What are lysosomal storage disorders?

Lysosomal storage disorders are inherited inborn errors of metabolism caused by defects in the genes that encode lysosomal enzymes, leading to enzyme deficiency.1 These enzymes break down and help to recycle macromolecules such as carbohydrates, lipids, nucleic acids and proteins, and are pivotal for cellular communication, response to infection and homeostasis.1,2 Lysosomal storage disorders affect the chemical composition of the lysosomal storage material and can be divided into three broad groups: sphingolipidoses, mucopolysaccharidoses and glycoproteinoses.3

Variants in the genes that encode lysosomal proteins (e.g., lysosomal glycosidases, proteases, integral membrane proteins, transporters, and enzyme modifiers or activators) can affect the functionality of the encoded protein, leading to the progressive accumulation of substrates within lysosomes, which ultimately leads to cell dysfunction and cell death. Collectively, there are 70 monogenic disorders of lysosomal catabolism, the majority of which are inherited as autosomal recessive traits, with only three linked to the X chromosome: Danon disease, Fabry disease and mucopolysaccharidosis II (also known as Hunter syndrome).1 Fabry disease is a rare lysosomal storage disorder caused by variants in the GLA gene, which is located on the X chromosome and encodes the alpha-galactosidase (α-Gal A) enzyme.4

Lysosomal storage disorders often present in infancy and childhood, but late-onset disease can occur in adulthood.1 The symptoms of lysosomal storage disorders may progress and evolve over time, and can involve multiple organs and systems.5 Diagnosis of lysosomal storage disorders may include enzymatic analysis and single-gene sequencing.1,5 Patients may present with a continuum of disease severity. Diagnosis may be delayed, especially in milder cases with longer survival, if clinical symptoms are similar to other more common conditions.1 Together, lysosomal storage disorders are common; however, individually, these disorders are considered rare. One Australian study estimated that lysosomal storage disorders affected 1 in 7700 live births; although, the prevalence of individual disorders was estimated to range from 1 in 57,000 live births for Gaucher disease to 1 in 4.2 million live births for sialidosis.6

 

C-ANPROM/INT/FAB/0015; Date of preparation: March 2021