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At least 19 recordsLinked to original sources
PubMed2006

Molecular pathologies of and enzyme replacement therapies for lysosomal diseases.

Lysosomal diseases comprise a group of inherited disorders resulting from defects of lysosomal enzymes and their cofactors, and in many of them the nervous system is affected. Recently, enzyme replacement therapy with recombinant lysosomal enzymes has been clinically available for several lysosomal diseases. Such enzyme replacement therapies can improve non-neurological disorders but is not effective for neurological ones. In this review, we discuss the molecular pathologies of lysosomal diseases from the protein structural aspect, current enzyme replacement therapies, and attempts to develop enzyme replacement therapies effective for lysosomal diseases associated with neurological disorders, i.e., production of enzymes, brain-specific delivery and incorporation of lysosomal enzymes into cells.

Animals↗
PubMed2006

[Status of lysosomal diseases amongst metabolic diseases].

Lysosomal diseases belong to the group of diseases which disturb the synthesis, catabolism or processing of complex molecules. These are the most common metabolic diseases, as they account for about one-third of all known metabolic diseases. They can be expressed as early as the intra-uterine stage of life, or appear after birth at any age, including during adulthood. They develop gradually, evolve independently of any intercurrent catabolic event and are independent of diet. Although they have long been associated with an inevitably fatal outcome, several can now be treated effectively, either by enzyme replacement therapy which increases catabolism of the overloaded substance thanks to an input of the deficient enzyme, or by drugs which reduce the synthesis of the overloaded substance.

Adult↗
PubMed1994

[Lysosomal diseases].

Lysosomal diseases are severe genetic enzymopathies generally affecting the child, with a progressively fatal issue in the first few years of life. The group is very heterogeneous regarding: the number of included affections (about 30), as well as the clinical, biological and molecular manifestations. The responsible genes for the respective enzyme deficiencies are located or cloned and the recently developed research allows to characterise the causal mutations and to elucidate the involved molecular mechanisms. In the absence of an efficient therapy a reliable prenatal diagnosis can be proposed. However, therapeutic prospects concerning substitutive therapy, bone marrow transplantation and, in a more long-term, gene therapy are encouraging.

Bone Marrow Transplantation↗
PubMed2000

Gene therapy in lysosomal diseases.

Lysosomal storage diseases are monogenic metabolic disorders resulting from a deficiency in intralysosomal enzymes involved in macromolecule catabolism. Various groups have been delineated according to the affected pathway and the accumulated substrate: mucopolysaccharidoses, lipidoses, glycoproteinoses and glycogenosis type II. Their clinical severity and the absence of efficient therapy for the majority of these disorders justify the development of gene transfer methods. Most of the genes encoding the normal lysosomal enzymes have been cloned and recently numerous animal models have been obtained for nearly all these diseases. Due to the clinical heterogeneity of lysosomal diseases, showing multivisceral involvement or affecting predominantly the reticuloendothelial system, muscle or central nervous system, various gene therapy strategies have to be developed. Vectors, ways of access, results and limits will be reviewed. Interesting results have already been obtained in the gene transfer for lysosomal diseases, but improvements are needed before a future application to humans.

Animals↗
PubMed1993

[Lysosome disease--Sandhoff disease].

Lysosomal beta-hexosaminidase occurs as two major isozymes hexosaminidase A and B. The alpha subunit is encoded by the HEXA gene and the subunit by HEXB gene. Defects in the beta subunit lead to Sandhoff disease. Patients with the defect lack the activity or formation of both hexosaminidase A and B. The disorders are classified according to the age of onset, as infantile, juvenile and adult form. Recent molecular genetic analysis has revealed a 50 kb deletion, 16 kb Alu type deletion, and compound heterozygous with other mutations. In the juvenile or adult type of the disease, point mutation of the HEXB gene, creating a new 3' splice acceptor site. The correlation of the clinical phenotype and the gene abnormalities is discussed.

