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The Journal of Biological Chemistry Jan 2005Salla disease and infantile sialic acid storage disorder are autosomal recessive neurodegenerative diseases characterized by loss of a lysosomal sialic acid transport...
Salla disease and infantile sialic acid storage disorder are autosomal recessive neurodegenerative diseases characterized by loss of a lysosomal sialic acid transport activity and the resultant accumulation of free sialic acid in lysosomes. Genetic analysis of these diseases has identified several unique mutations in a single gene encoding a protein designated sialin (Verheijen, F. W., Verbeek, E., Aula, N., Beerens, C. E., Havelaar, A. C., Joosse, M., Peltonen, L., Aula, P., Galjaard, H., van der Spek, P. J., and Mancini, G. M. (1999) Nat. Genet. 23, 462-465; Aula, N., Salomaki, P., Timonen, R., Verheijen, F., Mancini, G., Mansson, J. E., Aula, P., and Peltonen, L. (2000) Am. J. Hum. Genet. 67, 832-840). From the biochemical phenotype of the diseases and the predicted polytopic structure of the protein, it has been suggested that sialin functions as a lysosomal sialic acid transporter. Here we directly demonstrate that this activity is mediated by sialin and that the recombinant protein has functional characteristics similar to the native lysosomal sialic acid transport system. Furthermore, we describe the effect of disease-causing mutations on the protein. We find that the majority of the mutations are associated with a complete loss of activity, while the mutations associated with the milder forms of the disease lead to reduced, but residual, function. Thus, there is a direct correlation between sialin function and the disease state. In addition, we find with one mutation that the protein is retained in the endoplasmic reticulum, indicating that altered trafficking of sialin is also associated with disease. This analysis of the molecular mechanism of sialic acid storage disorders is a further step in identifying therapeutic approaches to these diseases.
Topics: Amino Acid Sequence; Biological Transport; Cell Membrane; Conserved Sequence; Endoplasmic Reticulum; HeLa Cells; Humans; Hydrogen-Ion Concentration; Molecular Sequence Data; Mutation; N-Acetylneuraminic Acid; Organic Anion Transporters; Protein Structure, Tertiary; Protein Transport; Sialic Acid Storage Disease; Symporters
PubMed: 15516337
DOI: 10.1074/jbc.M411295200 -
Genetics in Medicine : Official Journal... Feb 2019Quantitative definition of the natural history of free sialic acid storage disease (SASD, OMIM 604369), an orphan disorder due to the deficiency of the proton-driven...
PURPOSE
Quantitative definition of the natural history of free sialic acid storage disease (SASD, OMIM 604369), an orphan disorder due to the deficiency of the proton-driven carrier SLC17A5.
METHODS
Analysis of published cases with SASD (N = 116) respecting STROBE criteria.
MAIN OUTCOME PARAMETERS
survival and diagnostic delay. Phenotype, phenotype-biomarker associations, and geographical patient distribution were explored.
RESULTS
Median age at disease onset was 0.17 years. Median age at diagnosis was 3 years with a median diagnostic delay of 2.5 years. Median survival was 11 years. The biochemical phenotype clearly predicted the disease course: patients with a urinary free sialic acid excretion below 6.37-fold or an intracellular free sialic acid storage in fibroblasts below 7.37-fold of the mean of normal survived longer than patients with biochemical values above these thresholds. Cluster analysis of disease features suggested a continuous phenotypic spectrum. Patient distribution was panethnic.
CONCLUSION
Combination of neurologic symptoms, visceromegaly, and dysmorphic features and/or nonimmune hydrops fetalis should prompt specific tests for SASD, reducing diagnostic delay. The present quantitative data inform clinical studies and may stimulate and accelerate development of specific therapies. Biomarker-phenotype association is particularly important for both counseling parents and study design.
