-
Archives of Disease in Childhood Jun 1978A boy with fatal I-cell disease is reported. Defective ganglioside and glycoprotein metabolism is due to deficient neuraminidase activity.
A boy with fatal I-cell disease is reported. Defective ganglioside and glycoprotein metabolism is due to deficient neuraminidase activity.
Topics: Diagnosis, Differential; Humans; Infant; Male; Mucolipidoses; Mucopolysaccharidosis I
PubMed: 99090
DOI: 10.1136/adc.53.6.513 -
American Journal of Medical Genetics 1977Mucolipidosis I is characterized by Hurler-like features and skeletal dysplasia with a cherry-red macular spot and signs of neurodegeneration involving neuronal cells...
Mucolipidosis I is characterized by Hurler-like features and skeletal dysplasia with a cherry-red macular spot and signs of neurodegeneration involving neuronal cells and myelin. Excessive amounts of sialic acid-containing compounds were found in cultured fibroblasts, leukocytes, and urine of a patient with a clinical phenotype of mucolipidosis I. In cultured fibroblasts, profoundly diminished activity of an alpha-N-acetylneuraminidase (sialidase) was found. Mucolipidosis I thus appears to be a distinct disorder of complex carbohydrate catabolism caused by the genetic deficiency of a neuraminidase.
Topics: Cells, Cultured; Child; Child, Preschool; Follow-Up Studies; Humans; Hydrolases; Lysosomes; Male; Mucolipidoses; Neuraminidase; Phenotype; Sialic Acids; Skin
PubMed: 610423
DOI: 10.1002/ajmg.1320010104 -
Neuroscience Letters Jun 2021Mucolipidosis IV (MLIV) is an autosomal-recessive disease caused by loss-of-function mutations in the MCOLN1 gene encoding the non-selective cationic lysosomal channel...
Mucolipidosis IV (MLIV) is an autosomal-recessive disease caused by loss-of-function mutations in the MCOLN1 gene encoding the non-selective cationic lysosomal channel transient receptor potential mucolipin-1 (TRPML1). Patients with MLIV suffer from severe motor and cognitive deficits that manifest in early infancy and progressive loss of vision leading to blindness in the second decade of life. There are no therapies available for MLIV and the unmet medical need is extremely high. Here we review the spectrum of clinical presentations and the latest research in the MLIV pre-clinical model, with the aim of highlighting the progress in understanding the pathophysiology of the disease. These highlights include elucidation of the neurodevelopmental versus neurodegenerative features over the course of disease, hypomyelination as one of the major brain pathological disease hallmarks, and dysregulation of cytokines, with emerging evidence of IFN-gamma pathway upregulation in response to TRPML1 loss and pro-inflammatory activation of astrocytes and microglia. These scientific advances in the MLIV field provide a basis for future translational research, including biomarker and therapy development, that are desperately needed for this patient population.
Topics: Brain; Humans; Lysosomes; Mucolipidoses; Myelin Sheath; Transient Receptor Potential Channels
PubMed: 33965501
DOI: 10.1016/j.neulet.2021.135944 -
Molecular Genetics and Metabolism Jul 2001Mucolipidosis type IV (MLIV) is a neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmological abnormalities, including... (Review)
Review
Mucolipidosis type IV (MLIV) is a neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmological abnormalities, including corneal opacities, retinal degeneration, and strabismus. Severely affected as well as milder patients have been described. Over 80% of the MLIV patients are Ashkenazi Jews; the estimated heterozygote frequency in this population is 1/100. The disease is classified as a mucolipidosis due to the simultaneous lysosomal storage of lipids together with water-soluble substances. A broad spectrum of lipids and acid mucopolysaccharides were identified as the storage substances. Kinetic studies demonstrated that this heterogeneous storage stems from an abnormal endocytosis process in cells from MLIV patients of membrane components from late endosomes to the lysosomes and/or delayed efflux to the Golgi apparatus. The MLIV gene was mapped to chromosome 19p13.2--13.3 where a novel gene, MCOLN1, with MLIV-causing mutations, was identified. Two mutations were found among 95% of the Ashkenazi MLIV alleles, including an intronic acceptor splice-site mutation in 72% of the alleles and a partial gene deletion in 23%. Each of these mutations was associated with a defined haplotype in this chromosomal region. Other mutations were mostly identified in single, Ashkenazi and non-Ashkanazi patients, including missense, nonsense nucleotide deletions, and insertions. All mutations but one were identified in patients exhibiting the severe phenotype, an in-frame amino acid deletion was identified in a mild patient. MCOLN1 encodes a 580 aa protein, mucolipin 1, which is a member of a new protein family of unknown function at present, the mucolipins. Mucolipin 1 is a membrane protein with 6 transmembrane domains, a serine lipase, and nuclear localization signal motives. The protein shows homology to a group of calcium channels of the TRP/TRPL family. The involvement of this protein in the endocytosis process of membrane components is currently studied. A population screening operation among the Ashkenazi population for the detection of heterozygotes has been started in Israel as a prevention program.
