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Human Mutation Nov 2003Lysosomal sialidase (EC 3.2.1.18) has a dual physiological function; it participates in intralysosomal catabolism of sialylated glycoconjugates and is involved in... (Review)
Review
Lysosomal sialidase (EC 3.2.1.18) has a dual physiological function; it participates in intralysosomal catabolism of sialylated glycoconjugates and is involved in cellular immune response. Mutations in the sialidase gene NEU1, located on chromosome 6p21.3, result in autosomal recessive disorder, sialidosis, which is characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. Sialidosis type I is a milder, late-onset, normosomatic form of the disorder. Type I patients develop visual defects, myoclonus syndrome, cherry-red macular spots, ataxia, hyperreflexia, and seizures. The severe early-onset form, sialidosis type II, is also associated with dysostosis multiplex, Hurler-like phenotype, mental retardation, and hepatosplenomegaly. We summarize information on the 34 unique mutations determined so far in the sialidase gene, including four novel missense and one novel nonsense mutations found in two Czech and two French sialidosis patients. The analysis of sialidase mutations in sialidosis revealed considerable molecular heterogeneity, reflecting the diversity of clinical phenotypes that make molecular diagnosis difficult. The majority of sialidosis patients have had missense mutations, many of which have been expressed; their effects on activity, stability, intracellular localization, and supramolecular organization of sialidase were studied. A structural model of sialidase allowed us to localize mutations in the sialidase molecule and to predict their impact on the tertiary structure and biochemical properties of the enzyme.
Topics: Amino Acid Sequence; Humans; Molecular Sequence Data; Mucolipidoses; Mutation; Neuraminidase; Sequence Alignment
PubMed: 14517945
DOI: 10.1002/humu.10268 -
Nihon Rinsho. Japanese Journal of... 1977
Topics: Child; Child, Preschool; Humans; Infant; Mucolipidoses
PubMed: 612748
DOI: No ID Found -
Molecular Genetics and Metabolism Nov 2012Stuttering is a common but poorly understood speech disorder. Consistent evidence for the involvement of genetic factors in stuttering has motivated studies aimed at... (Review)
Review
Stuttering is a common but poorly understood speech disorder. Consistent evidence for the involvement of genetic factors in stuttering has motivated studies aimed at identifying causative genetic variants that could shed light on the underlying molecular and cellular deficits in this disorder. Such studies have begun to identify causative genes. The purpose of this review is to summarize the gene discoveries to date, and to cover the subsequent functional studies that are beginning to provide insights into how these gene mutations might cause stuttering. Surprisingly, the first variant genes to be associated with stuttering are those encoding the lysosomal targeting system, GNPTAB, GNPTG, and NAGPA. Although mutations in NAGPA have not been associated with a disorder in humans, mutations in GNPTAB and GNPTG cause mucolipidosis types II and III, which are rare autosomal recessive lysosomal storage disorders, associated with pathology of bone, connective tissue, liver, spleen, and brain. Analysis of mutations in these genes has so far identified predominantly missense mutations in stuttering, in contrast to the truncating and other mutations that result in very low GNPTAB/G enzyme activity and are historically associated with mucolipidosis. Genetic evidence for the role of lysosomal targeting mutations in stuttering has now been buttressed by biochemical studies of the mutant enzymes found in this disorder. While data on the GlcNAc-phosphotransferase encoded by GNPTAB/G remains limited and only suggestive, a study of the enzyme encoded by NAGPA has shown that the mutations found in stuttering reduce the overall cellular activity of this enzyme by about half, and that they result in deficits in intracellular processing and trafficking that lead to a reduced cellular half life. How these deficits result in the presumed speech-specific neuropathology associated with stuttering is not yet known. However these findings have opened several new lines of inquiry, including studies in mice carrying human stuttering mutations, that represent promising approaches to this disorder.
Topics: Animals; Biological Transport; Disease Models, Animal; Humans; Lysosomes; Mice; Mucolipidoses; Mutation; Phosphoric Diester Hydrolases; Stuttering; Transferases (Other Substituted Phosphate Groups); Vocalization, Animal
PubMed: 22884963
DOI: 10.1016/j.ymgme.2012.07.020 -
Gene Therapy May 2024Patients with sialidosis (mucolipidosis type I) type I typically present with myoclonus, seizures, ataxia, cherry-red spots, and blindness because of mutations in the...
Patients with sialidosis (mucolipidosis type I) type I typically present with myoclonus, seizures, ataxia, cherry-red spots, and blindness because of mutations in the neuraminidase 1 (NEU1) gene. Currently, there is no treatment for sialidosis. In this study, we developed an adeno-associated virus (AAV)-mediated gene therapy for a Neu1 knockout (Neu1) mouse model of sialidosis. The vector, AAV9-P3-NP, included the human NEU1 promoter, NEU1 cDNA, IRES, and CTSA cDNA. Untreated Neu1 mice showed astrogliosis and microglial LAMP1 accumulation in the nervous system, including brain, spinal cord, and dorsal root ganglion, together with impaired motor function. Coexpression of NEU1 and protective protein/cathepsin A (PPCA) in neonatal Neu1 mice by intracerebroventricular injection, and less effective by facial vein injection, decreased astrogliosis and LAMP1 accumulation in the nervous system and improved rotarod performance of the treated mice. Facial vein injection also improved the grip strength and survival of Neu1 mice. Therefore, cerebrospinal fluid delivery of AAV9-P3-NP, which corrects the neurological deficits of mice with sialidosis, could be a suitable treatment for patients with sialidosis type I. After intracerebroventricular or facial vein injection of AAV vectors, NEU1 and PPCA are expressed together. PPCA-protected NEU1 is then sent to lysosomes, where β-Gal binds to this complex to form a multienzyme complex in order to execute its function.
