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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 -
Carbohydrate Research Jun 2022N-acetylneuraminic acid (sialic acid) is an abundantly found carbohydrate moiety covering the surface of all vertebrate cells and secreted glycoproteins. The human...
N-acetylneuraminic acid (sialic acid) is an abundantly found carbohydrate moiety covering the surface of all vertebrate cells and secreted glycoproteins. The human N-acetylneuraminate pyruvate lyase (NPL) interconverts sialic acid to N-acetylmannosamine and pyruvate, and mutations of the NPL gene were found to cause sialuria and impair the functionality of muscles. Here we report the soluble and functional expression of human NPL in Escherichia coli, which allowed us to study the biochemical properties of two clinically relevant NLP mutations (Asn45Asp and Arg63Cys). The Asn45Asp mutant variant was enzymatically active, but had lower expression levels and showed reduced stability when compared to the wild-type NPL variant. Expression trials of the Arg63Cys mutant did not yield any recombinant protein and consequently, no enzymatic activity was detected. The locations of these clinically relevant amino acid substitutions are also discussed by using a human NPL homology model.
Topics: Escherichia coli; Humans; Lyases; N-Acetylneuraminic Acid; Oxo-Acid-Lyases; Pyruvates
PubMed: 35487178
DOI: 10.1016/j.carres.2022.108561 -
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 -
Clinical Genetics Nov 2021We performed a systematic review of the literature to evaluate the incidence and types of lysosomal storage disorders (LSD) in case series of nonimmune hydrops fetalis... (Meta-Analysis)
Meta-Analysis
We performed a systematic review of the literature to evaluate the incidence and types of lysosomal storage disorders (LSD) in case series of nonimmune hydrops fetalis (NIHF). PubMed, Ovid, and clinicaltrials.gov were reviewed for case series evaluating the workup of NIHF diagnosed in utero or in the neonatal period in human subjects from 1979 to August 2020. Retrospective case series with at least five cases of fetal and/or neonatal NIHF with its workup mentioned were identified. Idiopathic NIHF was defined as NIHF without an apparent cause after initial standard-of-care workup. In total, 22 case series with 2678 total cases of NIHF were identified. The overall incidence of LSD was 6.6% (177/2663) in NIHF cases that were tested for any LSD, and 8.2% (177/2151) in idiopathic NIHF cases. The most common LSD identified in cases of NIHF were mucopolysaccharidosis type VII, galactosialidosis, infantile sialic acid storage disease, Gaucher disease, GM1 gangliosidosis, and sialidosis. More than 40% of the most common LSD causes of NIHF have a potential postnatal treatment. LSD testing for NIHF allows for early diagnosis, better counseling and appropriate management, planning for possible early treatment, and counseling for recurrence risk.
Topics: Animals; Biomarkers; Clinical Decision-Making; Disease Management; Disease Susceptibility; Female; Genetic Predisposition to Disease; Humans; Hydrops Fetalis; Lysosomal Storage Diseases; Molecular Diagnostic Techniques; Pregnancy
PubMed: 34057202
DOI: 10.1111/cge.14005 -
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 -
Neuroscience Letters Jun 2021Lysosomal free sialic acid storage disorder (FSASD) is an extremely rare, autosomal recessive, neurodegenerative, multisystemic disorder caused by defects in the... (Review)
Review
Lysosomal free sialic acid storage disorder (FSASD) is an extremely rare, autosomal recessive, neurodegenerative, multisystemic disorder caused by defects in the lysosomal sialic acid membrane exporter SLC17A5 (sialin). SLC17A5 defects cause free sialic acid and some other acidic hexoses to accumulate in lysosomes, resulting in enlarged lysosomes in some cell types and 10-100-fold increased urinary excretion of free sialic acid. Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia. Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features. Around 200 FSASD cases are reported worldwide, with the clinical spectrum ranging from a severe infantile onset form, often lethal in early childhood, to a mild, less severe form with subjects living into adulthood, also called Salla disease. The pathobiology of FSASD remains poorly understood and FSASD is likely underdiagnosed. Known patients have experienced a diagnostic delay due to the rarity of the disorder, absence of routine urine sialic acid testing, and non-specific clinical symptoms, including developmental delay, ataxia and infantile hypomyelination. There is no approved therapy for FSASD. We initiated a multidisciplinary collaborative effort involving worldwide academic clinical and scientific FSASD experts, the National Institutes of Health (USA), and the FSASD patient advocacy group (Salla Treatment and Research [S.T.A.R.] Foundation) to overcome the scientific, clinical and financial challenges facing the development of new treatments for FSASD. We aim to collect data that incentivize industry to further develop, obtain approval for, and commercialize FSASD treatments. This review summarizes current aspects of FSASD diagnosis, prevalence, etiology, and disease models, as well as challenges on the path to therapeutic approaches for FSASD.