Topics: Chromosomes, Human, Pair 19; Endocytosis; Golgi Apparatus; Heterozygote; Humans; Jews; Lipid Metabolism; Lysosomal Storage Diseases; Models, Genetic; Mucolipidoses; Mutation
PubMed: 11461186
DOI: 10.1006/mgme.2001.3195 -
Autophagy Jul 2023Degradation of macromolecules delivered to lysosomes by processes such as autophagy or endocytosis is crucial for cellular function. Lysosomes require more than 60...
Degradation of macromolecules delivered to lysosomes by processes such as autophagy or endocytosis is crucial for cellular function. Lysosomes require more than 60 soluble hydrolases in order to catabolize such macromolecules. These soluble hydrolases are tagged with mannose6-phosphate (M6P) moieties in sequential reactions by the Golgi-resident GlcNAc-1-phosphotransferase complex and NAGPA/UCE/uncovering enzyme (N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase), which allows their delivery to endosomal/lysosomal compartments through trafficking mediated by cation-dependent and -independent mannose 6-phosphate receptors (MPRs). We and others recently identified TMEM251 as a novel regulator of the M6P pathway via independent genome-wide genetic screening strategies. We renamed TMEM251 to LYSET (lysosomal enzyme trafficking factor) to establish nomenclature reflective to this gene's function. LYSET is a Golgi-localized transmembrane protein important for the retention of the GlcNAc-1-phosphotransferase complex in the Golgi-apparatus. The current understanding of LYSET's importance regarding human biology is 3-fold: 1) highly pathogenic viruses that depend on lysosomal hydrolase activity require LYSET for infection. 2) The presence of LYSET is critical for cancer cell proliferation in nutrient-deprived environments in which extracellular proteins must be catabolized. 3) Inherited pathogenic alleles of LYSET can cause a severe inherited disease which resembles GlcNAc-1-phosphotransferase deficiency (i.e., mucolipidosis type II). GlcNAc-1-PT: GlcNAc-1-phosphotransferase; KO: knockout; LSD: lysosomal storage disorder; LYSET: lysosomal enzyme trafficking factor; M6P: mannose 6-phosphate; MPRs: mannose-6-phosphate receptors, cation-dependent or -independent; MBTPS1/site-1 protease: membrane bound transcription factor peptidase, site 1; MLII: mucolipidosis type II; WT: wild-type.
Topics: Humans; Mucolipidoses; Mannose; Autophagy; Lysosomes; Hydrolases; Receptor, IGF Type 2; Cations; Phosphotransferases
PubMed: 36633450
DOI: 10.1080/15548627.2023.2167376 -
Birth Defects Original Article Series 1982
Topics: Alleles; Humans; Mucolipidoses; Terminology as Topic
PubMed: 7139113
DOI: No ID Found -
Journal of AAPOS : the Official... Dec 2018Mucolipidosis type IV is a rare autosomal recessive lysosomal storage disorder with psychomotor developmental delay, visual impairment, and achlorhydria. A mutation in...
Mucolipidosis type IV is a rare autosomal recessive lysosomal storage disorder with psychomotor developmental delay, visual impairment, and achlorhydria. A mutation in the MCOLN1 gene causes an alteration of the protein mucolipin-1 that results in the accumulation of lipids and proteins in cytoplasmic vacuoles derived from lysosomes. Visual impairment results mainly from corneal clouding and retinal degeneration. The involvement of the corneal epithelium has been proposed following clinical observation and confirmed by ultrastructural studies of the cornea. We present the case of a child of French Canadian origin affected by mucolipidosis type IV who showed abnormal optical coherence tomography imaging of the cornea, typical skin cell inclusions on electronic microscopy, and a novel pathogenic mutation.
Topics: Biopsy; Corneal Diseases; DNA; DNA Mutational Analysis; Diagnosis, Differential; Epithelium, Corneal; Humans; Infant; Liposomes; Male; Microscopy, Electron; Mucolipidoses; Mutation; Retinal Degeneration; Skin; Tomography, Optical Coherence; Transient Receptor Potential Channels
PubMed: 30120981
DOI: 10.1016/j.jaapos.2018.04.011 -
Journal of Inherited Metabolic Disease 2005The mucopolysaccharidoses (MPS) is characterized by accumulation of glycosaminoglycans (GAGs), and mucolipidosis (ML) by accumulation of GAGs and sphingolipids. Each...
