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Kubaski F, Cason A, Herbst ZAM, Kharbanda S, Lund TC, Orchard PJ, Pollard L. Analysis of serum oligosaccharides by UPLC-MS/MS for diagnosis and treatment monitoring of patients with alpha-mannosidosis. Mol Genet Metab 2025; 144:109042. [PMID: 39908789 DOI: 10.1016/j.ymgme.2025.109042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/24/2025] [Accepted: 01/25/2025] [Indexed: 02/07/2025]
Abstract
BACKGROUND Alpha-mannosidosis is a rare lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha-mannosidase, which leads to the accumulation of mannose-rich oligosaccharides. Serum oligosaccharides are useful biomarkers for the therapeutic monitoring of patients with alpha-mannosidosis. In this study, we have developed a ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay for thetrue quantitation of GlcNAc(Man)2, and semi-quantitation of GlcNAc(Man)3-6. RESULTS In plasma samples from 16 untreated alpha-mannosidosis patients, GlcNAc(Man)2-6 levels were significantly higher than in controls, demonstrating 100 % sensitivity. In plasma samples from patients with other glycoproteinosis disorders, GlcNAc(Man)2-6 levels were within the normal range, other than mild elevations observed in some Mucolipidosis II/III patients, demonstrating high specificity. We have evaluated if these biomarkers can be used for therapeutic monitoring of alpha-mannosidosis by testing plasma samples from 4 patients who had received hematopoietic stem cell transplantation (HSCT). All oligosaccharide species were largely reduced in treated patients. CONCLUSIONS This study indicates that the analysis of serum/plasma oligosaccharides by UPLC-MS/MS is a feasible and valuable tool for diagnosis, and treatment monitoring of patients with alpha-mannosidosis.
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Affiliation(s)
- Francyne Kubaski
- Greenwood Genetic Center, Biochemical Genetics Laboratory, Greenwood, USA.
| | - Allison Cason
- Greenwood Genetic Center, Biochemical Genetics Laboratory, Greenwood, USA
| | | | - Sandhya Kharbanda
- Department of Pediatric Bone Marrow Transplantation, UCSF Benioff Children's Hospitals, San Francisco, USA.
| | - Troy C Lund
- Division of Pediatric Blood Stem Cell Transplantation, University of Minnesota, Minneapolis, USA.
| | - Paul J Orchard
- Division of Pediatric Blood Stem Cell Transplantation, University of Minnesota, Minneapolis, USA.
| | - Laura Pollard
- Greenwood Genetic Center, Biochemical Genetics Laboratory, Greenwood, USA.
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2
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Marins M, Curiati MA, Gomes CP, Martin RP, Nicolicht-Amorim P, Yamamoto JUDS, D'Almeida V, Martins AM, Pesquero JB. α-mannosidosis diagnosis in Brazilian patients with MPS-like symptoms. Orphanet J Rare Dis 2024; 19:439. [PMID: 39593065 PMCID: PMC11600758 DOI: 10.1186/s13023-024-03419-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 10/13/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND α-mannosidosis is an inborn error of metabolism caused by the deficiency of the lysosomal enzyme α-mannosidase, which is encoded by the MAN2B1 gene and inherited in an autosomal recessive manner. The impairment of affected individuals is multisystemic and very similar to the observed in some mucopolysaccharidosis (MPS) patients. The aim of this study was to search for α-mannosidosis cases in individuals with clinical suspicion of MPS without a confirmed diagnosis. Biochemical and molecular analysis were standardized by our group for this study. Two hundred and fifty samples from patients with clinical suspicion of MPS, but with inconclusive MPS biochemical and/or molecular analysis, were screened for α-mannosidase activity. Subsequently the MAN2B1 gene was sequenced in samples from 53 patients by the Sanger method. RESULTS The measurement of enzymatic activity detected fifty-three samples with abnormal results, suggesting α-mannosidosis. Molecular analysis confirmed three affected families, which presented the nonsense variant p.Ser899Ter. This variant generates a premature stop codon in exon 22, resulting in a truncated protein with no residual enzymatic activity. CONCLUSION In conclusion, this work brings data for the beginning of a genetic characterization of α-mannosidosis in the Brazilian population. It also shows that α-mannosidosis cases may be underdiagnosed due to the clinical similarity to MPS and the lack of information about this ultra-rare disease. Based on our data, we strongly recommend to all screening centers to consider α-mannosidosis testing together with screening for MPS as a tool for diagnosis to MPS-like phenotype individuals, since the phenotype similarity between these diseases poses a significant challenge for clinicians worldwide and often leads to the failure of the correct clinical diagnosis and treatment.