Adolescent↗
PubMed1997

[Plasma chitotriosidase activity in Argentinian patients with Gaucher disease, various lysosomal diseases and other inherited metabolic disorders].

The striking and apparent specific elevation of the activity of chitotriosidase found in plasma from patients with Gaucher disease (GD) Type 1 (Mc Kusick 230800) is considered a new diagnostic hallmark of GD and should prove useful in assessing clinical manifestations and monitoring enzyme supplementation therapy. Further data have suggested that the increased levels of chitotriosidade activity in plasma from patients with unexplained diseases may be indicative of a lysosomal storage disorder. We present here an experience of the plasmatic chitotriosidase in an Argentinean population consisting of three groups: a) 25 healthy controls; b) subjects related with GD: 3 patients Type 1, 3 obligated heterocygotes and 1 patient with an atypical variant of GD; c) 42 patients with a precise nosologycal definition of inherited error of metabolism (IEM) and 5 patients presumably affected by a lysosomal pathology but without enzymatic confirmation. Methylumbellypheryl-tri-N-acetyl chitotrioside hydrolase activity was markedly increased: the mean activity being > 600 times and > 100 times the mean value in plasma of our healthy control (mean 17 nmol/min/ml, range 6-60.4 nmol/min/ml) in the plasma of the patients of Gaucher Type 1 disease and an atypical variant of GD, respectively. In the two more affected patients the elevated levels of chitotriosidase activity ran parallel to the severity of the disease and also as a response to the supplementation enzymatic therapy with a decrease of 50% of its activity at 10 months of therapy at a dose of 30 u/kg/month. Moreover, no increase of chitotriosidase activity was found in the 3 obligated heterozygotes of Gaucher Type 1 and Type 2 disease or in any other of the IEM. Chitotriosidase activity was absent in plasma of 2 control subjects and in 4 patients with exact diagnosis of an IEM. The physiological role of the human chitinase still has to be established and warrants further investigation and the natural consequence of the high frequency of a genetic deficiency in man. Meanwhile, reports on the purification and characterization of human chitotriosidase with chitinolytic activity toward chitin-containing pathogens and on the cloning of cDNA encoding chitinase will be crucial to obtain a better insight into this new chapter of medical genetics.

Adult↗
PubMed1976

Angiokeratoma corporis diffusum (Fabry disease). A lysosomal disease.

Angiokeratoma corporis diffusum (Fabry disease) is an X-linked recessive disease. We had an opportunity to examine a heterozygous female patient with angiokeratoma and cornea verticillata. The patient's serum alpha-galactosidase activity was reported to be about 50% of normal. Skin lesion biopsy specimens were stained with electron microscopic acid phsophatase (ACP), with proper controls. Acid phosphatase activity was demonstrable within membrane-bound inclusions of cutaneous vascular endothelial cells. This suggested that the accumulation of abnormal glycolipids in the vascular cells occurs in the lysosomes.

Acid Phosphatase↗
PubMed1994

Morphologic findings in biopsied skeletal muscle and cultured fibroblasts from a female patient with Danon's disease (lysosomal glycogen storage disease without acid maltase deficiency).

A family is reported in which three members were affected by cardiomyopathy. Two members died unexpectedly in their second decade. Only a 23-year-old male suffered from the triad of clinical manifestations (cardiomyopathy, mental retardation and vacuolar myopathy). Morphologic findings and biochemical studies of his biopsied skeletal muscle and cultured fibroblasts confirmed lysosomal glycogen storage disease with normal acid maltase that was first described by Danon et al. In this study we demonstrated early morphologic changes, storage of glycogen and abnormal membranous structures in disorganized myofibers in biopsied skeletal muscle from the elder sister, who only showed cardiomyopathy clinically. The aggregation of autophagosomes was prominent in cultured fibroblasts, with an increased glycogen content. The activity of acid alpha-glucosidase was higher than normal. This is a systemic storage disease with different expression in males and females.

Adolescent↗
PubMed2002

Gaucher disease: Perspectives on a prototype lysosomal disease.

