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MLII and mucolipidosis type III (MLIII) represent a spectrum of severity. The estimated combined prevalence at birth of MLII and MLIII is estimated between 1/ 37,000-455,000 worldwide. Whilst data is limited on MLIII, the prevalence at birth has been estimated at 1/1,250,000 in the Netherlands.

In MLIII, symptom onset is often in the first two decades of life and patients typically present with progressive hand deformities and restricted range of joint motion. For these symptoms, patients will often consult specialists such as rheumatologists and orthopedic or plastic surgeons. Progressive hip dysplasia may cause bone pain and leads to waddling gait. Other musculoskeletal problems like dysostosis multiplex, short stature, osteopenia, osteoarthritis, spinal cord compression and carpal tunnel syndrome are common in MLIII. Mild corneal clouding, cardiac valvular disease, mild coarsening of facial features, and mild intellectual disability are also possible.

There are two subtypes, the MLIII alpha/beta subtype due to pathogenic variants in GNPTAB (12q23.3) and the milder MLIII gamma subtype with pathogenic variants in GNPTG (16p13.3). These two genes encode for the activity of the enzyme N-acetylglucosamine-1-phosphotransferase, which is decreased in MLIII. This enzyme catalyzes the first step of the formation of mannose 6-phosphate (M6P) on specific lysosomal soluble hydrolases. MP6 is an essential targeting signal for the transport to the lysosomes and without this, the enzymes are missorted into the extracellular space and are not broken down within the lysosomes. This all leads to accumulation of the enzymes in connective tissues, cartilage, bones, ligaments, and other tissues.

Diagnostic procedures include clinical/radiographical examination as well measurement of the activity of several lysosomal enzymes in plasma and/or fibroblasts, where these enzymes are elevated in plasma and decreased in fibroblasts. Radiographs reveal increasing osteopenia and dysostosis multiplex. In addition, GlcNAc-1-phophotransferase activity can be measured in fibroblasts. Finally, molecular analysis of GNPTAB (MLII and III α, β) or GNPTG (MLIII γ) can be performed.

Differential diagnosis includes the different types of mucopolysaccharidosis and alpha-mannosidosis.

Antenatal diagnosis is possible in chorionic villi by molecular testing.

Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.

There are currently no curative or disease-modifying treatments available for MLIII. Musculoskeletal problems often requires surgical (orthopedic or plastic) interventions at a young age or pain and or/ anti-inflammatory medications. Bisphosphonate treatment in MLIII patients can decrease pain, increase bone density and improve mobility. However, long-term treatment with bisphosphonates is not to be recommended as this can induce femoral fractures.

The MLIII α/ β subtype has a broad phenotypic range, from severely affected patients that die in childhood to milder affected patients displaying primarily skeletal symptoms, who survive into adulthood. Osteoarthritis is rapidly progressive in all patients (due to dysostosis multiplex and osteopenia) and results in cartilage destruction and bone lesions. All patients clinically suffer from bone and joint pain which has a great impact on the quality of life.