Mucolipidosis Types II and III (ML II/III)

Mucolipidosis types II and III (ML II/III) are rare, autosomal recessive, inherited disorders that are disorders caused by the GNPTAB and GNPTG genes. ML II and ML III affect less than one in 50,000 individuals worldwide.

ML II is apparent at birth, and slowly progressive until death in childhood. ML II is characterized by growth delays, skeletal abnormalities, facial dysmorphism, stiff skin, developmental delay, cardiomegaly, respiratory insufficiency.

ML III becomes apparent around age 3 years, with death occurring in adulthood; characterized by slow growth, joint stiffness, and pain; coarsening of facial features, cardiorespiratory complications.

There is also another form of ML III called ML III gamma, which is a slowly progressive condition affecting skeletal, joint, and connective tissue, and is caused by a mutation in a different gene, GNPTG, that encodes for the gamma subunit of GNPT.

ML II and III are caused by deficiency of the Golgi enzyme GlcNAc-1-phosphotransferase (GNPT) due to mutations in the GNPTAB gene. ML II/ML III result from mutations in the 2 GNPTAB genes encoding the alpha and beta subunits of GNPT. GlcNAc-1 tags lysosomal enzymes with mannose 6-phosphate (M6P) onto the newly synthesized soluble lysosomal enzymes so they can be transported to the lysosome. In GNPTAB disorders, lysosomal enzymes do not contain M6P and are not properly targeted to the lysosome where they function. Consequently, undegraded cholesterol, phospholipids, glycosaminoglycans, and other substrates accumulate leading to cellular dysfunction and progressive disease.

There are currently no approved therapies to reverse the effects of ML II & III. Current approaches involve managing specific symptoms through targeted therapies.

M6PT is exploring potential gene therapy options to treat individuals with ML II and ML III.