Topics: Animals; Genetic Therapy; Neuraminidase; Mice; Dependovirus; Mucolipidoses; Mice, Knockout; Genetic Vectors; Disease Models, Animal; Cathepsin A; Humans; Brain
PubMed: 38321198
DOI: 10.1038/s41434-024-00443-3 -
Journal of Pediatric Ophthalmology and... 2022To present a case report of mucolipidosis type IV (ML4) and review the literature for all of the ophthalmic abnormalities associated with this disease. (Review)
Review
PURPOSE
To present a case report of mucolipidosis type IV (ML4) and review the literature for all of the ophthalmic abnormalities associated with this disease.
METHODS
A systematic review of the literature using PubMed/Medline was conducted, and with the addition of the current case report, the eye and ocular adnexa findings of 93 patients with ML4 are summarized.
RESULTS
The most common ophthalmic findings reported among the 93 patients included corneal clouding (90.3%), strabismus (58.1%), optic nerve pallor (52.2%), retinal dystrophy/pigmentary changes (50.5%), and retinal vascular attenuation (38.9%). Other less commonly reported findings included nystagmus, photophobia, ocular pain, excessive lacrimation, ptosis, and cataracts.
CONCLUSIONS
The ophthalmic findings discussed in the current case report and literature review serve as indicators for ML4. Early diagnosis of ML4 is important in forming a multidisciplinary management plan, genetic counseling strategy, and maximizing the visual development of affected individuals. .
Topics: Blepharoptosis; Corneal Diseases; Humans; Mucolipidoses; Nystagmus, Pathologic; Strabismus
PubMed: 35192386
DOI: 10.3928/01913913-20211206-03 -
Pediatrics and Neonatology Mar 2024
Topics: Female; Humans; Hydrops Fetalis; Mucolipidoses
PubMed: 38296756
DOI: 10.1016/j.pedneo.2022.05.023 -
International Journal of Rheumatic... Jul 2023Juvenile idiopathic arthritis is the most common form of chronic arthritis in children and at times misdiagnosed in those presenting with arthropathy secondary to...
Juvenile idiopathic arthritis is the most common form of chronic arthritis in children and at times misdiagnosed in those presenting with arthropathy secondary to non-inflammatory causes. The overlap of symptoms often pose a diagnostic challenge for clinicians. This mostly results in a delayed diagnosis subjecting children to unnecessary use of long-term immunosuppressants and disease-modifying drugs. We present the case of a 9-year-old boy who was previously misdiagnosed as a case of juvenile idiopathic arthritis. Detailed evaluation later led to the diagnosis of mucolipidosis (type III) which was confirmed on genetic testing. Emphasis on detailed history and clinical examination including the subtle hints like lack of signs of inflammation, family history, no morning stiffness and normal inflammatory markers should be picked up to make a timely diagnosis. In today's era of genetic testing and diagnosis, it is prudent to offer these tests for such patients to make an accurate diagnosis and prognosticate them for the long-term outcome.
Topics: Child; Male; Humans; Arthritis, Juvenile; Mucolipidoses; Joint Diseases; Inflammation; Immunosuppressive Agents
PubMed: 36869440
DOI: 10.1111/1756-185X.14620 -
Cell Calcium Nov 2017What do lysosomal storage disorders such as mucolipidosis type IV have in common with Ebola, cancer cell migration, or LDL-cholesterol trafficking? LDL-cholesterol,... (Review)
Review
What do lysosomal storage disorders such as mucolipidosis type IV have in common with Ebola, cancer cell migration, or LDL-cholesterol trafficking? LDL-cholesterol, certain bacterial toxins and viruses, growth factors, receptors, integrins, macromolecules destined for degradation or secretion are all sorted and transported via the endolysosomal system (ES). There are several pathways known in the ES, e.g. the degradation, the recycling, or the retrograde trafficking pathway. The ES comprises early and late endosomes, lysosomes and recycling endosomes as well as autophagosomes and lysosome related organelles. Contact sites between the ES and the endoplasmic reticulum or the Golgi apparatus may also be considered part of it. Dysfunction of this complex intracellular machinery can cause or contribute to the development of a number of diseases ranging from neurodegenerative, infectious, or metabolic diseases to retinal and pigmentation disorders as well as cancer and autophagy-related diseases. Endolysosomal ion channels such as mucolipins (TRPMLs) and two-pore channels (TPCs) play an important role in intracellular cation/calcium signaling and homeostasis and appear to critically contribute to the proper function of the endolysosomal trafficking network.
Topics: Animals; Autophagosomes; Biological Transport; Calcium; Calcium Channels; Calcium Signaling; Endoplasmic Reticulum; Endosomes; Gene Expression Regulation; Golgi Apparatus; Hemorrhagic Fever, Ebola; Homeostasis; Humans; Lysosomes; Mucolipidoses; Transient Receptor Potential Channels
PubMed: 28457591
DOI: 10.1016/j.ceca.2017.04.003 -
Birth Defects Original Article Series 1982
Topics: Cataract; Child; Child, Preschool; Cornea; Corneal Opacity; Female; Humans; Microscopy, Electron; Mucolipidoses; Retinal Diseases; Retinal Vessels
PubMed: 7171765
DOI: No ID Found -
Journal of Neuro-ophthalmology : the... Sep 2019
Topics: Adult; Diagnostic Techniques, Ophthalmological; Eye Movement Measurements; Humans; Male; Mucolipidoses; Tomography, Optical Coherence
PubMed: 31107347
DOI: 10.1097/WNO.0000000000000773