and FITC-labelled WGA was positively recorded from neurons in cases of GM 2-gangliosidoses and mucopolysaccharidoses, type HURLER. Particular interest was aroused by RCA-I and PNA-positive reactions in glial cells of globoid cell leucodystrophy, since no histochemical method had been available in the past for diagnosis of this storage disease. Hence, the findings recorded by ALROY et al. (1986) from Twitcher mice, an animal model of galactosylceramidosis, have been confirmed by human material.

Topics: G(M2) Ganglioside; Gangliosidoses; Histocytochemistry; Humans; Lectins; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Lipid Metabolism, Inborn Errors; Lipids; Mucopolysaccharidoses; Nervous System Diseases; Neurons; Niemann-Pick Diseases; Tay-Sachs Disease

Topics: Adult; Female; G(M2) Ganglioside; Humans; Leukodystrophy, Metachromatic; Lipid Metabolism, Inborn Errors; Male; Methods

Topics: Animals; Arylsulfatases; Brain; Disease Models, Animal; G(M2) Ganglioside; Gangliosides; Hexosaminidases; Isoenzymes; Leukodystrophy, Metachromatic; Lipidoses; Rats; Sulfatases; Vitamin E Deficiency