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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 -
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 -
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 -
European Child & Adolescent Psychiatry Oct 2023Salla disease (SD) is a rare lysosomal storage disorder characterised by intellectual disability ataxia, athetosis, nystagmus, and central nervous system demyelination.... (Review)
Review
Salla disease (SD) is a rare lysosomal storage disorder characterised by intellectual disability ataxia, athetosis, nystagmus, and central nervous system demyelination. Although the neurological spectrum of SD's clinical phenotype is well defined, psychotic symptoms in SD remain unreported. We reviewed the presence of psychiatric symptoms in patients diagnosed with SD. Medical records of all SD patients at Oulu University Hospital during the years 1982-2015 were systematically reviewed to evaluate the presence of psychiatric symptoms. Psychiatric symptoms were frequently associated with SD (10/24, 42%), and two patients were described as developing psychosis as adolescents. We reported their clinical characteristics in detail and assessed the prevalence of psychiatric symptoms in a cohort of 24 patients. Other psychiatric factors associated with SD were sleeping disorders (8/24, 32%), aggressive behaviour disorders or restlessness (6/24, 25%), and off-label antipsychotic medication (4/24, 17%). This report expands the knowledge of the phenotypic spectrum of SD and demonstrates the importance of recognising the possibility of psychiatric symptoms, including psychosis, in persons with SD.
Topics: Adolescent; Humans; Sialic Acid Storage Disease; Mental Disorders; Psychotic Disorders; Antipsychotic Agents; Phenotype
PubMed: 35796883
DOI: 10.1007/s00787-022-02031-5 -
Thrombosis and Haemostasis Jul 2022The gene encodes an enzyme that initiates and regulates the biosynthesis of -acetylneuraminic acid, a precursor of sialic acids. GNE mutations are classically...
The gene encodes an enzyme that initiates and regulates the biosynthesis of -acetylneuraminic acid, a precursor of sialic acids. GNE mutations are classically associated with Nonaka myopathy and sialuria, following an autosomal recessive and autosomal dominant inheritance pattern. Reports show that single GNE variants cause severe thrombocytopenia without muscle weakness. Using panel sequencing, we identified two compound heterozygous variants in in a young girl with life-threatening bleedings, severe congenital thrombocytopenia, and a platelet secretion defect. Both variants are located in the nucleotide-binding site of the -acetylmannosamin kinase domain of GNE. Lectin array showed decreased α-2,3-sialylation on platelets, consistent with loss of sialic acid synthesis and indicative of rapid platelet clearance. Hematopoietic stem cell transplantation (HSCT) normalized platelet counts. This is the first report of an HSCT in a patient with an inherited GNE defect leading to normal platelet counts.
Topics: Blood Platelets; Distal Myopathies; Female; Humans; Multienzyme Complexes; Mutation; N-Acetylneuraminic Acid; Thrombocytopenia
PubMed: 35052006
DOI: 10.1055/s-0041-1742207 -
Science Translational Medicine Dec 2021Lysosome dysfunction is a shared feature of rare lysosomal storage diseases and common age-related neurodegenerative diseases. Microglia, the brain-resident macrophages,...
Lysosome dysfunction is a shared feature of rare lysosomal storage diseases and common age-related neurodegenerative diseases. Microglia, the brain-resident macrophages, are particularly vulnerable to lysosome dysfunction because of the phagocytic stress of clearing dying neurons, myelin, and debris. CD22 is a negative regulator of microglial homeostasis in the aging mouse brain, and soluble CD22 (sCD22) is increased in the cerebrospinal fluid of patients with Niemann-Pick type C disease (NPC). However, the role of CD22 in the human brain remains unknown. In contrast to previous findings in mice, here, we show that CD22 is expressed by oligodendrocytes in the human brain and binds to sialic acid–dependent ligands on microglia. Using unbiased genetic and proteomic screens, we identify insulin-like growth factor 2 receptor (IGF2R) as the binding partner of sCD22 on human myeloid cells. Targeted truncation of IGF2R revealed that sCD22 docks near critical mannose 6-phosphate–binding domains, where it disrupts lysosomal protein trafficking. Interfering with the sCD22-IGF2R interaction using CD22 blocking antibodies ameliorated lysosome dysfunction in human mutant induced pluripotent stem cell–derived microglia-like cells without harming oligodendrocytes in vitro. These findings reinforce the differences between mouse and human microglia and provide a candidate microglia-directed immunotherapeutic to treat NPC.