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Affiliation(s)
- Maryana Marins
- Center for Research and Diagnosis of Genetic Diseases - Department of Biophysics, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Marco Antonio Curiati
- Inborn Errors of Metabolism Reference Center, Department of Pediatrics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Caio Perez Gomes
- Center for Research and Diagnosis of Genetic Diseases - Department of Biophysics, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Renan Paulo Martin
- Center for Research and Diagnosis of Genetic Diseases - Department of Biophysics, Universidade Federal de São Paulo, São Paulo, Brazil
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Priscila Nicolicht-Amorim
- Center for Research and Diagnosis of Genetic Diseases - Department of Biophysics, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Joyce Umbelino da Silva Yamamoto
- Laboratory of Inborn Errors of Metabolism, Department of Psychobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Vânia D'Almeida
- Laboratory of Inborn Errors of Metabolism, Department of Psychobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
| | - Ana Maria Martins
- Inborn Errors of Metabolism Reference Center, Department of Pediatrics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
| | - João Bosco Pesquero
- Center for Research and Diagnosis of Genetic Diseases - Department of Biophysics, Universidade Federal de São Paulo, São Paulo, Brazil.
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Bertolini A, Rigoldi M, Cianflone A, Mariani R, Piperno A, Canonico F, Cefalo G, Carubbi F, Simonati A, Urban ML, Beccari T, Parini R. Long-term outcome of a cohort of Italian patients affected with alpha-Mannosidosis. Clin Dysmorphol 2024; 33:1-8. [PMID: 37791705 PMCID: PMC10702697 DOI: 10.1097/mcd.0000000000000474] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 07/28/2023] [Indexed: 10/05/2023]
Abstract
Alpha-mannosidosis (MIM #248500) is an ultra-rare autosomal recessive lysosomal storage disease with multi-system involvement and a wide phenotypic spectrum. Information on long-term outcomes remains poor. We present the long-term outcomes (median, 19 years) of nine patients with alpha-mannosidosis, three females and six males, followed at a single center. The findings of the nine patients were collected from medical records and reported as mean ± SD or median, and range. The age of onset of the first symptoms ranged from 0-1 to 10 years. The diagnostic delay ranged from 2 to 22 years (median= 11 years). Coarse face, hearing, heart valves, joints, gait, language, dysarthria, psychiatric symptoms, I.Q., MRI, walking disabilities, orthopedic disturbances and surgeries showed a slow worsening over the decades. Our patients showed a slowly worsening progressive outcome over the decades. Psychiatric symptoms were present in 100% of our population and improved with the appropriate pharmacological intervention. This aspect requires attention when following up on these patients. Our description of the long-term evolution of alpha-mannosidosis patients may provide basic knowledge for understanding the effects of specific treatments.
