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.

Figure 1. Hypothetical scheme of an enzymatic reaction. Point mutations in the gene encoding an enzyme may alter its enzymatic activity leading to substrate accumulation and a lack of product. In addition, it may also cause the accumulated substrate to follow an alternative route. This is the cause of many LDs.

Figure 2. Tentative workflow for HSCT combined with newborn screening. After diagnosis of LDs, patients can receive a transplant as early as two weeks of age. ERT may start prior to the transplant and can be continued for the first few months until full chimerism is achieved. HSCT can also be combined with gene therapy, substrate reduction therapy, anti-inflammatories, and molecules that increase blood-brain barrier permeability to improve clinical outcomes. LD: lysosomal disorder; ERT: enzyme replacement therapy; BM: bone marrow; PSC: peripheral stem cell; CB: cord blood; GT: gene therapy; SRT: substrate reduction therapy; BBB: blood brain barrier; BBB*: molecules that increase BBB permeability.