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Journal of Pediatric Endocrinology &... Oct 2018Background Infantile free sialic acid storage disease (ISSD) is a severe multisystemic disorder characterized by the accumulation of free sialic acid in lysosomes. Case...
Background Infantile free sialic acid storage disease (ISSD) is a severe multisystemic disorder characterized by the accumulation of free sialic acid in lysosomes. Case presentation The patient presented prenatally with fetal ascites and large scrotal hernias, without pleural or pericardial effusion. During the infantile period, he was diagnosed with permanent isolated immunoglobulin G (IgG) hypogammaglobulinemia, which thus far has rarely been associated with ISSD. The analysis of the SLC17A5 gene revealed a novel homozygous 94 bp gene deletion. We further provide a detailed description of pre- and postnatal clinical and radiographic findings. Conclusions Fetal ascites could be the first sign of several lysosomal storage diseases (LSDs), including ISSD. The analysis of LSD gene panels is an effective approach to diagnosis in the case of non-specific symptoms and when specific biochemical tests are not easily available.
Topics: Agammaglobulinemia; Brain; Humans; Infant; Magnetic Resonance Imaging; Male; Mutation; Organic Anion Transporters; Sialic Acid Storage Disease; Symporters; Ultrasonography
PubMed: 30243016
DOI: 10.1515/jpem-2017-0397 -
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 -
JIMD Reports 2019Sialuria is a rare autosomal dominant inborn error of metabolism characterized by cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid...
Sialuria is a rare autosomal dominant inborn error of metabolism characterized by cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid due to failure of feedback inhibition of the rate-limiting enzyme in the sialic acid synthesis pathway, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK). To date, eight cases had been published worldwide, all with heterozygous missense variants at the allosteric site, specifically at Arginine 294 (formerly 263) and Arginine 297 (formerly 266) of GNE. The described cases so far have rather homogeneous clinical features which include developmental delay, mildly coarse features, hepatomegaly and prolonged neonatal jaundice. The apparent rarity of this disorder is hypothesized to be due to the variable and sometimes transient nature of the clinical features and to the absence of routine testing for urinary sialic acids. Here we present the ninth case of sialuria diagnosed in a child investigated because of clinical signs and symptoms and furthermore describe a novel pathogenic variant in the associated gene, GNE.
PubMed: 29923088
DOI: 10.1007/8904_2018_117 -
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 -
Progress in Molecular Biology and... 2018Gangliosides (GGs) are cell type-specific sialic acid-containing glycosphingolipids (GSLs), which are enriched in mammalian brain. Defects in GSL metabolism cause fatal... (Review)
Review
Gangliosides (GGs) are cell type-specific sialic acid-containing glycosphingolipids (GSLs), which are enriched in mammalian brain. Defects in GSL metabolism cause fatal human diseases. GSLs are composed of a hydrophilic oligosaccharide linked in 1-O-position to a hydrophobic ceramide anchor, which itself is composed of a long-chain amino alcohol, the sphingoid base, and an amide-bound acyl chain. Biosynthesis of mammalian GGs and other GSLs starts with the formation of their hydrophobic ceramide anchor in the endoplasmic reticulum, followed by sequential glycosylation reactions along the secretory pathway, mainly at the luminal surface of Golgi and trans-Golgi network (TGN) membranes. Few membrane-anchored and often promiscuous glycosyltransferases allow the formation of cell type-specific glycolipid patterns in a combinatorial process. Inherited defects of these transferases therefore affect not only single structures but defined glycolipid series. GGs and other GSLs are thereafter transported by an exocytotic membrane flow to the plasma membrane where they are expressed in cell type-specific patterns, which can be modified by metabolic reactions at or near the cellular surface. Endocytosed (glyco)sphingolipids are degraded, together with other membrane lipids in a stepwise fashion by endolysosomal enzymes with the help of small lipid-binding proteins, the sphingolipid activator proteins (SAPs), at the surface of intraluminal lysosomal vesicles. Inherited defects in a sphingolipid-degrading enzyme or SAP cause the accumulation of the corresponding lipid substrates. Endolysosomal GSL degradation is strongly modified by the lipid components of the organelle microenvironments.
Topics: Animals; Gangliosides; Health Status; Humans; Metabolic Diseases
PubMed: 29747811
DOI: 10.1016/bs.pmbts.2018.01.002 -
Scientific Reports May 2018Sialic acids (SAs) are nine carbon acidic amino sugars, found at the outermost termini of glycoconjugates performing various physiological and pathological functions. SA...