Topics: Age of Onset; Biomarkers; Child; Child, Preschool; Cohort Studies; Cross-Sectional Studies; Delayed Diagnosis; Female; Humans; Infant; Male; N-Acetylneuraminic Acid; Phenotype; Pregnancy; Prenatal Diagnosis; Sialic Acid Storage Disease; Survival Analysis
PubMed: 29875421
DOI: 10.1038/s41436-018-0051-3 -
Indian Pediatrics Dec 2015To study the etiology of neuroregression in children having deficiency of the lysosomal enzymes.
OBJECTIVE
To study the etiology of neuroregression in children having deficiency of the lysosomal enzymes.
DESIGN
Review of medical records.
SETTING
Specialized Genetic Center.
PARTICIPANTS
432 children aged 3 mo-18 y having regression in a learned skill, selected from 1453 patients referred for diagnostic workup of various Lysosomal storage disorders (LSDs).
METHODS
Plasma chitotriosidase, quantitative and qualitative glycosaminoglycans, and mucolipidosis-II/II screening followed by confirmatory enzyme study using specific substrate was carried out; Niemann-Pick disease Type-C was studied by fillipin stain method on skin fibroblasts.
RESULTS
Total 309 children (71.5%) were diagnosed with different lysosomal storage disorders as the underlying cause of neuroregression. Plasma chitotriosidase was raised in 82 of 135; 64 (78%) of these had various LSDs. 69 out of 90 cases showed high excretion of glycoaminoglycans, and 67 (97.1%) of these were confirmed to have enzyme deficiency for various mucoplysaccharide disorders. While 3 of 90 children with positive Icell screening had confirmed mucolipidosis II/III disease. Among all, glycolipid storage disorders were the most common (50.2%) followed by mucopolysaccharidosis (MPS) (21.7%) and sulphatide degradation defect (17.5%). Neuronal ceroid lipofucinosis1 and 2 (7.4%), mucolipidosis-II/III (1%), Sialic acid storage disorder (1%), Niemann-Pick disease type-C (1%) and Fucosidosis (0.3%) were observed with less frequency. Most common phenotypes in all subjects were cherry red spot (18.5%), hepatosplenomegaly (17.9%), coarse facies (15%), seizures (13.1%) and skeletal abnormalities (12.14%).
CONCLUSIONS
Lysosomal storage disorders are considered to be one of the common causes in children with regression in learned skill, dysmorphic features and cherry red spot. Among these, glycolipid storage disorders are the most common, followed by mucopolysaccharidosis.
Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Developmental Disabilities; Genetic Counseling; Humans; India; Infant; Lysosomal Storage Diseases
PubMed: 26713986
DOI: 10.1007/s13312-015-0768-x -
The Journal of Neuroscience : the... Dec 2009Salla disease and infantile sialic acid storage disease are autosomal recessive lysosomal storage disorders caused by mutations in the gene encoding sialin, a membrane...
Salla disease and infantile sialic acid storage disease are autosomal recessive lysosomal storage disorders caused by mutations in the gene encoding sialin, a membrane protein that transports free sialic acid out of the lysosome after it is cleaved from sialoglycoconjugates undergoing degradation. Accumulation of sialic acid in lysosomes defines these disorders, and the clinical phenotype is characterized by neurodevelopmental defects, including severe CNS hypomyelination. In this study, we used a sialin-deficient mouse to address how loss of sialin leads to the defect in myelination. Behavioral analysis of the sialin(-/-) mouse demonstrates poor coordination, seizures, and premature death. Analysis by histology, electron microscopy, and Western blotting reveals a decrease in myelination of the CNS but normal neuronal cytoarchitecture and normal myelination of the PNS. To investigate potential mechanisms underlying CNS hypomyelination, we studied myelination and oligodendrocyte development in optic nerves. We found reduced numbers of myelinated axons in optic nerves from sialin(-/-) mice, but the myelin that was present appeared grossly normal. Migration and density of oligodendrocyte precursor cells were normal; however, a marked decrease in the number of postmitotic oligodendrocytes and an associated increase in the number of apoptotic cells during the later stages of myelinogenesis were observed. These findings suggest that a defect in maturation of cells in the oligodendrocyte lineage leads to increased apoptosis and underlies the myelination defect associated with sialin loss.