Gaucher disease is an autosomal recessive trait and the most common lysosomal storage disease. The pathogenesis evolves from the diminished activity of the lysosomal hydrolase, acid beta-glucosidase and the resultant accumulation of glucosylceramide within lysosomes. The pathogenic mechanisms are poorly understood. During the past 2 decades, progress has been made in understanding the biochemical basis and molecular biology of the disease, but more fundamental knowledge is required to relate these advances to the cell and whole body phenotypes. Despite this lack of understanding, enzyme replacement therapy has proved a successful and effective management for Gaucher disease. However, basic details of this therapeutic efficacy require elucidation. Here, we review the current state of the molecular pathogenesis and provide our perspective of some major issues for continued advances in this prototype lysosomal storage disease.

Animals↗
PubMed1995

[Biochemical diagnosis and enzymic diagnosis of lysosomal diseases].

Originally, diagnosis of lysosomal diseases was primarily based on clinicopathological findings and on identification of abnormally stored substances by analytical biochemistry. Since extraneural tissues possess only very low levels of sphingolipids, lipid analysis with Folch method and/or its modifications is usually limited to nervous system, and their applicability is restricted to postmortem examination and, occasionally, to verification of a prenatal diagnosis after abortion. On the other hand, recently developed TLC/enzyme immunostaining method might be useful for antemortem analysis of abnormally stored glycosphingolipids, because it could detect glycosphingolipids quantitatively with clinically available 0.5 approximately 1 ml CSF. During the past two decades, however, diagnostic emphasis has shifted to enzymic assay, which provide relatively easy, noninvasive antemortem diagnosis because clinically available enzyme sources, such as serum, leukocytes and cultured fibroblasts, and also commercially available artificial substrates can be used. These procedures can be used to detect heterozygous carriers. Identification of affected fetus during early pregnancy is generally possible with similar procedures.

Chromatography, Thin Layer↗
PubMed1987

Recent progress of lysosomal diseases.

The majority of lysosomal storage diseases results from genetic inability to express one or another of the many activities of the lysosomal hydrolases. A few lysosomal diseases are caused by a defective transport of certain metabolites across the lysosomal membrane. The recognition of the specific lysosomal defects led to diagnostic tests also for first trimester prenatal diagnosis. The availability of cloned genes for a number of lysosomal enzymes marks the beginning of an understanding of the precise defects responsible for lysosomal storage diseases.

Humans↗
PubMed1998

Mouse models of human lysosomal diseases.

Genetically authentic animal models of human lysosomal diseases occur spontaneously in many mammalian species. However, most are among larger domestic or farm animals with only two well-defined genetic lysosomal diseases known among rodents. This status changed dramatically in recent years with the advent of the combined homologous recombination and embryonic stem cell technology, which allows directed generation of mouse models that are genetically equivalent to human diseases. Almost all known human sphingolipidoses, two mucopolysaccharidoses and aspartylglycosaminuria have so far been duplicated in mice and more are expected in the near future. This technology also allows generation of mouse mutants that are not known or are highly unlikely to exist in humans, such as "double-knockouts." These animal models will play an important role in studies of the pathogenesis and treatment of these disorders. While the utility of these mouse models is obvious, species differences in brain development and metabolic pathways must be always remembered, if the ultimate goal of the study is application to human patients.

Animals↗
PubMed2006

[Advances in the treatment of lysosomal diseases in infancy].

AIMS: The treatment of lysosomal diseases has undergone a number of significant changes in recent decades. Here we review the different therapeutic approaches that can be used: the well-consolidated haematopoietic stem-cell transplants (HST) and enzyme replacement therapy (ERT), the new therapeutic strategies with small molecules such as substrate reduction therapy (SRT) or enzyme 'enhancement' therapy (EET) and experimental approaches like gene therapy. DEVELOPMENT: We review the status of ERT in general and more particularly in Gaucher disease, Fabry disease, mucopolysaccharidosis type I, Pompe disease and the first stages of Hunter disease and Maroteaux-Lamy syndrome. Their outcomes, indications, safety and side effects are also evaluated. We examine the value of HST in these diseases and more particularly in Hurler syndrome, Maroteaux-Lamy syndrome, globoid cell leukodystrophy, metachromatic leukodystrophy and Gaucher disease. The initial results from using SRT, EET and with gene therapy are briefly outlined. CONCLUSIONS: A great deal of progress has been made in the treatment of some lysosomal diseases in recent decades due to careful use of HST and ERT. Furthermore, the application of the latest therapeutic instruments such as SRT and EET opens up new perspectives in this field.

