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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 -
Molecular Therapy. Nucleic Acids Dec 2023Free sialic acid storage disorders (FSASDs) result from pathogenic variations in the gene, which encodes the lysosomal transmembrane protein sialin. Loss or deficiency...
Free sialic acid storage disorders (FSASDs) result from pathogenic variations in the gene, which encodes the lysosomal transmembrane protein sialin. Loss or deficiency of sialin impairs FSA transport out of the lysosome, leading to cellular dysfunction and neurological impairment, with the most severe form of FSASD resulting in death during early childhood. There are currently no therapies for FSASDs. Here, we evaluated the efficacy of CRISPR-Cas9-mediated homology directed repair (HDR) and adenine base editing (ABE) targeting the founder variant, c.115C>T (p.Arg39Cys) in human dermal fibroblasts. We observed minimal correction of the pathogenic variant in HDR samples with a high frequency of undesired insertions/deletions (indels) and significant levels of correction for ABE-treated samples with no detectable indels, supporting previous work showing that CRISPR-Cas9-mediated ABE outperforms HDR. Furthermore, ABE treatment of either homozygous or compound heterozygous c.115C>T human dermal fibroblasts demonstrated significant FSA reduction, supporting amelioration of disease pathology. Translation of this ABE strategy to mouse embryonic fibroblasts harboring the c.115C>T variant in homozygosity recapitulated these results. Our study demonstrates the feasibility of base editing as a therapeutic approach for the FSASD variant c.115C>T and highlights the usefulness of base editing in monogenic diseases where transmembrane protein function is impaired.
PubMed: 37727271
DOI: 10.1016/j.omtn.2023.08.024 -
Pediatric Neurology Nov 2023Biallelic pathogenic variants in SLC17A5 cause three forms of free sialic acid storage disease categorized based on severity from least to most severe: Salla disease,...
BACKGROUND
Biallelic pathogenic variants in SLC17A5 cause three forms of free sialic acid storage disease categorized based on severity from least to most severe: Salla disease, intermediate-severe Salla disease, and infantile free sialic acid storage disease. Intermediate-severe Salla disease is the most recently described form. Here, we report a longitudinal characterization of intermediate-severe Salla disease progression in two sisters carrying the following biallelic variants in SLC17A5: c.406A>G (p.Lys136Glu) and c.819+1G>A.
METHODS
A retrospective review of medical records was performed. A developmental questionnaire was completed to obtain further clinical information. For functional characterization of the predicted splice site variant, RNA was extracted from patient blood samples and sequenced.
RESULTS
Disease onset occurred within the first six months of life in both patients. Early childhood development was delayed with achievement of some milestones followed by a developmental plateau in late childhood. After this, both patients began a slow and progressive neurological regression in adolescence. Functional studies confirmed the pathogenicity of the c.819+1G>A variant, resulting in a frameshift and deletion of exon 6.
CONCLUSIONS
We present a detailed study describing the clinical course of intermediate-severe Salla disease with over 15 to 20 years of evolution and demonstrate the pathogenicity of the c.819+1G>A splice site variant.
Topics: Adolescent; Humans; Child; Child, Preschool; Sialic Acid Storage Disease; Mutation; N-Acetylneuraminic Acid; Disease Progression
PubMed: 37713976
DOI: 10.1016/j.pediatrneurol.2023.08.013 -
Neurology Oct 2023
Topics: Child; Humans; Male; Mutation; Neuroimaging; Organic Anion Transporters; Sialic Acid Storage Disease; Symporters
PubMed: 37527937
DOI: 10.1212/WNL.0000000000207546 -
Zhongguo Dang Dai Er Ke Za Zhi =... May 2023A boy, aged 3 hours, was admitted due to a prenatal diagnosis of fetal hydrops at 3 hours after resuscitation for birth asphyxia. Prenatal examination at 5 months of...
A boy, aged 3 hours, was admitted due to a prenatal diagnosis of fetal hydrops at 3 hours after resuscitation for birth asphyxia. Prenatal examination at 5 months of gestation showed massive ascites in the fetus, and after birth, the boy had the manifestations of systemic hydroderma, massive ascites, coarse face, and hepatomegaly. Genetic testing revealed heterozygous mutations in the gene, and there was a significant increase in urinary free sialic acid. Placental pathology showed extensive vacuolization in villous stromal cells, Hofbauer cells, cytotrophoblast cells, and syncytiotrophoblast cells in human placental chorionic villi. The boy was finally diagnosed with free sialic acid storage disorders (FSASDs). This is the first case of FSASDs with the initial symptom of fetal hydrops reported in China. The possibility of FSASDs should be considered for cases with non-immune hydrops fetalis, and examinations such as placental pathology and urinary free sialic acid may help with early diagnosis and clinical decision making.
