Many genetic disorders have been identifed in individuals who have mutations in a gene that encodes lysosomal pro-teins. These diseases are termed lysosomal storage diseases (LSDs) and are characterized by dysfunctional lysosomes. The defective protein in most cases is a hy-drolytic enzyme or its cofactor; less commonly, lysosomal membrane proteins or proteins that are involved in sorting, targeting, and transporting lysosomal proteins are defec-tive. The result is an accumulation in cells of the specifc products that lysosomal enzymes normally use as sub-strates in their reactions. These undigested, accumulated products disrupt the normal function of the cell and lead to its death. Currently, 49 disorders are known LSDs with a collec-tive incidence of about 1 in 7,000 live births. The life ex-pectancy across the entire group of people with these disorders is 15 years. The frst LSD was described in 1881 by British ophthalmologist Warren Tay, who reported symp-toms of retinal abnormalities in a 12-month-old infant with severe neuromuscular symptoms. In 1896, U.S. neurologist Bernard Sachs described a patient with similar eye symp-toms found earlier by Tay. This disease is now known as Tay-Sachs disease. It is caused by the absence of one enzyme, a lysosomal galactosidase ( -hexosaminidase) that catalyzes a step in lysosomal breakdown of ganglio-sides in neurons. The resulting accumulation of the GM2 ganglioside that is found within concentric lamellated struc-tures in residual bodies of neurons interferes with normal cell function. Children born with LSDs usually appear normal at birth; however, they soon show clinical signs of the disease. They often experience slower growth, show changes in fa-cial features, and develop bone and joint deformities that lead to signifcant restrictions of limb movement. They may lose already attained skills such as speech and learning ability. Behavioral problems may occur, as well as mental retardation. They are prone to frequent lung infections and heart disease. Some children have enlarged internal or-gans such as the liver and spleen (hepatosplenomegaly). The most common LSDs in children are Gaucher disease, Hurler syndrome (MPS I), Hunter syndrome (MPS II), and Pompe disease. Not long ago, LSDs were seen as neurodegenerative disorders without any potential treatment. In the last two decades, there has been limited success in treating the symptoms of LSDs. Considerable effort has been devoted to genetic research and fnding methods to replace the missing enzymes that cause various forms of LSD. Enzyme-replacement therapy, which requires the cellu-lar delivery of a manufactured recombinant enzyme, is avail-able for some LSDs such as cystinosis and Gaucher disease. Enzymes have also been supplied by transplanta-tion of bone marrow containing normal genes from an un-affected person. Success of the enzyme-replacement therapy is often limited by insuffcient biodistribution of re-combinant enzymes and high costs. Recently emerging strategies for the treatment of LSDs include pharmaco-logical chaperone therapy in which chaperone molecules are delivered to affected cells. In some cases, synthetic chaparones can assist in folding of mutated en-zymes to improve their stability and advance their lysoso-mal delivery. In the future, the combination of different therapies such as enzyme replacement, pharmacological chaperone, and gene-transfer therapies with the devel-opment of newborn screening tests will enable early detec-tion and improve clinical outcome of patients with LSDs. 
FOLDER 2.1 Clinical Correlation: Lysosomal Storage Diseases