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Affiliation(s)
- Anna Bertolini
- Rare Diseases Unit, Department of Medicine and Surgery, San Gerardo Hospital IRCCS, University of Milano-Bicocca, Monza, Italy
| | - Miriam Rigoldi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Bergamo, Italy
| | - Annalia Cianflone
- Rare Diseases Unit, Department of Medicine and Surgery, San Gerardo Hospital IRCCS, University of Milano-Bicocca, Monza, Italy
| | - Raffaella Mariani
- Rare Diseases Unit, Department of Medicine and Surgery, San Gerardo Hospital IRCCS, University of Milano-Bicocca, Monza, Italy
| | - Alberto Piperno
- Rare Diseases Unit, Department of Medicine and Surgery, San Gerardo Hospital IRCCS, University of Milano-Bicocca, Monza, Italy
| | - Francesco Canonico
- Department of Radiology, San Gerardo Hospital IRCCS, University of Milano-Bicocca, Monza, Italy
| | - Graziella Cefalo
- Clinical Department of Pediatrics, San Paolo Hospital, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy
| | - Francesca Carubbi
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, NOCSAE Hospital, AOU Modena, Modena, Italy
| | - Alessandro Simonati
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona School of Medicine, Verona, Italy
| | - Maria Letizia Urban
- Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy
| | - Tommaso Beccari
- Department of Pharmaceutical Sciences; University of Perugia, Perugia, Italy
| | - Rossella Parini
- Rare Diseases Unit, Department of Medicine and Surgery, San Gerardo Hospital IRCCS, University of Milano-Bicocca, Monza, Italy
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Vashakmadze ND, Zhurkova NV, Mikhaylova LK, Babaykina MA, Karaseva MS, Pashkova KV, Zakharova EY, Namazova-Baranova LS. Alfa-mannosidosis: Frequent Symptoms in Rare Patient. CURRENT PEDIATRICS 2023. [DOI: 10.15690/vsp.v21i6s.2498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Background. Alfa-mannosidosis is ultra-rare autosomal recessive lysosomal storage disease caused by the mutation in the MAN2B1 gene. Pathogenic nucleotide variants and structural changes in this gene lead to acid alpha-mannosidase deficiency, this enzyme is involved in oligosaccharides degradation. This disease is characterized by multisystem involvement and chronic progressive course. Clinical case description. The clinical case attracted our attention due to the late disease diagnosis in a boy living in a metropolis. The child has classic clinical manifestations of the disease: typical phenotype, spinal deformity, developmental speech and motor delays, hearing loss, hepatomegaly, splenomegaly, umbilical and inguinal hernias. Despite developmental speech delay and frequent recurrent otitis, the patient has not been referred to surdologist examination until the age of 4.5 years. Intriguing fact is the presence of congenital cataract that was the reason for surgery twice. Conclusion. Congenital cataract is one of the early manifestation of this disease. 3 out of 8 patients with alfa-mannosidosis observed in our centre had congenital cataract. We assume that such patients should be referred to genetics for the early exclusion of alpha-mannosidosis. Late diagnosis and progressive course of the disease led to early disability of the patient. Nowadays, as enzyme replacement therapy is available, it is crucial to identify these patients timely in order to improve their quality of life and increase survivability.
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Affiliation(s)
- Nato D. Vashakmadze
- Research Institute of Pediatrics and Children’s Health in Petrovsky National Research Centre of Surgery; Pirogov Russian National Research Medical University
| | - Natalia V. Zhurkova
- Research Institute of Pediatrics and Children’s Health in Petrovsky National Research Centre of Surgery; Research Centre for Medical Genetics
| | - Ludmila K. Mikhaylova
- Research Institute of Pediatrics and Children’s Health in Petrovsky National Research Centre of Surgery
| | - Marina A. Babaykina
- Research Institute of Pediatrics and Children’s Health in Petrovsky National Research Centre of Surgery
| | - Maria S. Karaseva
- Research Institute of Pediatrics and Children’s Health in Petrovsky National Research Centre of Surgery
| | - Kristina V. Pashkova
- Research Institute of Pediatrics and Children’s Health in Petrovsky National Research Centre of Surgery
| | | | - Leyla S. Namazova-Baranova
- Research Institute of Pediatrics and Children’s Health in Petrovsky National Research Centre of Surgery; Pirogov Russian National Research Medical University
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5
