Background Lysosomal diseases

In the late 1950s and early 1960s, de Duve and colleagues identified and characterized the lysosome as a cellular organelle. Lysosomes are small vesicles surrounded by a single membrane that contain an array of enzymes capable of breaking down macromolecules.

They function as the digestive system of the cell, serving both to digest material from the cell itself (eg. when cellular structural components are being recycled) and to degrade material taken up from outside the cell. To accomplish the tasks associated with digestion, the lysosomes utilize about 40 different types of hydrolytic enzymes, all of which are manufactured in the endoplasmic reticulum and modified in the Golgi apparatus.

In lysosomal storage diseases, inherited genetic defects lead to an enzyme deficiency, which results in an abnormal accumulation of substances inside the lysosome, and thereby in organ damage. The storage diseases are inherited in an autosomal recessive fashion, except Fabry disease, Hunter disease (MPS II) and Danon disease that are all X-linked diseases. Certain disorders are more prevalent in certain geographic areas or among those of a particular ethnicity. Gaucher disease and Tay-Sachs disease are for instance almost 100 times more prevalent in Ashkenazi Jewish descendants than in the general population. Individually, lysosomal storage diseases occur with incidences of less than 1:100.000, however, as a group the incidence is about 1:5000 - 1:10.000.

Because there are numerous specific deficiencies, storage diseases are usually grouped biochemically by the accumulated metabolite. Subgroups include:

  • Mucopolysaccharidoses, including Hurler disease (MPS I) and Hunter syndrome (MPS II);
  • (Sphingo)lipidoses, including Gaucher disease and Niemann-Pick disease;
  • Mucolipidoses, including Sialidosis (ML I).

Glycogen storage disease type II (Pompe disease) is also a defect in lysosomal metabolism, although it is otherwise classified.

Clinical picture

The clinical manifestations are widely varying across the lysosomal storage disorders, depending on the genetic defect and the particular substrate stored. Even within a particular disease, phenotypes may differ. Some of the disorders may present in a mild form with patients surviving into adulthood, while others have a rather severe phenotype resulting in early death.

Symptoms may include developmental delay, movement disorders, seizures, dementia, deafness and/or blindness. In other diseases, hepatosplenomegaly, pancytopenia, pulmonary and cardiac problems, and bone manifestation are prominent symptoms and signs.


The main method for diagnosis of lysosomal storage disorders is enzyme assay, available for most lysosomal storage disorders. These tests compare enzyme levels in a patient sample (generally blood, urine, or skin fibroblasts) against normal benchmarks. Low levels of a particular enzyme confirm the LSD associated with that enzyme defect. In addition, mutation analysis may be performed for certain disorders. Prenatal testing is often possible, most reliably through amniocentesis or chorionic villus sampling.


Treatment options include hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy (ERT), substrate reduction therapy and chaperone therapy.

In HSCT, healthy stem cells, typically from the bone marrow, are transplanted into the individual in order to create the missing enzyme in the body. This procedure does cross the blood/brain barrier and, therefore, can treat mental disabilities that exist in certain lysosomal disorders. But this treatment poses problems, such as transplant rejection, along with disabling side effects.

With ERT, a synthesized enzyme is infused into the bloodstream. Enzymes are currently available for Gaucher disease, Fabry disease, Hurler’s syndrome, and Pompe’s disease. ERT has been proven to be highly effective in some of the diseases. Drawbacks are the high costs of the therapy, and, more importantly, the formation of antibodies against the enzyme. Furthermore, the enzyme does not cross the blood/brain barrier.

Substrate reduction therapy is currently used for some of these diseases. Using this method, the synthesis of a certain macromolecule is decreased with the aim of creating a better balance between synthesis and breaking down of the particular molecule.

At last, chaperone therapy, a technique used to stabilize the defective enzymes produced by patients, is currently being examined for certain of these disorders.


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