Topics: Infant, Newborn; Male; Humans; Female; Pregnancy; Hydrops Fetalis; N-Acetylneuraminic Acid; Placenta; Ascites
PubMed: 37272184
DOI: 10.7499/j.issn.1008-8830.2303041 -
Journal of Inherited Metabolic Disease Mar 2023Oligosaccharidoses, sphingolipidoses and mucolipidoses are lysosomal storage disorders (LSDs) in which defective breakdown of glycan-side chains of glycosylated proteins...
Oligosaccharidoses, sphingolipidoses and mucolipidoses are lysosomal storage disorders (LSDs) in which defective breakdown of glycan-side chains of glycosylated proteins and glycolipids leads to the accumulation of incompletely degraded oligosaccharides within lysosomes. In metabolic laboratories, these disorders are commonly diagnosed by thin-layer chromatography (TLC) but more recently also mass spectrometry-based approaches have been published. To expand the possibilities to screen for these diseases, we developed an ultra-high-performance liquid chromatography (UHPLC) with a high-resolution accurate mass (HRAM) mass spectrometry (MS) screening platform, together with an open-source iterative bioinformatics pipeline. This pipeline generates comprehensive biomarker profiles and allows for extensive quality control (QC) monitoring. Using this platform, we were able to identify α-mannosidosis, β-mannosidosis, α-N-acetylgalactosaminidase deficiency, sialidosis, galactosialidosis, fucosidosis, aspartylglucosaminuria, GM1 gangliosidosis, GM2 gangliosidosis (M. Sandhoff) and mucolipidosis II/III in patient samples. Aberrant urinary oligosaccharide excretions were also detected for other disorders, including NGLY1 congenital disorder of deglycosylation, sialic acid storage disease, MPS type IV B and GSD II (Pompe disease). For the latter disorder, we identified heptahexose (Hex7), as a potential urinary biomarker, in addition to glucose tetrasaccharide (Glc4), for the diagnosis and monitoring of young onset cases of Pompe disease. Occasionally, so-called "neonate" biomarker profiles were observed in young patients, which were probably due to nutrition. Our UHPLC/HRAM-MS screening platform can easily be adopted in biochemical laboratories and allows for simple and robust screening and straightforward interpretation of the screening results to detect disorders in which aberrant oligosaccharides accumulate.
Topics: Humans; Chromatography, High Pressure Liquid; Glycogen Storage Disease Type II; Lysosomal Storage Diseases; Mucolipidoses; Tandem Mass Spectrometry; Oligosaccharides; Mucopolysaccharidosis IV
PubMed: 36752951
DOI: 10.1002/jimd.12597 -
Science Advances Jan 2023Malfunction of the sialic acid transporter caused by various genetic mutations in the gene encoding Sialin leads to a spectrum of neurodegenerative conditions called...
Malfunction of the sialic acid transporter caused by various genetic mutations in the gene encoding Sialin leads to a spectrum of neurodegenerative conditions called free sialic acid storage disorders. Unfortunately, how Sialin transports sialic acid/proton (H) and how pathogenic mutations impair its function are poorly defined. Here, we present the structure of human Sialin in an inward-facing partially open conformation determined by cryo-electron microscopy, representing the first high-resolution structure of any human SLC17 member. Our analysis reveals two unique features in Sialin: (i) The H coupling/sensing requires two highly conserved Glu residues (E171 and E175) instead of one (E175) as implied in previous studies; and (ii) the normal function of Sialin requires the stabilization of a cytosolic helix, which has not been noticed in the literature. By mapping known pathogenic mutations, we provide mechanistic explanations for corresponding functional defects. We propose a structure-based mechanism for sialic acid transport mediated by Sialin.
Topics: Humans; N-Acetylneuraminic Acid; Cryoelectron Microscopy; Sialic Acid Storage Disease; Mutation; Symporters; Ion Transport
PubMed: 36662855
DOI: 10.1126/sciadv.ade8346 -
Brain Research Jan 2023Synapses can experience long-term enhancements in its efficacy transmission in an activity-dependent manner (LTP, Long-Term Potentiation). This could contribute to store...
Synapses can experience long-term enhancements in its efficacy transmission in an activity-dependent manner (LTP, Long-Term Potentiation). This could contribute to store the living experiences in memory. Consequently, loss of synaptic plasticity can lead to failures in memory encoding and storage. Hence, finding ways to restore synaptic function can help restore learning and memory ability. Erythropoietin (EPO) has shown beneficial effects in the brain as a neuroprotector, improving affected learning, memory, and synaptic plasticity among other. In the present study, using the fimbria-fornix lesion model, we address the question whether the administration of erythropoietin restores the synaptic capacity to produce long-lasting increases in their transmission efficiency. A series of experiments was designed in which a control group of healthy young animals and one of injured young animals were formed. A subgroup of injured animals was injected with EPO or the vehicle in which the EPO is diluted (Veh). EPO or Veh was administered 15 min before LTP induction. Our data show that EPO produces a recovery in LTP in the group of fimbria-fornix lesioned animals, which show a severe impairment in the maintenance of LTP. Furthermore, LTP in the injured animals that received EPO was similar to that of the healthy control animals. LTP is widely accepted as a cellular mechanism of memory. Restoring LTP by EPO might be a potential tool for the treatment of memory disturbing diseases like Alzheimeŕs disease. Ongoing clinical trials are evaluating a potential therapeutic effect of low sialic acid-EPO (NeuroEPO) on degenerative diseases.