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Del Grosso A, Parlanti G, Mezzena R, Cecchini M. Current treatment options and novel nanotechnology-driven enzyme replacement strategies for lysosomal storage disorders. Adv Drug Deliv Rev 2022; 188:114464. [PMID: 35878795 DOI: 10.1016/j.addr.2022.114464] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 04/26/2022] [Accepted: 07/19/2022] [Indexed: 11/01/2022]
Abstract
Lysosomal storage disorders (LSDs) are a vast group of more than 50 clinically identified metabolic diseases. They are singly rare, but they affect collectively 1 on 5,000 live births. They result in most of the cases from an enzymatic defect within lysosomes, which causes the subsequent augmentation of unwanted substrates. This accumulation process leads to plenty of clinical signs, determined by the specific substrate and accumulation area. The majority of LSDs present a broad organ and tissue engagement. Brain, connective tissues, viscera and bones are usually afflicted. Among them, brain disease is markedly frequent (two-thirds of LSDs). The most clinically employed approach to treat LSDs is enzyme replacement therapy (ERT), which is practiced by administering systemically the missed or defective enzyme. It represents a healthful strategy for 11 LSDs at the moment, but it solves the pathology only in the case of Gaucher disease. This approach, in fact, is not efficacious in the case of LSDs that have an effect on the central nervous system (CNS) due to the existence of the blood-brain barrier (BBB). Additionally, ERT suffers from several other weak points, such as low penetration of the exogenously administered enzyme to poorly vascularized areas, the development of immunogenicity and infusion-associated reactions (IARs), and, last but not least, the very high cost and lifelong needed. To ameliorate these weaknesses lot of efforts have been recently spent around the development of innovative nanotechnology-driven ERT strategies. They may boost the power of ERT and minimize adverse reactions by loading enzymes into biodegradable nanomaterials. Enzyme encapsulation into biocompatible liposomes, micelles, and polymeric nanoparticles, for example, can protect enzymatic activity, eliminating immunologic reactions and premature enzyme degradation. It can also permit a controlled release of the payload, ameliorating pharmacokinetics and pharmacodynamics of the drug. Additionally, the potential to functionalize the surface of the nanocarrier with targeting agents (antibodies or peptides), could promote the passage through biological barriers. In this review we examined the clinically applied ERTs, highlighting limitations that do not allow to completely cure the specific LSD. Later, we critically consider the nanotechnology-based ERT strategies that have beenin-vitroand/orin-vivotested to improve ERT efficacy.
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Affiliation(s)
- Ambra Del Grosso
- NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy
| | - Gabriele Parlanti
- NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy
| | - Roberta Mezzena
- NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy
| | - Marco Cecchini
- NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy
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6
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Haslund-Gourley BS, Aziz PV, Heithoff DM, Restagno D, Fried JC, Ilse MB, Bäumges H, Mahan MJ, Lübke T, Marth JD. Establishment of blood glycosidase activities and their excursions in sepsis. PNAS NEXUS 2022; 1:pgac113. [PMID: 35967980 PMCID: PMC9364217 DOI: 10.1093/pnasnexus/pgac113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 07/05/2022] [Indexed: 02/05/2023]
Abstract
Glycosidases are hydrolytic enzymes studied principally in the context of intracellular catabolism within the lysosome. Therefore, glycosidase activities are classically measured in experimentally acidified assay conditions reflecting their low pH optima. However, glycosidases are also present in the bloodstream where they may retain sufficient activity to participate in the regulation of glycoprotein half-lives, proteostasis, and disease pathogenesis. We have, herein, established at physiological pH 7.4 in blood plasma and sera the normal ranges of four major glycosidase activities essential for blood glycoprotein remodeling in healthy mice and humans. These activities included β-galactosidase, β-N-acetylglucosaminidase, α-mannosidase, and α-fucosidase. We have identified their origins to include the mammalian genes Glb1, HexB, Man2a1, and Fuca1. In experimental sepsis, excursions of glycosidase activities occurred with differences in host responses to discrete bacterial pathogens. Among similar excursions in human sepsis, the elevation of β-galactosidase activity was a prognostic indicator of increased likelihood of patient death.