Child↗
PubMed1995

[Gene diagnosis of lysosomal diseases].

Molecular genetic analysis of lysosomal storage diseases has revealed numerous mutant genes for each disease, and the results have been applied to gene diagnosis in patients and their family members. In general, the same mutant gene is not always found in different families. Confirmation of a mutant gene is necessary for each proband case in a family, although some common mutations can be screened for patients in a specific ethnic population, such as 151T mutation of the beta-galactosidase gene among Japanese cases of adult GM1-gangliosidosis. The result of gene analysis is generally clear and provides a solid diagnosis for each member at risk in a family. Gene analysis and conventional enzyme assays should be performed in a mutually complementary manner for laboratory diagnosis of lysosomal diseases.

Adult↗
PubMedDate not supplied

[Prenatal diagnosis of hereditary lysosomal diseases].

Prenatal diagnosis was carried out in 10 families suffering from lysosomal diseases: Tay-Sachs disease--5 families, Sandhoff disease--1 family, GM1-gangliosidosis--1 family and Hunter disease--3 families. Diagnosis of Tay-Sachs disease was excluded in fetuses of two families, Sandhoff disease--in one family, GM1-gangliosidosis--in one family, Hunter disease--in two families. Tay-Sachs disease was found in two fetuses and in one neonate. In two fetuses was found Hunter disease (twin pregnancy). The results of prenatal diagnosis were corroborated by postnatal studies of the neonates funicular blood and of autopsies of the aborted fetuses tissues. Application of several independent procedures for prenatal diagnosis of hereditary lysosomal diseases enabled to exclude erroneous diagnosis.

Female↗
PubMed1986

Studies on the defect underlying the lysosomal storage of sialic acid in Salla disease. Lysosomal accumulation of sialic acid formed from N-acetyl-mannosamine or derived from low density lipoprotein in cultured mutant fibroblasts.

Salla disease is a lysosomal storage disorder characterized by mental retardation and disturbed sialic acid metabolism. To study endogenous synthesis and breakdown of sialic acid, fibroblasts were incubated for 5 d in the presence and then in the absence of N-[3H]acetylmannosamine. Labeling of free sialic acid was 5-10 times higher in mutant than in normal cells. Radioactivity decreased in 4 d by 75% in normal but only by 30% in mutant fibroblasts. The labeling pattern was not normalized upon coculture of mutant and normal cells. To study the metabolism of extracellular sialic acid, low-density lipoprotein (LDL) was labeled in the sialic acid moiety (periodate-NaB3H4) or in the protein moiety (125I). Binding, internalization, lysosomal degradation, and exit of products of protein catabolism were similar in normal and mutant fibroblasts. Upon incubation with LDL labeled in the sialic acid moiety, mutant cells accumulated 2-3 times more free sialic acid radioactivity than normal fibroblasts, mostly in the lysosomal fraction. After a 24-h chase incubation, radioactivity in free sialic acid decreased by 70-80% in normal but only by 10-30% in mutant cells. In mutant fibroblasts, 40% of the radioactivity remained in lysosomes, whereas no labeled free sialic acid was detected in lysosomes from normal fibroblasts. We conclude that in Salla disease, fibroblast endogenous synthesis of sialic acid and lysosomal cleavage of exogenous glycoconjugates is normal, but free sialic acid cannot leave the lysosome. These findings suggest that the basic defect in Salla disease is deficient transport of free sialic acid through the lysosomal membrane.

Cells, Cultured↗