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International Journal of Molecular... Sep 2020Mucolipidosis II and III (ML II/III) are caused by a deficiency of uridine-diphosphate -acetylglucosamine: lysosomal-enzyme--acetylglucosamine-1-phosphotransferase... (Review)
Review
Mucolipidosis II and III (ML II/III) are caused by a deficiency of uridine-diphosphate -acetylglucosamine: lysosomal-enzyme--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 -acetylglucosamine-1-phosphodiester α--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.
Topics: Animals; Biological Transport, Active; Disease Models, Animal; Enzyme Replacement Therapy; Genetic Therapy; Glycosaminoglycans; Hematopoietic Stem Cell Transplantation; Humans; Lysosomes; Mannosephosphates; Mucolipidoses
PubMed: 32957425
DOI: 10.3390/ijms21186812 -
Perspectives in Pediatric Pathology 1993
Review
Topics: Histocytochemistry; Humans; Lysosomes; Microscopy, Electron; Mucolipidoses; Prenatal Diagnosis
PubMed: 8316526
DOI: No ID Found -
Handbook of Clinical Neurology 2013The mucopolysaccharidoses (MPS) and mucolipidoses (ML) are progressive storage disorders that share many clinical features varying from facial dysmorphism, bone... (Review)
Review
The mucopolysaccharidoses (MPS) and mucolipidoses (ML) are progressive storage disorders that share many clinical features varying from facial dysmorphism, bone dysplasia, hepatosplenomegaly, neurological abnormalities, developmental regression, and a reduced life expectancy at the severe end of the clinical spectrum to an almost normal clinical phenotype and life span in patients with more attenuated disease. MPS and ML are transmitted in an autosomal recessive manner, except for the X-linked MPS II (Hunter syndrome). Diagnosis is initially by detecting partially degraded GAG or oligosaccharide in urine and confirmed by specific enzyme assays in serum, leukocytes, or skin fibroblasts. For the majority of disorders treatment is palliative, but there have been important advances in the use of specific enzyme replacement therapy strategies for some MPS disorders and this is an area of very rapid development. In addition, hematopoietic stem cell transplantation (HSCT) can improve outcome in carefully selected patients with MPS (especially MPS IH, Hurler syndrome), but this procedure is associated with significant risk. Gene augmentation/transfer using a variety of vectors has been successful in animal models but has not yet been successfully performed in a human patient with one of these disorders. It is important to remember that prenatal diagnosis is possible for all of these disorders.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Mucolipidoses; Mucopolysaccharidoses
PubMed: 23622395
DOI: 10.1016/B978-0-444-59565-2.00042-3 -
Bone Feb 2021The hips are frequently involved in inheritable diseases which affect the bones. The clinical and radiological presentation of these diseases may be very similar to... (Review)
Review
The hips are frequently involved in inheritable diseases which affect the bones. The clinical and radiological presentation of these diseases may be very similar to common hip disorders as developmental dysplasia of the hip, osteoarthritis and avascular necrosis, so the diagnosis may be easily overlooked and treatment may be suboptimal. Mucopolysaccharidosis (MPS) and Mucolipidosis (ML II and III) are lysosomal storage disorders with multisystemic involvement. Characteristic skeletal abnormalities, known as dysostosis multiplex, are common in MPS and ML and originate from intra-lysosomal storage of glycosaminoglycans in cells of the cartilage, bones and ligaments. The hip joint is severely affected in MPS and ML. Hip pathology results in limitations in mobility and pain from young age, and negatively affects quality of life. In order to better understand the underlying process that causes hip disease in MPS and ML, this review first describes the normal physiological (embryonic) hip joint development, including the interplay between the acetabulum and the femoral head. In the second part the factors contributing to altered hip morphology and function in MPS and ML are discussed, such as abnormal development of the pelvic- and femoral bones (which results in altered biomechanical forces) and inflammation. In the last part of this review therapeutic options and future perspectives are addressed.
Topics: Acetabulum; Hip Joint; Humans; Mucolipidoses; Mucopolysaccharidoses; Quality of Life
PubMed: 33130340
DOI: 10.1016/j.bone.2020.115729 -
Epileptic Disorders : International... Sep 2016Sialidoses are autosomal recessive disorders caused by NEU1 gene mutations and are classified on the basis of their phenotype and onset age. Sialidosis type II, with... (Review)
Review
Sialidoses are autosomal recessive disorders caused by NEU1 gene mutations and are classified on the basis of their phenotype and onset age. Sialidosis type II, with infantile onset, has a more severe phenotype characterized by coarse facial features, hepatomegaly, dysostosis multiplex, and developmental delay while patients with the late and milder type, known as "cherry red spot-myoclonus syndrome" develop myoclonic epilepsy, visual impairment and ataxia in the second or third decade of life. The diagnosis is usually suggested by increased urinary bound sialic acid excretion. We recently described genetically diagnosed patients with a specially mild phenotype, no retinal abnormalities and normal urinary sialic acid. This observation suggests that genetic analysis or the demonstration of the neuraminidase enzyme deficiency in cultured fibroblasts are needed to detect and diagnose mildest phenotypes.
