Mucolipidoses Overview: Past, Present, and Future

Abstract

Mucolipidosis II and III (ML II/III) are caused by a deficiency of uridine-diphosphate N-acetylglucosamine: lysosomal-enzyme-N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase, EC2.7.8.17), which tags lysosomal enzymes with a mannose 6-phosphate (M6P) marker for transport to the lysosome. The process is performed by a sequential two-step process: first, GlcNAc-1-phosphotransferase catalyzes the transfer of GlcNAc-1-phosphate to the selected mannose residues on lysosomal enzymes in the cis-Golgi network. The second step removes GlcNAc from lysosomal enzymes by N-acetylglucosamine-1-phosphodiester α-N-acetylglucosaminidase (uncovering enzyme) and exposes the mannose 6-phosphate (M6P) residues in the trans-Golgi network, in which the enzymes are targeted to the lysosomes by M6Preceptors. A deficiency of GlcNAc-1-phosphotransferase causes the hypersecretion of lysosomal enzymes out of cells, resulting in a shortage of multiple lysosomal enzymes within lysosomes. Due to a lack of GlcNAc-1-phosphotransferase, the accumulation of cholesterol, phospholipids, glycosaminoglycans (GAGs), and other undegraded substrates occurs in the lysosomes. Clinically, ML II and ML III exhibit quite similar manifestations to mucopolysaccharidoses (MPSs), including specific skeletal deformities known as dysostosis multiplex and gingival hyperplasia. The life expectancy is less than 10 years in the severe type, and there is no definitive treatment for this disease. In this review, we have described the updated diagnosis and therapy on ML II/III.

Anaesthesia-Relevant Disease Manifestations and Perianaesthetic Complications in Patients with Mucolipidosis—A Retrospective Analysis of 44 Anaesthetic Cases in 12 Patients

“…In MLII and III, an absent or reduced GlcNAc-1-phosphotransferase activity results in global mis-sorting of lysosomal enzymes and subsequent secretion into the extracellular compartment. Consecutively, partially degraded macromolecules (i.e., glycosaminoglycans, phospholipids, cholesterol) accumulate in the lysosomes impairing cellular function [4].…”

“…The estimated incidence of MLII and III globally ranges from 0.22 to 2.70 per 100,000 live births [5]. No curative therapy is yet available [4].…”

“…The overlapping progressive symptoms comprise craniofacial dysmorphism (i.e., flat face, shallow orbits, depressed nasal bridge, macroglossia), a short neck, respiratory insufficiency and upper airway obstruction, sleep apnoea, cardiac dysfunction, skeletal deformities (e.g., growth impairment, spine and chest deformity), and neurocognitive delay. Radiological features are subsumed as dysostosis multiplex [4][5][6]8,9]. For patients with MPS, these symptoms are known to be associated with a high risk of morbidity and mortality when undergoing general anaesthesia [10].…”

Mucopolysaccharidoses diagnosis in the era of enzyme replacement therapy in Egypt

“…Also, Khan and Tomatsu stated that these disorders share characteristic bone deformities. In addition, several lysosomal glycosidases and sulfatases enzymes are deficient in ML lysosomes and are involved in a step by step degradation of GAGs [ 48 ]. During the study period, 47 mucolipidosis cases were diagnosed.…”

GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway

“…Disruption of M6P biogenesis or its sorting results in the mistargeting of most lysosomal enzymes 8 . Mutations in GNPT cause two distinct lysosome storage diseases (LSDs) 8,9 .…”