What are lysosomal storage diseases?

Lysosomal storage diseases are inherited metabolic disorders caused by defects in the gene that encodes 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 diseases affect the chemical composition of the lysosomal storage material and can be divided into three broad groups: sphingolipidoses, mucopolysaccharidoses and glycoproteinoses.3

Mutations 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 gradual 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.1 Gaucher disease is one of the most prevalent lysosomal storage diseases,4-8 with the estimated worldwide prevalence ranging from 0.70 to 1.75 per 100,000 individuals, and a birth incidence ranging from 0.39 to 5.80 per 100,000 individuals.9 However, compared with the general population, the prevalence of Gaucher disease is higher in the Ashkenazi Jewish population, affecting approximately 1 in 850 individuals, with a carrier frequency of 1:17.10-12

Lysosomal storage diseases often present in infancy and childhood, but late-onset disease can occur in adulthood.1 Clinical features of lysosomal storage diseases are heterogeneous, but may include enlargement of abdominal organs and skeletal dysmorphia, which can be associated with developmental delay or other deficits associated with the central nervous system.1,13 Diagnosis of lysosomal storage diseases is based on clinical symptoms and diagnostic testing, including enzymatic analysis and single gene sequencing. 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

Despite the complex cellular pathogenesis of lysosomal storage diseases, several can be treated with approved treatments such as enzyme replacement therapy.1

C-ANPROM/INT//7566; Date of preparation: September 2020