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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 -
Biochimica Et Biophysica Acta.... Dec 2020Disorders caused by defects in lysosomal membrane transporters form a distinct subgroup of lysosomal storage disorders (LSDs). To date, defects in only 10 lysosomal... (Review)
Review
Disorders caused by defects in lysosomal membrane transporters form a distinct subgroup of lysosomal storage disorders (LSDs). To date, defects in only 10 lysosomal membrane transporters have been associated with inherited disorders. The clinical presentations of these diseases resemble the phenotypes of other LSDs; they are heterogeneous and often present in children with neurodegenerative manifestations. However, for pathomechanistic and therapeutic studies, lysosomal membrane transport defects should be distinguished from LSDs caused by defective hydrolytic enzymes. The involved proteins differ in function, localization, and lysosomal targeting, and the diseases themselves differ in their stored material and therapeutic approaches. We provide an overview of the small group of disorders of lysosomal membrane transporters, emphasizing discovery, pathomechanism, clinical features, diagnostic methods and therapeutic aspects. We discuss common aspects of lysosomal membrane transporter defects that can provide the basis for preclinical research into these disorders.
Topics: Amino Acid Transport Systems, Neutral; Cystinosis; Histiocytosis; Humans; Lysosomal Storage Diseases; Lysosomes; Membrane Transport Proteins; Nucleoside Transport Proteins; Organic Anion Transporters; Sialic Acid Storage Disease; Symporters
PubMed: 32389669
DOI: 10.1016/j.bbamem.2020.183336 -
Molecular Genetics and Metabolism May 2020Mucopolysaccharidosis VII (MPS VII) is a rare lysosomal storage disease characterized by a deficiency in the enzyme β-glucuronidase that has previously been...
Mucopolysaccharidosis VII (MPS VII) is a rare lysosomal storage disease characterized by a deficiency in the enzyme β-glucuronidase that has previously been successfully treated in a mouse model with enzyme replacement therapy. Here, we present the generation of a novel, highly sialylated version of recombinant human β-glucuronidase (rhGUS), vestronidase alfa, that has high uptake, resulting in an improved enzyme replacement therapy for the treatment of patients with MPS VII. In vitro, vestronidase alfa has 10-fold more sialic acid per mole of rhGUS monomer than a prior rhGUS version (referred to as GUS 43/44) and demonstrated very high affinity at ~1 nM half maximal uptake in human MPS VII fibroblasts. Vestronidase alfa has a longer enzymatic half-life after uptake into fibroblasts compared with other enzymes used as replacement therapy for MPS (40 days vs 3 to 4 days, respectively). In pharmacokinetic and tissue distribution experiments in Sprague-Dawley rats, intravenous administration of vestronidase alfa resulted in higher serum rhGUS levels and enhanced β-glucuronidase activity distributed to target tissues. Weekly intravenous injections of vestronidase alfa (0.1 mg/kg to 20 mg/kg) in a murine model of MPS VII demonstrated efficient enzyme delivery to all tissues, including bone and brain, as well as reduced lysosomal storage of glycosaminoglycans (GAGs) in a dose-dependent manner, resulting in increased survival after 8 weeks of treatment. Vestronidase alfa was well-tolerated and demonstrated no toxicity at concentrations that reached 5-times the proposed clinical dose. In a first-in-human phase 1/2 clinical trial, a dose-dependent reduction in urine GAG levels was sustained over 38 weeks of treatment with vestronidase alfa. Together, these results support the therapeutic potential of vestronidase alfa as an enzyme replacement therapy for patients with MPS VII.
Topics: Administration, Intravenous; Adult; Animals; CHO Cells; Child; Cricetulus; Enzyme Replacement Therapy; Female; Fibroblasts; Glucuronidase; Glycosaminoglycans; Humans; Lysosomes; Male; Mice; Mice, Transgenic; Mucopolysaccharidosis VII; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Tissue Distribution
PubMed: 32192868
DOI: 10.1016/j.ymgme.2020.02.009 -
Lysosomal storage disease spectrum in nonimmune hydrops fetalis: a retrospective case control study.Prenatal Diagnosis May 2020Nonimmune hydrops fetalis (NIHF) accounts for 90% of hydrops fetalis cases. About 15% to 29% of unexplained NIHF cases are caused by lysosomal storage diseases (LSD). We...
OBJECTIVES
Nonimmune hydrops fetalis (NIHF) accounts for 90% of hydrops fetalis cases. About 15% to 29% of unexplained NIHF cases are caused by lysosomal storage diseases (LSD). We review the spectrum of LSD and associated clinical findings in NIHF in a cohort of patients referred to our institution.
METHODS
We present a retrospective case-control study of cases with NIHF referred for LSD biochemical testing at a single center. Cases diagnosed with LSD were matched to controls with NIHF and negative LSD testing and analyzed according to the STROBE criteria to the extent the retrospective nature of this study allowed.
RESULTS
Between January 2006 and December 2018, 28 patients with NIHF were diagnosed with a LSD. Eight types of LSD were diagnosed: galactosialidosis 8/28 (28.6%), sialic acid storage disease (SASD) 5/28 (17.9%), mucopolysaccharidosis VII 5/28 (17.9%), Gaucher 4/28 (14.3%), sialidosis 2/28 (7.1%), GM1 gangliosidosis 2/28 (7.1%), Niemann-Pick disease type C 1/28 (3.6%), and mucolipidosis II/III 1/28 (3.6%). Associated clinical features were hepatomegaly 16/21 (76.2%) vs 22/65 (33.8%), P < .05, splenomegaly 12/20 (60.0%) vs 14/58 (24.1%), P < .05, and hepatosplenomegaly 10/20 (50.0%) vs 13/58 (22.4%) P < .05.