Topics: Humans; Mucolipidoses
PubMed: 27621198
DOI: 10.1684/epd.2016.0845 -
The Journal of Pediatrics Feb 2021
Topics: Humans; Infant, Newborn; Male; Mucolipidoses; Radiography
PubMed: 33038345
DOI: 10.1016/j.jpeds.2020.09.070 -
The Pan African Medical Journal 2018
Topics: Dehydration; Diarrhea; Humans; Hypernatremia; Infant, Newborn; Infant, Premature; Malabsorption Syndromes; Male; Microvilli; Mucolipidoses
PubMed: 30364420
DOI: 10.11604/pamj.2018.30.109.12330 -
Cell Calcium Jan 2018Efficient functioning of lysosome is necessary to ensure the correct performance of a variety of intracellular processes such as degradation of cargoes coming from the... (Review)
Review
Efficient functioning of lysosome is necessary to ensure the correct performance of a variety of intracellular processes such as degradation of cargoes coming from the endocytic and autophagic pathways, recycling of organelles, and signaling mechanisms involved in cellular adaptation to nutrient availability. Mutations in lysosomal genes lead to more than 50 lysosomal storage disorders (LSDs). Among them, mutations in the gene encoding TRPML1 (MCOLN1) cause Mucolipidosis type IV (MLIV), a recessive LSD characterized by neurodegeneration, psychomotor retardation, ophthalmologic defects and achlorhydria. At the cellular level, MLIV patient fibroblasts show enlargement and engulfment of the late endo-lysosomal compartment, autophagy impairment, and accumulation of lipids and glycosaminoglycans. TRPML1 is the most extensively studied member of a small family of genes that also includes TRPML2 and TRPML3, and it has been found to participate in vesicular trafficking, lipid and ion homeostasis, and autophagy. In this review we will provide an update on the latest and more novel findings related to the functions of TRPMLs, with particular focus on the emerging role of TRPML1 and lysosomal calcium signaling in autophagy. Moreover, we will also discuss new potential therapeutic approaches for MLIV and LSDs based on the modulation of TRPML1-mediated signaling.
Topics: Animals; Autophagy; Calcium; Humans; Lysosomes; Molecular Targeted Therapy; Mucolipidoses; TRPM Cation Channels
PubMed: 28689729
DOI: 10.1016/j.ceca.2017.06.006 -
Biochemical Society Transactions Jun 2015TRPML1 is a ubiquitously expressed cation channel found on lysosomes and late endosomes. Mutations in TRPML1 cause mucolipidosis type IV and it has been implicated in... (Review)
Review
TRPML1 is a ubiquitously expressed cation channel found on lysosomes and late endosomes. Mutations in TRPML1 cause mucolipidosis type IV and it has been implicated in Alzheimer's disease and HIV. However, the mechanisms by which TRPML1 activity is regulated are not well understood. This review summarizes the current understanding of TRPML1 activation and regulation.
Topics: Alzheimer Disease; Endosomes; Gene Expression Regulation; HIV Infections; Humans; Lysosomes; Mucolipidoses; Mutation; Transient Receptor Potential Channels
PubMed: 26009188
DOI: 10.1042/BST20140311 -
Sub-cellular Biochemistry 2018Transient Receptor Potential (TRP) channels are evolutionarily conserved integral membrane proteins. The mammalian TRP superfamily of ion channels consists of 28 cation... (Review)
Review
Transient Receptor Potential (TRP) channels are evolutionarily conserved integral membrane proteins. The mammalian TRP superfamily of ion channels consists of 28 cation permeable channels that are grouped into six subfamilies based on sequence homology (Fig. 6.1). The canonical TRP (TRPC) subfamily is known for containing the founding member of mammalian TRP channels. The vanilloid TRP (TRPV) subfamily has been extensively studied due to the heat sensitivity of its founding member. The melastatin-related TRP (TRPM) subfamily includes some of the few known bi-functional ion channels, which contain functional enzymatic domains. The ankyrin TRP (TRPA) subfamily consists of a single chemo-nociceptor that has been proposed to be a target for analgesics. The mucolipin TRP (TRPML) subfamily channels are found primarily in intracellular compartments and were discovered based on their critical role in type IV mucolipidosis (ML-IV). The polycystic TRP (TRPP) subfamily is a diverse group of proteins implicated in autosomal dominant polycystic kidney disease (ADPKD). Overall, this superfamily of channels is involved in a vast array of physiological and pathophysiological processes making the study of these channels imperative to our understanding of subcellular biochemistry.
Topics: Animals; Humans; Mucolipidoses; Multigene Family; Polycystic Kidney, Autosomal Dominant; Protein Domains; Sequence Homology, Amino Acid; Transient Receptor Potential Channels
PubMed: 29464560
DOI: 10.1007/978-981-10-7757-9_6