Lysosomal diseases: Overview on current diagnosis and treatment

Abstract

Lysosomal diseases (LDs), also known as lysosomal storage diseases (LSDs), are a heterogeneous group of conditions caused by defects in lysosomal function. LDs may result from deficiency of lysosomal hydrolases, membrane-associated transporters or other non-enzymatic proteins. Interest in the LD field is growing each year, as more conditions are, or will soon be treatable. In this article, we review the diagnosis of LDs, from clinical suspicion and screening tests to the identification of enzyme or protein deficiencies and molecular genetic diagnosis. We also cover the treatment approaches that are currently available or in development, including hematopoietic stem cell transplantation, enzyme replacement therapy, small molecules, and gene therapy.

Diagnosis of Mucopolysaccharidoses

“…Most enzyme assays for lysosomal disorders diagnosis rely on spectrofluorometry, which uses enzyme-specific substrates with a fluorogenic radical (4-methylumbelliferyl) to generate a fluorophore product that will absorb energy at a specific wavelength and then emit it at another, longer wavelength to determine the quantity of product produced. Spectrophotometry is also a widely used technique based on chromophores (as p-nitrochatechol sulfate specific for arylsulfatase B) that excite themselves and emit colors depending on the energy released by the change from the basal to the excited state [2] (Table 3). To assure the quality of the enzymatic assays, it is important to always include positive and negative controls to analyze an additional enzyme, to confirm the integrity of the sample.…”

“…The mucopolysaccharidoses (MPSs) comprises 11 lysosomal diseases in which there is a deficiency in a specific step of the degradation of glycosaminoglycans (GAGs). This deficiency leads to storage of GAGs in tissues and to a range of clinical consequences, which may include CNS impairment, depending on the specific MPS type [1,2]. Each MPS is clinically heterogeneous, with severe and attenuated cases within each MPS type, a fact that may be related to small variations in the residual enzyme activity, conditioned by the genetic variation present in the patient [3].…”

“…The correct diagnosis enables specific therapeutic measures (available for most MPS patients) to be taken, and also phenotype prediction, carrier identification, genetic counseling, and prenatal diagnosis. As therapy outcomes seem to be better when the disease is identified early in life, screening for MPS in high-risk groups and even newborn screening programs for selected MPS types are taking place [2,[4][5][6][7][8].…”

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

“…Hematopoietic stem cell therapy (HSCT) is one of the more common treatments of LSDs. HSCT is the main therapy for mucopolysaccharidosis (MPS) I and Krabbe disease, and has been used in other LSDs including MPS II, MPS IVA, MPS VII, metachromatic leukodystrophy and fucosidosis (Poswar et al, 2019). HSCT allows for the delivery and engraftment of donor derived stem cells in patients with LSDs.…”

“…The first use of ERT was the use of glucocerebrosidase for Gaucher disease in 1991 (Barton et al, 1991). ERT has since been used for Farber's disease, Pompe disease, MPS types I, II, IVA, VI, and VII and lysosomal acid lipase deficiency, and is currently being developed for others (Poswar et al, 2019). It is now possible to mass produce purified enzyme due to advances in recombinant DNA techniques.…”