Topics: Animals; Apoptosis; Axons; Brain; Cell Count; Cell Movement; Longevity; Mice; Mice, Knockout; Motor Activity; Myelin Basic Protein; Myelin Sheath; Nerve Tissue Proteins; Neurons; Oligodendroglia; Optic Nerve; Organic Anion Transporters; Peripheral Nervous System; Seizures; Spinal Cord; Stem Cells; Symporters; Transcription Factors
PubMed: 20007460
DOI: 10.1523/JNEUROSCI.3005-09.2009 -
Annals of Medicine and Surgery (2012) Apr 2024Sialidosis is a rare variety of lysosomal storage disease that results in intracellular accumulation of sialic acid containing compounds. The authors report the first...
BACKGROUND
Sialidosis is a rare variety of lysosomal storage disease that results in intracellular accumulation of sialic acid containing compounds. The authors report the first case of type II sialidosis, juvenile subtype in a 30-month-old male child from Nepal.
CASE PRESENTATION
Progressive hearing loss with coarse facies, hepatomegaly, kyphoscoliosis, dysostosis multiplex were the major features in a 30-month-old child born to healthy non-consanguineous parents. With the suspicion of lysosomal storage disease, urinary oligosaccharides were tested and were positive. Whole-exome sequencing revealed a mutation in the neuraminidase gene (NEU1) and established the diagnosis of sialidosis.
CLINICAL DISCUSSION
Sialidosis is a rare autosomal recessive type of lysosomal storage disease resulting due to mutation of the neuraminidase gene leading to intracellular accumulation of sialic acid compounds. Based on the presence of visual symptoms, sialidosis is classified into type I and II varieties. Our case is of type II juvenile sialidosis.
CONCLUSION
Despite rare, sialidosis is a life-threatening, and disabling disease. Exploring targeted therapy is the utmost to treat this condition.
PubMed: 38576973
DOI: 10.1097/MS9.0000000000001768 -
The Journal of Biological Chemistry Dec 1998Sialic acid and glucuronic acid are monocarboxylated monosaccharides, which are normally present in sugar side chains of glycoproteins, glycolipids, and...
Sialic acid and glucuronic acid are monocarboxylated monosaccharides, which are normally present in sugar side chains of glycoproteins, glycolipids, and glycosaminoglycans. After degradation of these compounds in lysosomes, the free monosaccharides are released from the lysosome by a specific membrane transport system. This transport system is deficient in the human hereditary lysosomal sialic acid storage diseases (Salla disease and infantile sialic acid storage disease, OMIM 269920). The lysosomal sialic acid transporter from rat liver has now been purified to apparent homogeneity in a reconstitutively active form by a combination of hydroxyapatite, lectin, and ion exchange chromatography. A 57-kDa protein correlated with transport activity. The transporter recognized structurally different types of acidic monosaccharides, like sialic acid, glucuronic acid, and iduronic acid. Transport of glucuronic acid was inhibited by a number of aliphatic monocarboxylates (i.e. lactate, pyruvate, and valproate), substituted monocarboxylates, and several dicarboxylates. cis-Inhibition, trans-stimulation, and competitive inhibition experiments with radiolabeled glucuronic acid as well as radiolabeled L-lactate demonstrated that L-lactate is transported by the lysosomal sialic acid transporter. L-Lactate transport was proton gradient-dependent, saturable with a Km of 0.4 mM, and mediated by a single mechanism. These data show striking biochemical and structural similarities of the lysosomal sialic acid transporter with the known monocarboxylate transporters of the plasma membrane (MCT1, MCT2, MCT3, and Mev).
