Molecular pathogenesis

The primary defect in a lysosomal storage disorder is caused by a genetic defect in either a

specific lysosomal enzyme,

specific lysosomal enzyme co-factor (saponin),

lysosomal enzyme modifying protein,

lysosomal enzyme protecting protein, or

lysosomal membrane protein

The majority of LSDs is caused by a specific lysosomal enzyme deficiency, leading to the intralysosomal accumulation of the macromolecules (substrates) whose next step in degradation actually requires to that enzyme. To date, more than 30 different primary single enzyme deficiencies have been identified as a cause of a LSD.

Lysosomal enzyme co-factor deficiency is a rare cause of LSD, mimicking the deficiency of the enzyme that actually requires assistance by that co-factor. There are three sphingolipidoses which can result from an enzyme deficiency as well as a co-factor defect.

Saponin C (SAP C) deficiency mimics a severe form of Gaucher disease

SAP B deficiency resembles metachromatic leukodystrophy (MLD)

GM2 activator protein deficiency is a potential cause of GM2 gangliosidosis

Lysosomal enzymes are initially made as precursors, and defects in post-translational modification are responsible for two severe, multiple lysosomal enzyme deficiencies.

In I-cell disease (mucolipidoses II & III), there is a defect of one of the two enzymes - in the Golgi network - involved in tagging lysosomal enzymes with mannose-6-phosphate (M6P) groups. M6P groups are critical for the subsequent binding to M6P-receptors (MPR) and transport to the endosomal-lysosomal compartment.

In multiple sulfatase deficiency, there is a defect of the SUMF1 gene product which – in the endoplasmatic reticulum - is responsible for a modification of cystein residues in lysosomal acid sulfatases to generate a fully functional active site

Following delivery to and final modification in lysosomes at least some lysosomal enzymes actually need to be protected against degradation themselves. The two lysosomal enzymes beta-D-galactosidase and N-acetyl-alpha-neuraminidase need to form a complex with protective protein cathepsin A (PPCA) in order to maintain stability. Defects in these two enzymes individually cause GM1 gangliosidosis and sialidosis, respectively, but PPCA deficiency causes galactosialidosis, a disease characterized by their combined deficiency, plus by increased chaperone-mediated autophagy (reflecting loss of PPCA’s catalytic function).

Lysosomes carry a number of membrane proteins with specific roles in lysosomal functioning, including enzymatic activity, substrate transport, metabolite export, lysosomal acidification, and interactions with other elements of the endosomal-lysosomal compartment. Several LSDs caused by defects of membrane proteins have now been recognized.

Membrane-bound enzymes (e.g. in Sanfilippo type C [MPS III C])

Substrate trafficking (e.g. in Niemann-Pick C)

Metabolite export (e.g. in cystinosis or Salla disease)

Ion channel or proton pump (e.g. in mucolipidosis type IV or osteopetrosis)

Proteins with diverse functions (e.g. in Danon disease or neuronal ceroid lipofuscinosis type 3)