Mucolipidoses, Multiple Sulfatase Deficiency, and Cathepsin K and C Deficiency

Summary

Mucolipidosis type II/III (ML II/III) and multiple sulfatase deficiency (MSD) share clinical features with the mucopolysaccharidoses. Both ML II/III and MSD result from enzymatic defects that affect the post-translational modification of lysosomal enzymes. In ML II/III the mannose-6-phosphate marker, essential for routing lysosomal enzymes towards the lysosomes, is lacking. This leads to the excretion of lysosomal enzymes in plasma where they are unable to execute their function. In MSD lysosomal sulfatases, as well as sulfatases from the endoplasmic reticulum and Golgi complex, cannot be activated due to the inability to modify a conserved cysteine residue at the active site. In mucolipidosis type IV (ML IV), lysosomal dysfunction is caused by the deficiency of transient receptor potential channel mucolipin-1 (TRPML1), a nonselective cation channel present in late endosomal and lysosomal membranes necessary for autophagy, vesicular trafficking, and mTOR and TFEB signaling. Neurological dysfunction and visual impairment are the most predominant clinical features; skeletal abnormalities are not seen in ML IV. Deficiency of the lysosomal enzymes cathepsin K (pycnodysostosis) and C (Papillon–Lefèvre or Haim–Munk syndrome) presents both with a very distinct clinical picture. Cathepsin K is important for bone resorption and extracellular matrix remodeling. Its deficiency results in stunted growth, facial dysmorphism, osteopetrosis, and dental abnormalities. In cathepsin C deficiency, premature loss of both deciduous and permanent teeth due to periodontitis in combination with palmoplantar keratosis is the main clinical feature.

All disorders are ultra-rare and have autosomal recessive inheritance. Their clinical spectrum is not yet fully known, and patients are likely still underdiagnosed. No specific biomarkers are available that can lead to the diagnosis. All disorders have in common that no curative treatments are available and specialized multidisciplinary supportive care is needed to minimize the disease burden and provide an adequate quality of life.