Topics: Animals; Biological Transport; Carboxylic Acids; Cell Fractionation; Chromatography; Chromatography, Affinity; Chromatography, Ion Exchange; Durapatite; Humans; Intracellular Membranes; Lectins; Liver; Lysosomal Storage Diseases; Lysosomes; Membrane Transport Proteins; Monosaccharides; Organic Anion Transporters; Plant Lectins; Rats; Rats, Wistar; Substrate Specificity; Symporters
PubMed: 9852127
DOI: 10.1074/jbc.273.51.34568 -
Neurology Jan 2010To investigate body fluids of patients with undiagnosed leukodystrophies using in vitro (1)H-NMR spectroscopy (H-NMRS).
OBJECTIVE
To investigate body fluids of patients with undiagnosed leukodystrophies using in vitro (1)H-NMR spectroscopy (H-NMRS).
METHODS
We conducted a cross-sectional study using high-resolution in vitro H-NMRS on CSF and urine samples.
RESULTS
We found a significant increase of free sialic acid in CSF or urine in 6 of 41 patients presenting with hypomyelination of unknown etiology. Molecular genetic testing revealed pathogenic mutations in the SLC17A5 gene in all 6 patients. H-NMRS revealed an increase of N-acetylaspartylglutamate in the CSF of all patients with SLC17A5 mutation (range 13-114 micromol/L, reference <12 micromol/L).
CONCLUSION
In patients with undiagnosed leukodystrophies, increased free sialic acid in CSF or urine is a marker for free sialic acid storage disorder and facilitates the identification of the underlying genetic defect. Because increase of N-acetylaspartylglutamate in CSF has been observed in other hypomyelinating disorders, it can be viewed as a marker of a subgroup of hypomyelinating disorders.
Topics: Child; Child, Preschool; Cross-Sectional Studies; Demyelinating Diseases; Dipeptides; Female; Genetic Testing; Genotype; Humans; Infant; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Mutation; N-Acetylneuraminic Acid; Organic Anion Transporters; Sialic Acid Storage Disease; Symporters; Young Adult
PubMed: 20101035
DOI: 10.1212/WNL.0b013e3181cbcdc4 -
Molecular Genetics and Metabolism... Jun 2018Sialidosis is an autosomal recessive lysosomal storage disease caused by pathogenic variants in which encodes lysosomal sialidase (neuraminidase 1). Lysosomal...
Sialidosis is an autosomal recessive lysosomal storage disease caused by pathogenic variants in which encodes lysosomal sialidase (neuraminidase 1). Lysosomal neuraminidase catalyzes the removal of terminal sialic acid molecules from glycolipids, glycoproteins and oligosaccharides. Sialidosis is classified into two types, based on phenotype and age of onset. Patients with the milder type 1 typically present late, usually in the second or third decade, with myoclonus, ataxia and visual defects. Type 2 is more severe and presents earlier with coarse facial features, developmental delay, hepatosplenomegaly and dysostosis multiplex. Presentation and severity of the disease are related to whether lysosomal sialidase is inactive or there is some residual activity. Diagnosis is suspected based on clinical features and increased urinary bound sialic acid excretion and confirmed by genetic testing showing pathogenic variants in . We report a patient with type 1 sialidosis who presented mainly with ataxia and both generalized and myoclonic seizures but no visual involvement. Whole exome sequencing of the proband detected compound heterozygous likely pathogenic variants (S182G and G227R) in .
PubMed: 30023283
DOI: 10.1016/j.ymgmr.2017.12.005 -
The Biochemical Journal Jul 2002Free oligosaccharides (FOS) are generated both in the endoplasmic reticulum (ER) and in the cytosol during glycoprotein biosynthesis. ER lumenal FOS possessing the...
