We are developing therapies to treat all patients with lysosomal storage disorders (LSDs).
Lysosomal storage disorders (LSDs) are a family of approximately 50 rare, genetic, and life-threatening diseases characterized by a deficiency in a specific lysosomal enzyme. LSDs are caused by DNA mutations that prevent an individual’s body from making critical enzymes that break down and recycle certain natural cellular products within lysosomes. These disorders cause a buildup of substances such as lipids, carbohydrates, and proteins within cells’ lysosomal compartments, leading to problems that have significant systemic impact and can cause high morbidity and mortality.
Collectively, LSDs affect approximately one in every 5,000 live births worldwide, but the prevalence of each of the individual diseases is significantly lower, with some being as rare as one in 4.2 million live births.1 However, the prevalence of LSDs may be higher than originally thought; recent advances in diagnostics may lead to the identification of additional patients.
LSDs, which can present in infancy, childhood, as well adulthood, are progressive, and represent significant burden for patients, their families, and the healthcare systems. Currently, there are no known cures for these disorders. Enzyme replacement therapy (ERT) is the most common treatment approach.
Glossary of Terms
Below please find more additional information about LSDs.
Glycan degradation disorders
This category of LSDs is by far the largest, covering approximately 30 of the most common LSDs. The problem with the LSDs in this category is that these disorders are not able to break down glycans, also known as polysaccharides. These are large, complex sugar molecules that play a role in biologic systems and processes. The prefix “glyco” implies that there is a sugar component to a particular molecule.
Glycolipid degradation disorders
Glycolipids are lipids that contain carbohydrate residues. They are a key component of the lipid bilayer that makes up cellular membranes, and they help to facilitate cellular recognition, organization, and tissue formation. Gaucher disease, gangliosidosis, Tay-Sachs disease, Fabry disease, and Krabbe disease are all examples of glycolipid degradation disorders.
Glycoprotein degradation disorders
Glycoproteins are proteins that contain oligosaccharide side chains. These macromolecules are often membrane-bound and play important roles in intracellular trafficking, cell-to-cell signaling, and host-pathogen response. Alpha-mannosidosis, beta-mannosidosis, and fucosidosis are examples of glycoprotein degradation disorders.
Glycosaminoglycan degradation disorders
Glycosaminoglycans, also known as mucopolysaccharides, perform several important roles in the body. These long, linear polysaccharides bind to water, thereby lubricating joints, enabling connective tissues to stretch, and supporting a variety of motor functions. The degradation of different types of glycosaminoglycans may result in similar glycosidases and sulfatases. Similarly, a single enzyme defect may lead to different types of partially degraded glycosaminoglycans. As a result, the multiple diseases collectively termed mucopolysaccharidoses share similar clinical phenotypes, with varying degrees of severity. Individuals with any variant of mucopolysaccharidosis (MPS) may experience organomegaly, dysostosis multiplex, decreased growth, and recurrent infections from these chronic, progressive diseases. Because most types of MPS do not affect the central nervous system, these glycosaminoglycan degradation disorders are considered potentially amenable to enzyme replacement therapy.
Lipid degradation disorders
Lipids store energy, act as signaling vehicles, and play a key structural role in cell membranes. Because they are insoluble in water, they require transport proteins and vesicles to move through plasma and reach the tissues that need them. Lipid degradation disorders include two main subcategories.
Cholesterol ester and triglyceride degradation disorders
Cholesterol is the primary component of a cell’s phospholipid bilayer and is the precursor to many bioactive compounds, including steroid hormones. Triglycerides are key energy storage molecules in adipose tissue. Wolman disease is one example of a cholesterol ester and triglyceride degradation disorder.
Sphingomyelin degradation disorders
Sphingomyelin is an important structural component of the Schwann cells that form the sheaths surrounding the axons of myelinated neurons. It is also found in red blood cells and the lenses of the eye. Niemann-Pick disease types A and B and Farber disease are examples of sphingomyelin degradation disorders.
Protein degradation disorders
Proteins have a wide variety of responsibilities in biological systems, including catalyzing metabolic reactions, DNA replication, response to stimuli, and intra- and intercellular transport. Most protein degradation disorders are rarer than other LSDs. This category includes Batten disease and pyknodysostosis.
Post-translational modification defects
After a protein is translated from mRNA, additional modification, typically by enzymes, occurs through the bonding of side chains and/or removal of amino acids from the N- or C-terminus. Newly formed proteins often require post-translational modification in order to be transported correctly to their final destinations and/or to become biologically active. Mannose phosphorylation is an example of post-translational modification. Mucolipidosis types II and III and multiple sulfatase deficiency are examples of diseases caused by post-translational modification defects.
Integral membrane protein disorders
Integral membrane proteins (IMPs) are located along the lysosomal membrane. IMPs may also be found on other plasma membranes, such as the endoplasmic reticulum and Golgi apparatus, as well as on the cell membrane itself. IMPs are thought to be involved in multiple cellular processes, including autophagy, maintaining lysosomal pH, endocytosis, protein trafficking within cells, and cellular apoptosis, but many of their exact roles are still unclear. Mucolipidosis type IV and Niemann-Pick disease type C are examples of IMP disorders.
Lysosomal-related trafficking defects
Deficient proteins may not be directly linked to a specific lysosomal location but may instead be present in the trafficking route of lysosomal proteins between the endoplasmic reticulum, Golgi apparatus, endosomes, and lysosomes. This is an active area of basic science research, so more diseases in this class may be discovered in the near future. Chediak-Higashi syndrome and Hermansky-Pudlak syndrome are examples of diseases caused by lysosomal-related trafficking defects.
- National Organization for Rare Disorders. Lysosomal Storage Disorders. Available at: https://rarediseases.org/rare-diseases/lysosomal-storage-disorders/#:~:text=Affected%20Populations,many%20people%20around%20the%20world. Accessed on Jan. 8, 2021.