What are Lysosomal Storage Diseases (LSDs)?

From the Guidelines

Lysosomal Storage Diseases (LSDs) are a heterogeneous group of almost 50 disorders caused by genetic defects in lysosomal function, leading to the accumulation of specific substrates and progressive cellular and tissue damage, ultimately resulting in significant morbidity and decreased lifespan 1. These conditions are characterized by the accumulation of undigested macromolecules within lysosomes, leading to cellular dysfunction and progressive tissue and organ damage.

Key Characteristics of LSDs

• Caused by genetic defects in a lysosomal acid hydrolase, receptor, activator protein, membrane protein, or transporter
• Result in the accumulation of specific substrates, such as mucopolysaccharides, oligosaccharides, sphingolipids, and gangliosides
• Affect various organ systems, including the central nervous system (CNS), and can lead to significant morbidity and decreased lifespan
• Often categorized according to the type of substrate stored, such as mucopolysaccharidoses, oligosaccharidoses, sphingolipidoses, and gangliosidoses

Diagnosis and Management

• Diagnosis must be established by specific enzyme assays and mutational analysis 1
• Urinary mucopolysaccharides and oligosaccharides can be useful for screening, but can be normal and increased nonspecifically in healthy neonates
• Management requires a multidisciplinary approach addressing specific organ involvement, which may include cardiac, neurological, skeletal, and respiratory manifestations
• Treatment approaches vary by specific disease, but often include enzyme replacement therapy (ERT), substrate reduction therapy, and bone marrow transplantation

Inheritance and Epidemiology

• Most LSDs are inherited in an autosomal recessive fashion, except for Fabry, Hunter, and Danon diseases, which are X-linked 1
• The frequency of LSDs as a group is estimated to be one in 7000-8000 live births, although this may be an underestimate due to the identification of mild and adult-onset forms of the diseases
• Certain disorders are more prevalent in specific geographic areas or population groups, such as Gaucher, Tay-Sachs, and Niemann-Pick type A in Ashkenazi Jews 1

From the FDA Drug Label

In this lysosomal storage disorder (LSD), clinical features are reflective of the accumulation of Gaucher cells in the liver, spleen, bone marrow, and other organs.

Lysosomal Storage Diseases (LSDs) are conditions where there is an accumulation of substances in the lysosomal compartment of cells, leading to cellular dysfunction.

• They are caused by deficiencies in lysosomal enzymes, resulting in the accumulation of substrates.
• Gaucher disease is an example of an LSD, where the accumulation of Gaucher cells in various organs leads to clinical features such as organomegaly, anemia, and thrombocytopenia. 2

From the Research

Definition and Characteristics of Lysosomal Storage Diseases (LSDs)

• Lysosomal storage diseases (LSDs) comprise a rare and heterogeneous group of nearly 50 heritable metabolic disorders caused by mutations in proteins critical for cellular lysosomal function 3.
• LSDs are characterized by defects in the function of specific enzymes responsible for breaking down substrates within cellular organelles (lysosomes) essential for the processing of macromolecules 4.
• These disorders are individually rare but collectively affect 1 in 5,000 live births, and are typically inherited as autosomal recessive traits 5.

Clinical Presentation and Diagnosis

• The classification and clinical presentation of different LSDs are dependent on the type of accumulated substrate, with some clinical signs and symptoms common across multiple LSDs, while others are more specific to a particular syndrome 3.
• Clinical features vary depending on the degree and type of enzyme deficiency, the type and extent of substrate accumulated, and the tissues affected 4.
• Diagnosis can be challenging due to the rarity and wide clinical diversity of LSDs, and is often delayed for months or years 3.

Treatment Approaches

• Treatments, such as enzyme replacement therapy, haemopoietic stem cell transplantation, and substrate reduction therapy, are now available for some of the LSDs 3, 6.
• Small-molecule therapies, including substrate reduction and chaperone therapies, have also been developed and are approved for some LSDs 5.
• Gene therapy and genome editing are at advanced preclinical stages and, for a few disorders, have already progressed to the clinic 5.