Free oligosaccharides (FOS) are generated both in the endoplasmic reticulum (ER) and in the cytosol during glycoprotein biosynthesis. ER lumenal FOS possessing the di-N-acetylchitobiose moiety at their reducing termini (FOSGN2) are exported into the cytosol where they, along with their cytosolically generated counterparts possessing a single N-acetylglucosamine residue at their reducing termini (FOSGN1), are trimmed in order to be imported into lysosomes for final degradation. Both the ER and lysosomal FOS transport processes are unable to translocate triglucosylated FOS across membranes. In the present study, we have examined FOS trafficking in HepG2 cells treated with the glucosidase inhibitor castanospermine. We have shown that triglucosylated FOSGN2 generated in the ER are transported to the Golgi apparatus where they are deglucosylated by endomannosidase and acquire complex, sialic acid-containing structures before being secreted into the extracellular space by a Brefeldin A-sensitive pathway. FOSGN2 are also secreted from glucosidase I-deficient Lec23 cells and from the castanospermine-treated parental Chinese-hamster ovary cell line. Despite the secretion of FOSGN2 from Lec23 cells, we noted a transient intracellular accumulation (60 nmol/g cells) of triglucosylated FOSGN1 in these cells. Finally, in glucosidase I-compromised cells, FOS trafficking was severely perturbed leading to both the secretion of FOSGN2 into the extracellular space and a growth-dependent pile up of triglucosylated FOSGN1 in the cytosol. The possibility that these abnormalities contributed to the severe and rapidly progressive pathology in a patient with congenital disorders of glycosylation type IIb (glucosidase I deficiency) is discussed.
Topics: Animals; CHO Cells; Cell Line; Cricetinae; Endoplasmic Reticulum; Enzyme Inhibitors; Glycogen Storage Disease Type II; Glycoside Hydrolase Inhibitors; Humans; Indolizines; Oligosaccharides; alpha-Glucosidases
PubMed: 11942856
DOI: 10.1042/BJ20011786 -
Journal of Medical Genetics Nov 2005Sialic acid storage diseases (SASDs) are caused by the defective transport of free sialic acid outside the lysosome. Apart from the Salla presentation in Finland, SASD...
BACKGROUND
Sialic acid storage diseases (SASDs) are caused by the defective transport of free sialic acid outside the lysosome. Apart from the Salla presentation in Finland, SASD is a very rare form of lysosomal storage disease (LSD) with approximately 35 cases, all diagnosed after birth, having been reported worldwide. We report a series of 12 French patients with very early manifestations, including eight fetuses diagnosed in utero.
RESULTS
Ultrasound examination, fetal autopsy, or clinical examination showed prominent ascites, rarely progressing to complete hydrops, and highlighted the early severity of bone disease. Dramatic increase of free sialic acid in various biological samples confirmed the diagnosis in all cases. Storage staining affinities and storage distribution in placenta and fetal organs allowed differential diagnosis from other LSDs but cannot differentiate between SASD, sialidosis, and galactosialidosis. Fourteen different mutations were identified, showing the molecular heterogeneity of SASD in the French population. We found that the previously described p.Y306X mutation generated two different transcripts, and we identified seven novel mutations: three deletions (del exon 7, del exons10+11 and c.1296delT), one splice site mutation (c.1350+1G-->T) one nonsense mutation (p.W339X), and two missense mutations (p.R57C and p.G127E).
CONCLUSIONS
The severity of our patients' genotypes is in agreement with their phenotypes but not with the importance and early appearance of the very frequent in utero manifestations. Minimal fetal disease in some patients and a reported case of heterogeneity of fetal involvement within a family suggest that factors other than the genotype influence fetal manifestations.
Topics: Female; Gene Deletion; Genotype; Gestational Age; Humans; Infant; Infant, Newborn; Lysosomal Storage Diseases; Male; Mutation; N-Acetylneuraminic Acid; Phenotype; Pregnancy; Prenatal Diagnosis; Sialic Acid Storage Disease
PubMed: 15805149
DOI: 10.1136/jmg.2004.029744