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Affiliation(s)
- Benjamin S Haslund-Gourley
- Sanford-Burnham-Prebys Medical Discovery Institute, Infectious and Inflammatory Diseases Center, La Jolla, CA 92037, USA
| | - Peter V Aziz
- Sanford-Burnham-Prebys Medical Discovery Institute, Infectious and Inflammatory Diseases Center, La Jolla, CA 92037, USA
| | - Douglas M Heithoff
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, CA 93106, USA
| | - Damien Restagno
- Sanford-Burnham-Prebys Medical Discovery Institute, Infectious and Inflammatory Diseases Center, La Jolla, CA 92037, USA
| | - Jeffrey C Fried
- Department of Pulmonary and Critical Care Medicine, Cottage Hospital of Santa Barbara, Santa Barbara, CA 93105, USA
| | - Mai-Britt Ilse
- Department of Chemistry, Biochemistry, Bielefeld University, D-33615, Germany
| | - Hannah Bäumges
- Department of Chemistry, Biochemistry, Bielefeld University, D-33615, Germany
| | - Michael J Mahan
- Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, CA 93106, USA
| | - Torben Lübke
- Department of Chemistry, Biochemistry, Bielefeld University, D-33615, Germany
| | - Jamey D Marth
- Sanford-Burnham-Prebys Medical Discovery Institute, Infectious and Inflammatory Diseases Center, La Jolla, CA 92037, USA
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7
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Marchetti M, Faggiano S, Mozzarelli A. Enzyme Replacement Therapy for Genetic Disorders Associated with Enzyme Deficiency. Curr Med Chem 2021; 29:489-525. [PMID: 34042028 DOI: 10.2174/0929867328666210526144654] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/23/2021] [Accepted: 03/17/2021] [Indexed: 11/22/2022]
Abstract
Mutations in human genes might lead to loss of functional proteins, causing diseases. Among these genetic disorders, a large class is associated with the deficiency in metabolic enzymes, resulting in both an increase in the concentration of substrates and a loss in the metabolites produced by the catalyzed reactions. The identification of therapeutic actions based on small molecules represents a challenge to medicinal chemists because the target is missing. Alternative approaches are biology-based, ranging from gene and stem cell therapy, CRISPR/Cas9 technology, distinct types of RNAs, and enzyme replacement therapy (ERT). This review will focus on the latter approach that since the 1990s has been successfully applied to cure many rare diseases, most of them being lysosomal storage diseases or metabolic diseases. So far, a dozen enzymes have been approved by FDA/EMA for lysosome storage disorders and only a few for metabolic diseases. Enzymes for replacement therapy are mainly produced in mammalian cells and some in plant cells and yeasts and are further processed to obtain active, highly bioavailable, less degradable products. Issues still under investigation for the increase in ERT efficacy are the optimization of enzymes interaction with cell membrane and internalization, the reduction in immunogenicity, and the overcoming of blood-brain barrier limitations when neuronal cells need to be targeted. Overall, ERT has demonstrated its efficacy and safety in the treatment of many genetic rare diseases, both saving newborn lives and improving patients' life quality, and represents a very successful example of targeted biologics.
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Affiliation(s)
- Marialaura Marchetti
- Biopharmanet-TEC Interdepartmental Center, University of Parma, Parco Area delle Scienze, Bldg 33., 43124, Parma, Italy
| | - Serena Faggiano
- Department of Food and Drug, University of Parma, Parco Area delle Scienze 23/A, 43124, Parma, Italy
| | - Andrea Mozzarelli
- Institute of Biophysics, National Research Council, Via Moruzzi 1, 56124, Pisa, Italy
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8
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Naumchik BM, Gupta A, Flanagan-Steet H, Steet RA, Cathey SS, Orchard PJ, Lund TC. The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases. Cells 2020; 9:cells9061411. [PMID: 32517081 PMCID: PMC7348849 DOI: 10.3390/cells9061411] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 06/02/2020] [Accepted: 06/02/2020] [Indexed: 12/12/2022] Open
Abstract
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
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Affiliation(s)
- Brianna M. Naumchik
- Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, MN 55455, USA; (B.M.N.); (A.G.); (P.J.O.)
| | - Ashish Gupta
- Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, MN 55455, USA; (B.M.N.); (A.G.); (P.J.O.)
| | | | - Richard A. Steet
- Greenwood Genetic Center, Greenwood, SC 29646, USA; (H.F.-S.); (R.A.S.); (S.S.C.)
| | - Sara S. Cathey
- Greenwood Genetic Center, Greenwood, SC 29646, USA; (H.F.-S.); (R.A.S.); (S.S.C.)
| | - Paul J. Orchard
- Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, MN 55455, USA; (B.M.N.); (A.G.); (P.J.O.)
| | - Troy C. Lund
- Division of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, MN 55455, USA; (B.M.N.); (A.G.); (P.J.O.)
