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The mucopolysaccharidoses (a review).

The mucopolysaccharidoses are a group of genetic diseases characterized by storage of incompletely degraded glycosaminoglycans. Such storage causes marked distortion of many tissues with consequent severe somatic changes and mental retardation. Storage of glycosaminoglycans results from markedly diminished activity of specific hydrolases requisite for the normal degradation of glycosaminoglycans. The specific enzymic defects have been identified in nine different diseases. In some cases evidence has been obtained indicating the existence of additional allelic diseases based on the same enzyme.

Myoblast gene therapy in canine mucopolysaccharidosis. I: Abrogation by an immune response to alpha-L-iduronidase.

Three dogs with deficiency of the lysosomal enzyme alpha-L-iduronidase were treated by gene replacement therapy targeted at muscle. Direct intramuscular injections of plasmid encoding the alpha-L-iduronidase gene cDNA resulted in no detectable enzyme production, but may have resulted in immunologic sensitization to iduronidase protein, which the dogs lack totally. Myoblasts were grown from skeletal muscle biopsies and transduced with a retroviral vector containing the canine gene under control of the muscle creatine kinase enhancer. Several hundred-fold overexpression of enzyme production occu

Individualized long-term enzyme therapy for Gaucher disease type 1 in Slovenia.

BACKGROUND: Gaucher disease type 1 (GD1) was the first lysosomal storage disorder for which an effective enzyme replacement therapy was developed. We describe the management of eight GD1 patients in Slovenia who were diagnosed between the ages of 2 and 15 years. METHODS: Patients were individually assessed to establish initial enzyme doses and monitored frequently to determine the effects of long-term enzyme dose regimens. Outcomes up to 10 years after long-term treatment are described by changes in the Zimran severity score index, chitotriosidase and acid phosphatase levels, and after 2001, …

Effects of cardiovascular drugs on TSH serum levels in patients on replacement therapy after thyroidectomy.

OBJECTIVE: Hypothyroidism is one of most common endocrine disorders resulting from deficiency of thyroid hormones. The aim of our study was to investigate whether cardiovascular drugs as well as gender, age, body-mass index, and habits, like smoking or drinking coffee affect thyroid-stimulating hormone (TSH) level in hypothyroid patients with thyroxine replacement therapy who suffer from cardiovascular disease. MATERIALS: The study was conducted on 150 hypothyroid patients who underwent total thyroidectomy for benign reasons; they were divided into five treatment groups: levothyroxine only gr

Therapeutic management of cystic fibrosis.

The therapeutic management of patients with cystic fibrosis (CF) is reviewed. CF is an autosomal-recessive genetic disease that affects all exocrine glands. Drug therapy is directed toward the relief of symptoms and prevention of complications. Chronic respiratory tract infections and pancreatic insufficiency are the major manifestations. The replacement of pancreatic enzymes is best achieved with microencapsulated preparations. The dose of enzymes is increased until a maximum effect on decreasing steatorrhea is observed. Pseudomonas aeruginosa and Staphylococcus aureus are the most common pat

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder.

Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to severe cardiac and skeletal muscle myopathy due to progressive accumulation of glycogen. The discovery that acid alpha-glucosidase resides in the lysosome gave rise to the concept of lysosomal storage diseases, and Pompe disease became the first among many monogenic diseases caused by loss of lysosomal enzyme activities. The only disease-specific treatment available for Pompe disease patients is enzyme replacement therapy (ERT) whic…

Rare Diseases in Glycosphingolipid Metabolism.

Sphingolipidoses is a cluster of genetic rare disorders regarding glycosphingolipid metabolism, classified as lysosomal storage disorders (L … d for treating sphingolipidoses, with some potential strategies for further evaluation. In general, enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and molecular chaperones are feasible choices for enzyme deficiency disorders, but these therapies are limited to relieve CNS lesions and symptoms due to prevention from blood-brain barrier. Other possible t …

Млекопитающие сульфаты: биохимия, симптомы заболеваний и терапия.

Sulfatas — это ферменты, которые катализируют удаление сульфата из биологических веществ, что является необходимым процессом для гомеостаза тела. Они, как правило, активируются необычным аминокислотным формилглицином, который образуется из циштейна в каталитическом центре при помощи фермента, генерирующего формилглицин, в качестве послетрансляционной модификации. Сульфатазы выражаются в различных клеточных отсеках, таких как лизосома, эндоплазмический ретикулум и аппарат Голги. Подложки млекопитающих — сульфатопиды, гликосаминогликаны и стероидные гормоны. Эти ферменты поддерживают нейрональну

Совпадение в аннотации оригинала
Sulfatases are enzymes that catalyze the removal of sulfate from biological substances, an essential process for the homeostasis of the body … unclear. As for the genes responsible for pathogenesis, therapeutic strategies have been developed. Enzyme replacement therapy with recombinant enzyme agents and gene therapy with therapeutic transgenes delivered by viral vectors are administered to patients. In this review, the biochemical substrates, disease manifestation, and therapy for sulfatases are summarized.

Control of malabsorption in cystic fibrosis.

Intestinal malabsorption is severe and of early onset in virtually all people who have cystic fibrosis. The main cause is deficiency of panc … s. All who have evidence of fat malabsorption are deemed pancreatic insufficient and candidates for enzyme replacement therapy. Effective treatment should allow a normal diet to be taken, control symptoms, correct malabsorption and achieve a normal nutritional state and growth. The occurrence of fibrosing colonopathy in some patients receiving very high doses of those enzym …

Treatment of Gastrointestinal Problems in Cystic Fibrosis.

The gastrointestinal (GI) manifestations of cystic fibrosis (CF) are varied and include pancreatic insufficiency, meconium ileus, distal intestinal obstruction syndrome (DIOS), liver disease, and other less common manifestations. Treatment of pancreatic insufficiency consists of providing appropriate pancreatic enzyme replacement therapy and may include raising duodenal pH to allow for optimal action of these enzymes. Despite a number of pancreatic enzyme replacement products, malabsorption cannot be normalized. Management of DIOS depends on the severity of the symptoms; adequate hydration is …

Digestive Enzyme Supplementation in Gastrointestinal Diseases.

BACKGROUND: Digestive enzymes are able to break down proteins and carbohydrates and lipids, and their supplementation may play a role in the management of digestive disorders, from lactose intolerance to cystic fibrosis. To date, several formulations of digestive enzymes are available on the market, being different each other in terms of enzyme type, source and origin, and dosage. METHODS: This review, performed through a non-systematic search of the available literature, will provide an overview of the current knowledge of digestive enzyme supplementation in gastrointestinal disorders, discu

Preclinical lentiviral hematopoietic stem cell gene therapy corrects Pompe disease-related muscle and neurological manifestations.

Pompe disease, a rare genetic neuromuscular disorder, is caused by a deficiency of acid alpha-glucosidase (GAA), leading to an accumulation of glycogen in lysosomes, and resulting in the progressive development of muscle weakness. The current standard treatment, enzyme replacement therapy (ERT), is not curative and has limitations such as poor penetration into skeletal muscle and both the central and peripheral nervous systems, a risk of immune responses against the recombinant enzyme, and the requirement for high doses and frequent infusions. To overcome these limitations, lentiviral vector-m…

Alpha-galactosidase A-Tat fusion enhances storage reduction in hearts and kidneys of Fabry mice.

The protein transduction domain from human immunodeficiency virus (HIV) Tat allows proteins to penetrate the cell membrane. Enhanced cellular uptake of therapeutic proteins could benefit a number of disorders. This is especially true for lysosomal storage disorders (LSDs) where enzyme replacement therapy (ERT) and gene therapy have been developed. We developed a novel recombinant lentiviral vector (LV) that engineers expression of alpha-galactosidase A (alpha-gal A)-Tat fusion protein for correction of Fabry disease, the second-most prevalent LSD with manifestations in the brain, kidney and he…

Role of autophagy in the pathogenesis of Pompe disease.

In Pompe disease, a deficiency of lysosomal acid alpha-glucosidase, glycogen accumulates in multiple tissues, but clinical manifestations are mainly due to skeletal and cardiac muscle involvement. A major advance has been the development of enzyme replacement therapy (ERT), which recently became available for Pompe patients. Based on clinical and pre-clinical studies, the effective clearance of skeletal muscle glycogen appears to be more difficult than anticipated. Skeletal muscle destruction and resistance to therapy remain unsolved problems. We have found that the cellular pathology in Pompe…

Changes of the peripheral blood mononuclear cells membrane fluidity from type 1 Gaucher disease patients: an electron paramagnetic resonance study.

Gaucher disease (GD) is a lysosomal storage disorder, caused by an impaired function of β-glucocerebrosidase, which results in accumulation of glucocerebroside in cells, and altered membrane ordering. Using electron paramagnetic resonance spin labeling, a statistically significant difference in the order parameter between the peripheral blood mononuclear cell membranes of GD patients and healthy controls was observed. Moreover, the results show that the introduction of the enzyme replacement therapy leads to the restoration of the physiological membrane fluidity. Accordingly, this simple metho…

Optimization of concomitant medication in Fabry cardiomyopathy.

UNLABELLED: We describe a male patient with Fabry disease and use this case study to illustrate the importance of a detailed cardiovascular evaluation and the role of supportive therapy in routine management of the disease. The major areas of discussion include the management of exertional chest pain, progressive heart failure and the diagnosis and treatment of atrial and ventricular arrhythmia. CONCLUSION: In the era of enzyme replacement therapy, conventional pharmacological and device-based therapies remain central to the management of cardiovascular symptoms and the prevention of complica…

Acid beta-glucosidase: insights from structural analysis and relevance to Gaucher disease therapy.

In mammalian cells, glucosylceramide (GlcCer), the simplest glycosphingolipid, is hydrolyzed by the lysosomal enzyme acid beta-glucosidase (GlcCerase). In the human metabolic disorder Gaucher disease, GlcCerase activity is significantly decreased owing to one of approximately 200 mutations in the GlcCerase gene. The most common therapy for Gaucher disease is enzyme replacement therapy (ERT), in which patients are given intravenous injections of recombinant human GlcCerase; the Genzyme product Cerezyme has been used clinically for more than 15 years and is administered to approximately 4000 pat…

Mannose-Binding Lectin Protein Deficiency Among Patients with Primary Immunodeficiency Disease Receiving IVIG Therapy.

BACKGROUND: Primary immunodeficiencies (PIDs) are inherited disorders in which one or several components of the immune system are defective. Immunoglobulin replacement therapy is the mainstay of treatment for patients with impaired antibody production. However, recurrent infections would continue to occur in some patients due to the other high frequent concomitant defects, such as mannose-binding lectin (MBL) deficiency. METHODS: A total of 51 PID patients participated in this cross-sectional study. A detailed questionnaire was completed by interviewing patients in order to record demographic

Active site mutant transgene confers tolerance to human beta-glucuronidase without affecting the phenotype of MPS VII mice.

Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is an autosomal recessive lysosomal storage disorder due to an inherited deficiency of beta-glucuronidase. A naturally occurring mouse model for this disease was discovered at The Jackson Laboratory and shown to be due to homozygosity for a 1-bp deletion in exon 10 of the gus gene. The murine model MPS VII (gus(mps/mps)) has been very well characterized and used extensively to evaluate experimental strategies for lysosomal storage diseases, including bone marrow transplantation, enzyme replacement therapy, and gene therapy. To enhance the …

Fat malabsorption in pancreatic cancer: Pathophysiology and management.

Exocrine pancreatic insufficiency (EPI) is common in pancreatic ductal adenocarcinoma (PDAC) and may lead to significant nutrition compromise. In the setting of cancer cachexia and gastrointestinal toxicities of cancer treatments, untreated (or undertreated) EPI exacerbates weight loss, sarcopenia, micronutrient deficiencies, and malnutrition. Together, these complications contribute to poor tolerance of oncologic therapies and negatively impact survival. Treatment of EPI in PDAC involves the addition of pancreatic enzyme replacement therapy, with titration to improve gastrointestinal symptoms…