CONCLUSION
The most common LSD in NIHF were galactosialidosis, SASD, mucopolysaccharidosis VII, and Gaucher disease. LSD should be considered in unexplained NIHF cases, particularly if hepatomegaly, splenomegaly, or hepatosplenomegaly is visualized on prenatal ultrasound.
Topics: Adult; Ascites; Case-Control Studies; Edema; Female; Gaucher Disease; Gestational Age; Hepatomegaly; Humans; Hydrops Fetalis; Infant, Newborn; Lysosomal Storage Diseases; Male; Mucolipidoses; Mucopolysaccharidosis VII; Niemann-Pick Disease, Type C; Pericardial Effusion; Pleural Effusion; Polyhydramnios; Pregnancy; Prenatal Diagnosis; Retrospective Studies; Sialic Acid Storage Disease; Skin; Splenomegaly; Young Adult
PubMed: 32134517
DOI: 10.1002/pd.5678 -
JCI Insight Dec 2018Sialic acids are important components of glycoproteins and glycolipids essential for cellular communication, infection, and metastasis. The importance of sialic acid...
Sialic acids are important components of glycoproteins and glycolipids essential for cellular communication, infection, and metastasis. The importance of sialic acid biosynthesis in human physiology is well illustrated by the severe metabolic disorders in this pathway. However, the biological role of sialic acid catabolism in humans remains unclear. Here, we present evidence that sialic acid catabolism is important for heart and skeletal muscle function and development in humans and zebrafish. In two siblings, presenting with sialuria, exercise intolerance/muscle wasting, and cardiac symptoms in the brother, compound heterozygous mutations [chr1:182775324C>T (c.187C>T; p.Arg63Cys) and chr1:182772897A>G (c.133A>G; p.Asn45Asp)] were found in the N-acetylneuraminate pyruvate lyase gene (NPL). In vitro, NPL activity and sialic acid catabolism were affected, with a cell-type-specific reduction of N-acetyl mannosamine (ManNAc). A knockdown of NPL in zebrafish resulted in severe skeletal myopathy and cardiac edema, mimicking the human phenotype. The phenotype was rescued by expression of wild-type human NPL but not by the p.Arg63Cys or p.Asn45Asp mutants. Importantly, the myopathy phenotype in zebrafish embryos was rescued by treatment with the catabolic products of NPL: N-acetyl glucosamine (GlcNAc) and ManNAc; the latter also rescuing the cardiac phenotype. In conclusion, we provide the first report to our knowledge of a human defect in sialic acid catabolism, which implicates an important role of the sialic acid catabolic pathway in mammalian muscle physiology, and suggests opportunities for monosaccharide replacement therapy in human patients.
Topics: Adult; Animals; Disease Models, Animal; Edema, Cardiac; Gene Expression Regulation, Developmental; Gene Knockdown Techniques; Genetic Diseases, Inborn; HEK293 Cells; Hexosamines; Humans; Male; Muscle, Skeletal; Muscular Diseases; Mutation; N-Acetylneuraminic Acid; Oxo-Acid-Lyases; Sialic Acid Storage Disease; Young Adult; Zebrafish
PubMed: 30568043
DOI: 10.1172/jci.insight.122373 -
Advances in Carbohydrate Chemistry and... 2018Sialic acids are cytoprotectors, mainly localized on the surface of cell membranes with multiple and outstanding cell biological functions. The history of their... (Review)
Review
Sialic acids are cytoprotectors, mainly localized on the surface of cell membranes with multiple and outstanding cell biological functions. The history of their structural analysis, occurrence, and functions is fascinating and described in this review. Reports from different researchers on apparently similar substances from a variety of biological materials led to the identification of a 9-carbon monosaccharide, which in 1957 was designated "sialic acid." The most frequently occurring member of the sialic acid family is N-acetylneuraminic acid, followed by N-glycolylneuraminic acid and O-acetylated derivatives, and up to now over about 80 neuraminic acid derivatives have been described. They appeared first in the animal kingdom, ranging from echinoderms up to higher animals, in many microorganisms, and are also expressed in insects, but are absent in higher plants. Sialic acids are masks and ligands and play as such dual roles in biology. Their involvement in immunology and tumor biology, as well as in hereditary diseases, cannot be underestimated. N-Glycolylneuraminic acid is very special, as this sugar cannot be expressed by humans, but is a xenoantigen with pathogenetic potential. Sialidases (neuraminidases), which liberate sialic acids from cellular compounds, had been known from very early on from studies with influenza viruses. Sialyltransferases, which are responsible for the sialylation of glycans and elongation of polysialic acids, are studied because of their significance in development and, for instance, in cancer. As more information about the functions in health and disease is acquired, the use of sialic acids in the treatment of diseases is also envisaged.
Topics: Animals; Carbohydrate Conformation; Humans; Lysosomal Storage Diseases; Mucolipidoses; N-Acetylneuraminic Acid; Neoplasms; Sialic Acid Storage Disease
PubMed: 30509400
DOI: 10.1016/bs.accb.2018.09.001 -
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