- Correspondence: ; Tel.: +612-625-4185
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9
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Ilarslan NEÇ, Gunay F, Cobanoglu N, Karaman M, Eminoglu FT. Respiratory manifestations in inherited metabolic diseases: 6-year single-center experience. Pediatr Pulmonol 2019; 54:1190-1199. [PMID: 31115165 DOI: 10.1002/ppul.24359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 04/15/2019] [Accepted: 04/28/2019] [Indexed: 11/08/2022]
Abstract
OBJECTIVES We aimed to call attention to respiratory system manifestations which occur in the course of many inherited metabolic diseases (IMD), and present as the leading cause of death. MATERIALS AND METHODS We retrospectively reviewed the diagnosis, treatment, and outcome of patients evaluated at our hospital between June 2012 and June 2018 with a diagnosis of IMD and accompanying respiratory manifestations. RESULTS A total of 50 children (29 [58%] male, 21 [42%] female) with IMD and respiratory manifestations were defined. Disorders of intracellular metabolism (n = 33, 66%) formed the majority, followed by intoxication type metabolic disorders (n = 9, 18%) and energy metabolism disorders (n = 8, 16%). The most frequent respiratory symptoms were snoring (20, 40%), tachypnea (16, 32%) and wheezing (14, 28%). Physical examination findings were signs of respiratory distress (n = 28, 56%), crackles (n = 24, 48%), thoracic deformity (n = 23, 46%), decreased breath sounds (n = 17, 34%), rhonchus (n = 17, 34%), wheezing (n = 17, 34%) and stridor (n = 10, 20%). Major respiratory manifestations were chronic airway aspiration (n = 23, 46%), upper airway obstruction (n = 23, 46%), and recurrent pneumonia (n = 18, 36%). Twenty-three 23 patients (46%) experienced endotracheal intubation, 9 patients (18%) required whole-house mechanical ventilation and tonsilloadenoidectomy was performed in 7 patients (14%). Overall survival rate was 70% (n = 35) in a median follow-up period of 2.36 (0.05-5.86) years. CONCLUSIONS Respiratory system manifestations of IMD strongly relate with increased morbidity and mortality. Therefore, prompt diagnosis and correct intervention of respiratory complications with a multidisciplinary team including pediatric metabolic diseases specialists, pulmonologists, otorhinolaryngologists, physiotherapists, and anesthesiologists are crucial to prevent progression and irreversible damage.
