Collectively Common, Individually Rare Many

OUTLOOK LYSOSOMAL STORAGE DISORDERS MYRIAD MALADIES

u A tophag os om e Mutations affecting an es enzyme that labels other som do 3 enzymes for delivery to n the lysosome result in E 4 mucolipidosis-II Defects in a protein that helps endosomes and autophagosomes fuse with the lysosome cause Danon disease Defects in processing enzymes can cause Ly undigested material to Go soso lgi 2 me accumulate, such as in Gaucher’s disease and 5 Hunter syndrome En doplas mic retic ulum

Failure of processing in the endoplasmic reticulum can inac- 6 tivate a whole class Loss of transport proteins of enzymes, such as causes the lysosome to retain molecular building blocks in Nucleus in multiple sulfatase deficiency diseases such as cystinosis or sialic acid storage disease

MANY MOVING PARTS The lysosome uses specialized enzymes to help cells to digest external biological materials and recycle defective proteins and damaged cellular machinery. Many LSDs arise from mutations in the genes that encode those enzymes, but there are numerous other ways in which this process can break down (red stars).

1 The endoplasmic The Golgi apparatus Endosomes transport The autophagosome Within the lysosome, Molecular building blocks reticulum performs the further processes and enzymes from the Golgi delivers damaged enzymes convert are released into cell for initial processing of labels specific enzymes and materials from organelles and misfolded molecules such as sugars, reuse newly synthesized for delivery to the outside the cell to the proteins to the lysosome proteins and lipids into lysosomal enzymes lysosome lysosome for recycling simpler building blocks

COLLECTIVELY COMMON, INDIVIDUALLY RARE LSDs are not especially rare; estimates suggest that 1 in just over 5,000 newborns newborns worldwide, and the rarest have been described only a handful of times. will be affected. However, each individual disease occurs with much lower The diseases shown are those for which there are most data. Numbers have been frequency — the most common, Gaucher’s disease, affects only 1 in 40,000 estimated and are approximate.

80 PE MILLION LIVE BITHS MPS-I Gaucher’s Metachromatic leukodystrophy (Hurler/Scheie) Krabbe Cystinosis GM1-gangliosidosis 25 15 10 10 10 7

Pompe MPS-III Fabry’s* Neuronal ceroid Niemann−Pick type C Others 25 (Sanlippo) 13 lipofuscinosis (all forms) 7 34 14 10

Others: Mucopolysaccharidosis (MPS)-IV, 5.0; MPS-VII, 4.0; Niemann–Pick type A/B, 4.0; MPS-II (Hunter)*, 3.8; Sandhoff, 3.2; Wolman, 2.9; Tay–Sachs, 2.9; MPS-VI, 2.5; alpha-mannosidosis, 2.0; pycnod- ysostosis, 1.3; Danon, 0.3; Schindler, 0.3; beta-mannosidosis, 0.3; fucosidosis, 0.3; aspartylglucosaminuria, 0.3; Farber, 0.3; multiple sulfatase deficiency, 0.3; galactosialidosis, 0.3; sialic acid storage, 0.3.

*Almost exclusively in males. HOME REFERENCE/ GENETICS DISORDERS AND STROKE; OF NEUROLOGICAL INSTITUTE US NATIONAL SOURCES: GENE REVIEWS; MEDSCAPE OF MEDICINE; WWW.OMIM.ORG; WWW.ORPHA.NET; LIBRARY NATIONAL

LYSOSOMAL STORAGE DISORDERS OUTLOOK Lysosomal storage disorders (LSDs) highlight the diverse ways in which the failure of a single organelle can bring cells to their knees. Most are rare and poorly understood, making the development of therapies a daunting task. By Michael Eisenstein, infographic by Denis Mallet.

BONE-MARROW TRANSPLANT This is an aggressive treatment in which the patient’s blood-cell-producing 4 haematopoietic stem cells are wiped out by chemotherapy and replaced with healthy donor cells.

Ly soso me 3

m ulu tic i re lg ic o sm G la op nd E

2 1 Nucleus

POTENTIAL ROADS TO RECOVERY The past 25 years have seen considerable progress in the development of treatments that can improve the quality of life for some patients. Most treatments focus on changing intracellular processes. The exception is bone-marrow transplant, in which the patient receives an entire set of healthy stem cells from a suitable donor.

1 Enzyme-replacement therapy involves Substrate-reduction therapy blocks Chaperone therapy protects or refolds In gene therapy, a functional replacing missing or defective enzymes the production of materials that would mutant enzymes. This prevents them replacement enzyme-producing gene is with synthetic counterparts, which are otherwise accumulate in the lysosome from being degraded in the endoplasmic delivered using a vector such as a virus. internalized by cells and delivered to owing to a lack of appropriate digestive reticulum and ejected, and allows them This technology is still being developed lysosomes enzymes to reach the lysosome. (page S158).

THE LONG ROAD TO DISCOVERY The first LSDs were identified more than 80 years before researchers were able to identify the cellular structures involved. Since then, new LSDs have been identified along with, more recently, the genes involved and drugs that help to repair the damage.

1881 1955 1973 1981 1991 2008 Warren Tay describes Christian de Duve and Roscoe Brady and col- First successful bone- Genzyme’s Ceredase, First clinical trial of gene the first LSD, which is colleagues discover leagues do the first trial marrow transplant for an derived from human therapy for LSDs neuronal later named Tay–Sachs enzyme-rich granules of enzyme-replacement LSD (Hurler syndrome) placenta, is approved to ceroid lipofuscinosis 50 disease that he dubs lysosomes therapy in humans to treat Gaucher’s disease treat Fabry’s disease 40

20 LSDs identified LSD genes cloned LSD treatments Cumulative total 10

0 1880 1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010