Topics: Rats; Animals; Long-Term Potentiation; Fornix, Brain; Hippocampus; Rats, Wistar; Erythropoietin; Synapses; Memory Disorders; Synaptic Transmission
PubMed: 36442648
DOI: 10.1016/j.brainres.2022.148178 -
Advances in Neurobiology 2023Glycosphingolipids (GSLs) are a diverse group of membrane components occurring mainly on the surfaces of mammalian cells. They and their metabolites have a role in...
Glycosphingolipids (GSLs) are a diverse group of membrane components occurring mainly on the surfaces of mammalian cells. They and their metabolites have a role in intercellular communication, serving as versatile biochemical signals (Kaltner et al, Biochem J 476(18):2623-2655, 2019) and in many cellular pathways. Anionic GSLs, the sialic acid containing gangliosides (GGs), are essential constituents of neuronal cell surfaces, whereas anionic sulfatides are key components of myelin and myelin forming oligodendrocytes. The stepwise biosynthetic pathways of GSLs occur at and lead along the membranes of organellar surfaces of the secretory pathway. After formation of the hydrophobic ceramide membrane anchor of GSLs at the ER, membrane-spanning glycosyltransferases (GTs) of the Golgi and Trans-Golgi network generate cell type-specific GSL patterns for cellular surfaces. GSLs of the cellular plasma membrane can reach intra-lysosomal, i.e. luminal, vesicles (ILVs) by endocytic pathways for degradation. Soluble glycoproteins, the glycosidases, lipid binding and transfer proteins and acid ceramidase are needed for the lysosomal catabolism of GSLs at ILV-membrane surfaces. Inherited mutations triggering a functional loss of glycosylated lysosomal hydrolases and lipid binding proteins involved in GSL degradation cause a primary lysosomal accumulation of their non-degradable GSL substrates in lysosomal storage diseases (LSDs). Lipid binding proteins, the SAPs, and the various lipids of the ILV-membranes regulate GSL catabolism, but also primary storage compounds such as sphingomyelin (SM), cholesterol (Chol.), or chondroitin sulfate can effectively inhibit catabolic lysosomal pathways of GSLs. This causes cascades of metabolic errors, accumulating secondary lysosomal GSL- and GG- storage that can trigger a complex pathology (Breiden and Sandhoff, Int J Mol Sci 21(7):2566, 2020).
Topics: Animals; Glycosphingolipids; Gangliosides; Acid Ceramidase; Sphingomyelins; Sulfoglycosphingolipids; N-Acetylneuraminic Acid; Chondroitin Sulfates; Lysosomal Storage Diseases; Ceramides; Cholesterol; Glycosyltransferases; Glycoproteins; Glycoside Hydrolases; Mammals
PubMed: 36255681
DOI: 10.1007/978-3-031-12390-0_12 -
Clinical Chemistry and Laboratory... Oct 2022Urine free sialic acid (UFSA) is an important diagnostic biomarker for sialuria ( variants) and infantile sialic acid storage disease/Salla disease ( variants)....
OBJECTIVES
Urine free sialic acid (UFSA) is an important diagnostic biomarker for sialuria ( variants) and infantile sialic acid storage disease/Salla disease ( variants). Traditionally, UFSA has been measured using specific single-plex methodology in relatively small cohorts of patients with clinical symptoms suggestive of these disorders. The use of multiplex tandem mass spectrometry urine screening (UMSMS) has meant that UFSA can be measured semi-quantitatively in a much larger cohort of patients being investigated for suspected metabolic disorders. We hypothesised that the neuraminidase of may release free sialic acid from endogenous sialylated glycoconjugates and result in increased UFSA levels.
METHODS
We conducted a retrospective review of clinical records of patients who were identified as having infection and who also had UMSMS at the time of their acute infection.
RESULTS
We identified three cases of increased UFSA detected by UMSMS screening that were secondary to sepsis. Additional testing ruled out genetic causes of increased UFSA in the first patient. All three patients had overwhelming sepsis with multiorgan dysfunction which was fatal. Glycosylation abnormalities consistent with the removal of sialic acid were demonstrated in serum transferrin patterns in one patient.
CONCLUSIONS
We have demonstrated in a retrospective cohort that elevation of UFSA levels have been observed in cases of sepsis. This expands our knowledge of UFSA as a biomarker in human disease. This research demonstrates that infection with organisms with neuraminidase activity should be considered in patients with unexplained increases in UFSA.
Topics: Humans; N-Acetylneuraminic Acid; Neuraminidase; Retrospective Studies; Sepsis; Sialic Acid Storage Disease; Streptococcus pneumoniae; Transferrins
PubMed: 36000484
DOI: 10.1515/cclm-2022-0473