Topics: Animals; Genetic Therapy; Humans; N-Acetylneuraminic Acid; Organic Anion Transporters; Sialic Acid Storage Disease; Stem Cell Transplantation; Symporters
PubMed: 33862140
DOI: 10.1016/j.neulet.2021.135896 -
ACS Omega Feb 2021Rare diseases impact hundreds of millions of individuals worldwide. However, few therapies exist to treat the rare disease population because financial resources are...
Rare diseases impact hundreds of millions of individuals worldwide. However, few therapies exist to treat the rare disease population because financial resources are limited, the number of patients affected is low, bioactivity data is often nonexistent, and very few animal models exist to support preclinical development efforts. Sialidosis is an ultrarare lysosomal storage disorder in which mutations in the NEU1 gene result in the deficiency of the lysosomal enzyme sialidase-1. This enzyme catalyzes the removal of sialic acid moieties from glycoproteins and glycolipids. Therefore, the defective or deficient protein leads to the buildup of sialylated glycoproteins as well as several characteristic symptoms of sialidosis including visual impairment, ataxia, hepatomegaly, dysostosis multiplex, and developmental delay. In this study, we used a bibliometric tool to generate links between lysosomal storage disease (LSD) targets and existing bioactivity data that could be curated in order to build machine learning models and screen compounds . We focused on sialidase as an example, and we used the data curated from the literature to build a Bayesian model which was then used to score compound libraries and rank these molecules for testing. Two compounds were identified from testing using microscale thermophoresis, namely sulfameter ( 2.15 ± 1.02 μM) and mexenone ( 8.88 ± 4.02 μM), which validated our approach to identifying new molecules binding to this protein, which could represent possible drug candidates that can be evaluated further as potential chaperones for this ultrarare lysosomal disease for which there is currently no treatment. Combining bibliometric and machine learning approaches has the ability to assist in curating small molecule data and model building, respectively, for rare disease drug discovery. This approach also has the capability to identify new compounds that are potential drug candidates.
PubMed: 33553934
DOI: 10.1021/acsomega.0c05591 -
Stem Cell Research Jul 2020Sialidosis is an autosomal recessive lysosomal storage disease, belonging to the glycoproteinoses. The disease is caused by deficiency of the sialic acid-cleaving...
Sialidosis is an autosomal recessive lysosomal storage disease, belonging to the glycoproteinoses. The disease is caused by deficiency of the sialic acid-cleaving enzyme, sialidase 1 or neuraminidase 1 (NEU1). Patients with sialidosis are classified based on the age of onset and severity of the clinical symptoms into type I (normomorphic) and type II (dysmorphic). Patient-derived skin fibroblasts from both disease types were reprogrammed using the CytoTune™-iPS 2.0 Sendai Reprogramming Kit. iPSCs were characterized for pluripotency, three germ-layer differentiation, normal karyotype and absence of viral components. These cell lines represent a valuable resource to model sialidosis and to screen for therapeutics.
Topics: Cell Differentiation; Fibroblasts; Humans; Induced Pluripotent Stem Cells; Mucolipidoses; Mutation; Neuraminidase
PubMed: 32485644
DOI: 10.1016/j.scr.2020.101836