Sialic acids (SAs) are nine carbon acidic amino sugars, found at the outermost termini of glycoconjugates performing various physiological and pathological functions. SA synthesis is regulated by UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) that catalyzes rate limiting steps. Mutations in GNE result in rare genetic disorders, GNE myopathy and Sialuria. Recent studies indicate an alternate role of GNE in cell apoptosis and adhesion, besides SA biosynthesis. In the present study, using a HEK cell-based model for GNE myopathy, the role of Insulin-like Growth Factor Receptor (IGF-1R) as cell survival receptor protein was studied to counter the apoptotic effect of non-functional GNE. In the absence of functional GNE, IGF-1R was hyposialylated and transduced a downstream signal upon IGF-1 (IGF-1R ligand) treatment. IGF-1 induced activation of IGF-1R led to AKT (Protein Kinase B) phosphorylation that may phosphorylate BAD (BCL2 Associated Death Promoter) and its dissociation from BCL2 to prevent apoptosis. However, reduced ERK (Extracellular signal-regulated kinases) phosphorylation in GNE deficient cells after IGF-1 treatment suggests downregulation of the ERK pathway. A balance between the ERK and AKT pathways may determine the cell fate towards survival or apoptosis. Our study suggests that IGF-1R activation may rescue apoptotic cell death of GNE deficient cell lines and has potential as therapeutic target.
Topics: Apoptosis; Carbohydrate Epimerases; Gene Knockdown Techniques; HEK293 Cells; Humans; Mitochondria; N-Acetylneuraminic Acid; Protein Transport; Receptor, IGF Type 1; Receptors, Somatomedin
PubMed: 29743626
DOI: 10.1038/s41598-018-25510-9 -
Clinica Chimica Acta; International... Jul 2018Nonimmune hydrops fetalis is the most severe clinical manifestation of lysosomal storage diseases (LSDs). Around 14 different LSDs have been accounted for as 1-15% of...
Nonimmune hydrops fetalis is the most severe clinical manifestation of lysosomal storage diseases (LSDs). Around 14 different LSDs have been accounted for as 1-15% of the cause of nonimmune hydrops fetalis. We report a Korean infant affected by an extremely rare but severe form of sialic acid storage disease. The patient presented with nonimmune hydrops fetalis, dysmorphic facial features, hepatosplenomegaly, and dysostosis multiplex and died at 39 days of age due to persistent pulmonary hypertension. LSD was suspected based on the presence of diffuse vacuolation of syncytiotrophoblast, villous stromal cells, and intermediate trophoblast in placental biopsy. Increased excretion of urinary free sialic acid was detected by liquid chromatography-tandem mass spectrometry. The patient was compound heterozygous of the c.908G>A (p.Trp303Ter) and the splicing mutation c.1259+5G>T (IVS9+5 G>T) in the SLC17A5 gene.
Topics: Alternative Splicing; Humans; Hydrops Fetalis; Hypertension, Pulmonary; Infant; Infant, Newborn; Lysosomal Storage Diseases; Mutation; Organic Anion Transporters; Polymorphism, Single Nucleotide; Republic of Korea; Sialic Acid Storage Disease; Symporters
PubMed: 29654786
DOI: 10.1016/j.cca.2018.04.016 -
Pediatric Neurology Apr 2018
Topics: Genomics; Humans; Japan; Magnetic Resonance Imaging; Sialic Acid Storage Disease
PubMed: 29472023
DOI: 10.1016/j.pediatrneurol.2018.01.002 -
Translational Science of Rare Diseases May 2017Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead... (Review)
Review
Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively.
PubMed: 29152458
DOI: 10.3233/TRD-160005 -
Applied Microbiology and Biotechnology Jan 2018β-N-Acetylglucosaminidases (GlcNAcases) hydrolyse N-acetylglucosamine-containing oligosaccharides and proteins. These enzymes produce N-acetylglucosamine (GlcNAc) and... (Review)
Review
β-N-Acetylglucosaminidases (GlcNAcases) hydrolyse N-acetylglucosamine-containing oligosaccharides and proteins. These enzymes produce N-acetylglucosamine (GlcNAc) and have a wide range of promising applications in the food, energy, and pharmaceutical industries, such as synergistic degradation of chitin with endo-chitinases and using GlcNAc to produce sialic acid, bioethanol, single-cell proteins, and pharmaceutical therapeutics. GlcNAcases also play an important role in the dynamic balance of cellular O-linked GlcNAc levels, catabolism of ganglioside storage in Tay-Sachs disease, and bacterial cell wall recycling and flagellar assembly. In view of these important biological functions and the wide range of industrial applications of GlcNAcases, this review aims to provide a better understanding of various advances for these enzymes. It focuses on enzymatic properties of GlcNAcases, including substrate specificity, catalytic activity, pH optimum, temperature optimum, thermostability, the effects of various metal ions and organic reagents, and transglycosylation.
Topics: Acetylglucosamine; Acetylglucosaminidase; Amino Acid Sequence; Chitin; Chitinases; Cloning, Molecular; Enzyme Stability; Ethanol; Humans; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Phylogeny; Substrate Specificity; Tay-Sachs Disease; Temperature
PubMed: 29143882
DOI: 10.1007/s00253-017-8624-7