The mucopolysaccharidoses (MPS) is characterized by accumulation of glycosaminoglycans (GAGs), and mucolipidosis (ML) by accumulation of GAGs and sphingolipids. Each type of MPS accumulates specific GAGs. The lysosomal enzymes N-acetylgalactosamine-6-sulphate sulphatase and beta-galactosidase involve the stepwise degradation of keratan sulphate (KS). Deficiency of these enzymes results in elevation of KS levels in the body fluids and in tissues, leading to MPS IV disease. In this study, we evaluated blood and urine KS levels in types of MPS and ML other than MPS IV. Eighty-five plasma samples came from MPS I (n = 18), MPS II (n = 28), MPS III (n = 20), MPS VI (n = 3), MPS VII (n = 5) and ML (n = 11) patients while 127 urine samples came from MPS I (n = 34), MPS II (n = 34), MPS III (n = 32), MPS VI (n = 7), MPS VII (n = 9) and ML (n = 11) patients. KS levels were determined using the ELISA method. Plasma KS levels varied with age in both control and patient populations. In all age groups, the mean values of plasma KS in MPS and ML patients were significantly higher than those in the age-matched controls. Plasma KS values in four newborn patients were above the mean + 2SD of the age-matched controls (mean, 41 ng/ml). Overall, 85.9% of individual values in non-type IV MPS and ML patients were above the mean + 2SD of the age-matched controls. For urine KS levels, 24.4% of individual values in patients were above the mean + 2SD of the age-matched controls. In conclusion, KS in blood is elevated in each type of non-type IV MPS examined, in contrast to the conventional understanding. This finding suggests that measurement of KS level provides a new diagnostic biomarker in a wide variety of mucopolysaccharidoses and mucolipidoses in addition to MPS IV.
Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antibody Specificity; Biomarkers; Child; Child, Preschool; Cross Reactions; Enzyme-Linked Immunosorbent Assay; Humans; Infant; Infant, Newborn; Keratan Sulfate; Middle Aged; Mucolipidoses; Mucopolysaccharidoses; Sensitivity and Specificity
PubMed: 15877208
DOI: 10.1007/s10545-005-5673-3 -
Current Molecular Medicine Aug 2002Mucolipidosis Type IV (MLIV) is a lysosomal storage disorder that is characterized by severe neurologic and ophthalmologic abnormalities. It is a progressive disease... (Review)
Review
Mucolipidosis Type IV (MLIV) is a lysosomal storage disorder that is characterized by severe neurologic and ophthalmologic abnormalities. It is a progressive disease that usually presents during the first year of life with mental retardation, corneal opacities, and delayed motor milestones. First described in 1974, MLIV is a rare autosomal recessive disease and the majority of patients diagnosed to date are of Ashkenazi Jewish descent. MLIV was originally classified as a lysosomal storage disorder due to the abnormal accumulation of mucopolysaccharides and lipids. Extensive studies in MLIV cells, however, have shown that the abnormal storage is due to a defect in the late endocytic pathway. Positional cloning led to the recent discovery of a novel gene on human chromosome 19, MCOLN1, that is mutated in MLIV. To date 14 independent mutations have been reported in MCOLN1, with two mutations accounting for 95% of the Ashkenazi Jewish MLIV alleles. The identification of the MLIV gene has led to a simple tool for definitive diagnosis and will permit carrier screening in the Ashkenazi Jewish population. MCOLN1 is a new member of the transient receptor potential (TRP) cation channel gene family. The protein encoded by MCOLN1, mucolipin-1, has six predicted transmembrane domains and a putative channel pore. The identification of mutations in MCOLN1 represents the first example of a neurological disease caused by a TRP-related channel. While the function of mucolipin-1 is currently unknown, homology to the TRP superfamily and the recent description of the C. elegans mucolipin-1 homolog allow us to begin to speculate about the role of mucolipin-1 in diverse cellular processes.
Topics: Chromosomes, Human, Pair 19; Cloning, Molecular; Humans; Membrane Proteins; Models, Genetic; Mucolipidoses; Mutation; RNA, Messenger; TRPM Cation Channels; Transient Receptor Potential Channels
PubMed: 12125810
DOI: 10.2174/1566524023362276 -
The Journal of Bone and Joint Surgery.... Jul 1997Children with a mucopolysaccharidosis or mucolipidosis suffer progressive disability of the hands, particularly in relation to dysfunction of the median nerve. This is...
Children with a mucopolysaccharidosis or mucolipidosis suffer progressive disability of the hands, particularly in relation to dysfunction of the median nerve. This is an increasing problem because bone-marrow transplantation has dramatically improved survival without apparently changing the musculoskeletal manifestations. We have reviewed 48 children with these syndromes who required carpal tunnel decompression, recording symptoms, signs, radiological, electrophysiological and operative findings, histology and upper-limb function. In these children the carpal tunnel syndrome differs from that seen in adults. Symptoms are rare but signs such as decreased sweating, pulp atrophy, thenar wasting and manual clumsiness are much more common. At operation, the flexor retinaculum was thickened and a mass of white tenosynovium engulfed the flexor tendons. Most patients had some definite nerve constriction with a thickened epineurium. Functional improvement was seen after early decompression, with some benefit from simultaneous tendon release. Regular physiotherapy helped to maintain increased hand movement. We describe our assessment protocol, the physiotherapy and operative regime and the standard functional review which helps to maximise function in the hands and upper limbs of these children.
Topics: Adolescent; Carpal Tunnel Syndrome; Child; Child, Preschool; Female; Humans; Infant; Male; Mucolipidoses; Mucopolysaccharidoses; Neural Conduction; Retrospective Studies
PubMed: 9250742
DOI: 10.1302/0301-620x.79b4.7547