Lysosomal storage disorders:

  • group of inherited disorders caused by genetic defects in lysosomal hydrolases, membrane proteins, receptors or integral membranes causing accumulation of a variety of substrates that are specific to each disorder.
  • pathology à intra-lysosomal storage in multiple tissues and association of visceral, ocular, hematologic, skeletal and neurological manifestations.
  • progressive, and ultimately fatal, characterized by a spectrum of clinical manifestations with variable disease progression rates.
  • Affected individuals generally appear normal at birth and develop clinical manifestations of the disease months, years, or even decades later.
  • LSDS are generally classified by the nature of the primary stored material involved
  • Lipid Storage Disorders – sphingolipidoses and ganglosidosis,
  • Mucopolysacharidosis – Hunter and Hurler’s Disease,
  • Glycoprotein storage disorders and Mucolipidoses.

Functionally these disease can be classified as:

1. deficiencies of a single lysosomal hydrolase.

2. multiple hydrolase deficiencies secondary to the default of co- or posttranslational maturation step.

3. deficiencies in lysosomal membrane transporters for small molecules.

4. diseases of the endolysosomal system.

5. deficiencies in other lysosomal proteins.

Accumulation of lysosomal storage causes lysosomal dysfunction, leading to cellular, tissue and organ damage, and increased manifestations of disease.


  • They are cytoplasmic cellular organelle that is responsible for the digestion of endocytosed molecules. They are present in all nucleated eukaryotic cell.
  • Lysosomes are characterised by an acidic internal pH (pH 4.6 — 5).
  • Their primary function is the degradation and recycling of macromolecules obtained by endocytosis, autophagy, and other cellular trafficking pathways.
  • Newly synthesized enzymes transverse the rough endoplasmic reticulum where they receive N-linked oligosaccharide side chains.
  • Subsequently, they pass through the Golgi apparatus where the oligosaccharide side receive the mannose- 6-phosphate (M6P) recognition marker
  • Lysosomal enzymes bearing the M6P marker bind to the M6P receptors in the trans-Golgi network, are packed into clathrin-coated vesicles and transported to late endosomes, either directly or indirectly via early endosomes.
  • Due to the low pH in this cellular compartment the receptor–ligand complexes dissociate and the lysosomal enzymes are delivered to the lysosome. This mechanism is important for the success of Enzyme Replacement Therapy.

Enzyme replacement therapy:

  • It was proposed that lysosomes would be accessible to the molecules presented at the cell surface.
  • It was achieved by targeting the mannose and mannose 6 receptors on the cell membranes.
  • An effective enzyme replacement therapy was first developed for Type I Gaucher’s Disease, where the enzyme glucosidase is defective, and affects tissue macrophages.
  • This paved the way for the development of Enzyme Replacement Therapies for other lysosomal disorder.
  • Subsequently enzymes targeting Mannose 6 Phosphate receptors were developed to treat other types of lysosomal storage disorders.
  • ERT products are produced using recombinant DNA methods in Chinese hamster ovary cell cultures and human cell line.
  • Each ERT product is specific for only one LSD.
  • For maximum benefit of available therapies, treatment should start before the onset of significant clinical disease.
DiseaseDeficient enzymePathological macromolecule accumulatedFDA Approved enzyme
Fabry Diseaseα-galactosidase AGlycosphingolipidsFabrazyme®
Type 1 Gaucher diseaseGlucocerebrosidaseglucosylceramideCerezyme®, VPRIV™, Elelyso™
Glycogen Storage Disease type II (Pompe disease)acid alpha-glucosidaseGlycogenMyozyme®, Lumizyme®
MPS I (Hurler, Hurler-Scheie, or Scheie syndrome)alpha-L-iduronidaseglycosaminoglycansdermatansulfate and heparansulphateAldurazyme
MPS II (Hunter disease)iduronatesulfataseglycosaminoglycansdermatansulfate and heparansulphateElaprase®
MPS VI (Maroteaux-Lamy syndrome)arylsulfatase Bdermatansulfate glycosaminoglycanNaglazyme

Most LSD have CNS involvement, to overcome the blood brain barrier, direct infusion of enzymes in the spinal canal or intra ventricularly are being tried.

ERT does not alter the natural history of the skeletal disorder in mucopolysaccharidoses and children will still endure the skeletal changes of the disease due to poor vascularity of the cartilages and poor uptake due the lack of M6P receptors

In India, there are six centres in cities Mumbai, Delhi, Lucknow and Chennai for Enzyme Replacement Therapy. The major factor limiting the widespread use is the cost of these medications.

Some important therapeutic enzymes

CollagenaseSkin ulcers
HyaluronidaseHeart attack
LysozymeBacterial cell wall hydrolysis- Antibiotic
Streptokinase, UrokinaseBlood clots

As enzymes are specific biological catalysts, they should make the most desirable therapeutic agents for the treatment of metabolic diseases. Unfortunately a number of factors severely reduces this potential utility:

  • They are too large to be distributed simply within the body’s cells. This is the major reason why

enzymes have not yet been successful applied to the large number of human genetic diseases

  • Being generally foreign proteins to the body, they are antigenic and can elicit an immune response

which may cause severe and life threatening allergic reactions, particularly .on continued use

  • Their effective lifetime within the circulation may be only a matter of minutes.

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