Topics: Animals; Humans; Lysosomes; Macrophages; Mice; Microglia; Niemann-Pick Disease, Type C; Proteomics; Sialic Acid Binding Ig-like Lectin 2
PubMed: 34851695
DOI: 10.1126/scitranslmed.abg2919 -
Cold Spring Harbor Molecular Case... Oct 2021Nonimmune hydrops fetalis, the excessive accumulation of serous fluid in the subcutaneous tissues and serous cavities of the fetus, has many possible etiologies,...
Nonimmune hydrops fetalis, the excessive accumulation of serous fluid in the subcutaneous tissues and serous cavities of the fetus, has many possible etiologies, providing a diagnostic challenge for the physician. Lysosomal storage diseases have been reported in up to 5%-16% of nonimmune hydrops fetalis pregnancies. Infantile free sialic acid storage disease (ISSD) (OMIM #269920) is a severe form of autosomal recessive sialic acid storage disease. ISSD is caused by mutations in (OMIM #604322), which encodes sialin, a lysosomal-membrane sialic acid transporter. We describe a case of fetal hydrops due to a novel homozygous deletion in the gene. Prenatal single-nucleotide polymorphism (SNP) array analysis was performed on amniocytes after the discovery of fetal hydrops at 24 wk gestation revealing no copy-number variants. The SNP array, however, reported several regions of homozygosity (ROHs) including one on Chromosome 6 encompassing the gene. High levels of urine sialic acid in the newborn were detected. gene sequencing was initiated with no sequence variants identified; however, the assay failed to amplify exons 8 and 9, prompting an exon-level copy-number analysis that revealed a novel homozygous deletion of exons 8 and 9, inherited from heterozygous carrier parents. ISSD should be considered in the workup of patients with nonimmune hydrops fetalis, and analysis for deletions should be carried out when variants are not detected by gene sequencing.
Topics: Female; Homozygote; Humans; Hydrops Fetalis; Infant, Newborn; Pregnancy; Sequence Deletion; Sialic Acid Storage Disease
PubMed: 34667062
DOI: 10.1101/mcs.a006106 -
The Journal of Biological Chemistry 2021Acid alpha-glucosidase (GAA) is a lysosomal glycogen-catabolizing enzyme, the deficiency of which leads to Pompe disease. Pompe disease can be treated with systemic...
Acid alpha-glucosidase (GAA) is a lysosomal glycogen-catabolizing enzyme, the deficiency of which leads to Pompe disease. Pompe disease can be treated with systemic recombinant human GAA (rhGAA) enzyme replacement therapy (ERT), but the current standard of care exhibits poor uptake in skeletal muscles, limiting its clinical efficacy. Furthermore, it is unclear how the specific cellular processing steps of GAA after delivery to lysosomes impact its efficacy. GAA undergoes both proteolytic cleavage and glycan trimming within the endolysosomal pathway, yielding an enzyme that is more efficient in hydrolyzing its natural substrate, glycogen. Here, we developed a tool kit of modified rhGAAs that allowed us to dissect the individual contributions of glycan trimming and proteolysis on maturation-associated increases in glycogen hydrolysis using in vitro and in cellulo enzyme processing, glycopeptide analysis by MS, and high-pH anion-exchange chromatography with pulsed amperometric detection for enzyme kinetics. Chemical modifications of terminal sialic acids on N-glycans blocked sialidase activity in vitro and in cellulo, thereby preventing downstream glycan trimming without affecting proteolysis. This sialidase-resistant rhGAA displayed only partial activation after endolysosomal processing, as evidenced by reduced catalytic efficiency. We also generated enzymatically deglycosylated rhGAA that was shown to be partially activated despite not undergoing proteolytic processing. Taken together, these data suggest that an optimal rhGAA ERT would require both N-glycan and proteolytic processing to attain the most efficient enzyme for glycogen hydrolysis and treatment of Pompe disease. Future studies should examine the amenability of next-generation ERTs to both types of cellular processing.
Topics: Endosomes; Glycogen; Glycogen Storage Disease Type II; Glycopeptides; Humans; Hydrolysis; Polysaccharides; Proteolysis; alpha-Glucosidases
PubMed: 33971197
DOI: 10.1016/j.jbc.2021.100769