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Affiliation(s)
| | - Fatih Gunay
- Department of Pediatrics, Cebeci Hospital, Ankara University School of Medicine, Ankara, Turkey
| | - Nazan Cobanoglu
- Department of Pediatric Pulmonology, Cebeci Hospital, Ankara University School of Medicine, Mamak, Ankara, Turkey
| | - Merve Karaman
- Department of Pediatrics, Cebeci Hospital, Ankara University School of Medicine, Ankara, Turkey
| | - Fatma Tuba Eminoglu
- Department of Pediatric Metabolism, Cebeci Hospital, Ankara University School of Medicine, Ankara, Turkey
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10
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Lehalle D, Colombo R, O'Grady M, Héron B, Houcinat N, Kuentz P, Moutton S, Sorlin A, Thevenon J, Delanne J, Gay S, Racine C, Garde A, Tran Mau-Them F, Philippe C, Vitobello A, Nambot S, Huet F, Duffourd Y, Feillet F, Thauvin-Robinet C, Marlin S, Faivre L. Hearing impairment as an early sign of alpha-mannosidosis in children with a mild phenotype: Report of seven new cases. Am J Med Genet A 2019; 179:1756-1763. [DOI: 10.1002/ajmg.a.61273] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 05/18/2019] [Accepted: 05/21/2019] [Indexed: 01/16/2023]
Affiliation(s)
- Daphné Lehalle
- Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du Développement’ de l'Interrégion Est; Hôpital d'Enfants, CHU; Dijon France
| | - Roberto Colombo
- Institute of Clinical Biochemistry, Faculty of Medicine; Catholic University, IRCCS Policlinico Agostino Gemelli; Rome Italy
- Center for the Study of Rare Inherited Diseases; Niguarda Ca' Granda Metropolitan Hospital; Milan Italy
| | - Michael O'Grady
- Department of Paediatrics; Midland Regional Hospital; Mullingar Western Australia Australia
| | - Bénédicte Héron
- Centre de référence des maladies lysosomales, Service de Neuropédiatrie; Hôpital Armand Trousseau- La Roche Guyon, APHP; Paris France
- GRC N°19, Université Paris-Sorbonne; Paris France
| | - Nada Houcinat
- Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du Développement’ de l'Interrégion Est; Hôpital d'Enfants, CHU; Dijon France
| | - Paul Kuentz
- FHU TRANSLAD, Centre Hospitalier Universitaire et Université de Bourgogne-Franche Comté; Dijon France
- Equipe GAD (Génétique des Anomalies du Développement), UMR INSERM 1231, Université de Bourgogne; Dijon France
| | - Sebastien Moutton
- Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du Développement’ de l'Interrégion Est; Hôpital d'Enfants, CHU; Dijon France
- Equipe GAD (Génétique des Anomalies du Développement), UMR INSERM 1231, Université de Bourgogne; Dijon France
| | - Arthur Sorlin
- Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du Développement’ de l'Interrégion Est; Hôpital d'Enfants, CHU; Dijon France
- Equipe GAD (Génétique des Anomalies du Développement), UMR INSERM 1231, Université de Bourgogne; Dijon France
| | - Julien Thevenon
- Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du Développement’ de l'Interrégion Est; Hôpital d'Enfants, CHU; Dijon France
- Equipe GAD (Génétique des Anomalies du Développement), UMR INSERM 1231, Université de Bourgogne; Dijon France
| | - Julian Delanne
- Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du Développement’ de l'Interrégion Est; Hôpital d'Enfants, CHU; Dijon France
| | - Sebastien Gay
- Pédiatrie, Centre Hospitalier; Chalon-sur-Saône France
| | - Caroline Racine
- Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du Développement’ de l'Interrégion Est; Hôpital d'Enfants, CHU; Dijon France
| | - Aurore Garde
- Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du Développement’ de l'Interrégion Est; Hôpital d'Enfants, CHU; Dijon France
| | - Frédéric Tran Mau-Them
- FHU TRANSLAD, Centre Hospitalier Universitaire et Université de Bourgogne-Franche Comté; Dijon France
- UF d'innovation en génétique moléculaire, Plateau technique de biologie, CHU; Dijon France
| | - Christophe Philippe
- FHU TRANSLAD, Centre Hospitalier Universitaire et Université de Bourgogne-Franche Comté; Dijon France
- Equipe GAD (Génétique des Anomalies du Développement), UMR INSERM 1231, Université de Bourgogne; Dijon France
- UF d'innovation en génétique moléculaire, Plateau technique de biologie, CHU; Dijon France
| | - Antonio Vitobello
- Equipe GAD (Génétique des Anomalies du Développement), UMR INSERM 1231, Université de Bourgogne; Dijon France
- UF d'innovation en génétique moléculaire, Plateau technique de biologie, CHU; Dijon France
| | - Sophie Nambot
- Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du Développement’ de l'Interrégion Est; Hôpital d'Enfants, CHU; Dijon France
- Equipe GAD (Génétique des Anomalies du Développement), UMR INSERM 1231, Université de Bourgogne; Dijon France
| | - