Lysosomal storage diseases

Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively

Musings on genome medicine: enzyme-replacement therapy of the lysosomal storage diseases

The lysosomal storage diseases, such as Gaucher's disease, mucopolysaccharidosis I, II and IV, Fabry's disease, and Pompe's disease, are rare inherited disorders whose symptoms result from enzyme deficiency causing lysosomal accumulation. Until effective gene-replacement therapy is developed, expensive, and at best incomplete, enzyme-replacement therapy is the only hope for sufferers of rare lysosomal storage diseases. Preventive strategies involving carrier detection should be a priority toward the successful management of these conditions

Neuroinflammatory paradigms in lysosomal storage diseases.

Lysosomal storage diseases (LSDs) include approximately 70 distinct disorders that collectively account for 14% of all inherited metabolic diseases. LSDs are caused by mutations in various enzymes/proteins that disrupt lysosomal function, which impairs macromolecule degradation following endosome-lysosome and phagosome-lysosome fusion and autophagy, ultimately disrupting cellular homeostasis. LSDs are pathologically typified by lysosomal inclusions composed of a heterogeneous mixture of various proteins and lipids that can be found throughout the body. However, in many cases the CNS is dramatically affected, which may result from heightened neuronal vulnerability based on their post-mitotic state. Besides intrinsic neuronal defects, another emerging factor common to many LSDs is neuroinflammation, which may negatively impact neuronal survival and contribute to neurodegeneration. Microglial and astrocyte activation is a hallmark of many LSDs that affect the CNS, which often precedes and predicts regions where eventual neuron loss will occur. However, the timing, intensity, and duration of neuroinflammation may ultimately dictate the impact on CNS homeostasis. For example, a transient inflammatory response following CNS insult/injury can be neuroprotective, as glial cells attempt to remove the insult and provide trophic support to neurons. However, chronic inflammation, as seen in several LSDs, can promote neurodegeneration by creating a neurotoxic environment due to elevated levels of cytokines, chemokines, and pro-apoptotic molecules. Although neuroinflammation has been reported in several LSDs, the cellular basis and mechanisms responsible for eliciting neuroinflammatory pathways are just beginning to be defined. This review highlights the role of neuroinflammation in select LSDs and its potential contribution to neuron loss

Rheumatologic Manifestations of Lysosomal Storage Diseases

How to Cite this Article: Shiari R, VAdood Javadi P. Rheumatologic Manifestations of Lysosomal Storage Diseases. Iran J Child Neurol Autumn 2012; 6:4 (suppl. 1): 20. Pls see PDF.

Enzyme Replacement Therapies for Lysosomal Storage Diseases

Lysosomal Storage Disorders (LSDs): Genetic; Rare; Autosomal recessive (majority). Portugal - 1/4000; Almost 70!. The concept of enzyme replacement as a potential therapeutic approach to ameliorate lysosomal storage disorders (LSDs) is virtually as old as the concept of LSD itself. In fact, both concepts were established right after the first enzymatic deficiency underlying an LSD was described, and enzyme replacement therapy (ERT) remained the golden standard for LSD treatment for years. Nevertheless, its ineffectiveness to correct brain pathology, together with its high cost and lifelong dependence prompted the search for additional therapeutic approaches, which are currently being investigated: chaperone therapy; gene enhancement and gene therapy. Still, no matter how effective the treatment or cutting-edge the technology used in any of these cases, the underlying rationale is virtually the same: an attempt to provide or enhance the activity of the missing enzyme.FCT SFRH/BPD/101965/2014; SFRH/BD/124372/2016N/

Nonimmune hydrops fetalis and lysosomal storage diseases.

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Adenovirus RID-α activates an autonomous cholesterol regulatory mechanism that rescues defects linked to Niemann-Pick disease type C

Viral subversion of cholesterol homeostasis provides insights into sterol trafficking, autophagy, and lysosomal storage diseases

Enzyme replacement therapies: What is the best option?

Despite many beneficial outcomes of the conventional enzyme replacement therapy (ERT), several limitations such as the high-cost of the treatment and various inadvertent side effects including the occurrence of an immunological response against the infused enzyme and development of resistance to enzymes persist. These issues may limit the desired therapeutic outcomes of a majority of the lysosomal storage diseases (LSDs). Furthermore, the biodistribution of the recombinant enzymes into the target cells within the central nervous system (CNS), bone, cartilage, cornea, and heart still remain unresolved. All these shortcomings necessitate the development of more effective diagnosis and treatment modalities against LSDs. Taken all, maximizing the therapeutic response with minimal undesired side effects might be attainable by the development of targeted enzyme delivery systems (EDSs) as a promising alternative to the LSDs treatments, including different types of mucopolysaccharidoses (MPSs ) as well as Fabry, Krabbe, Gaucher and Pompe diseases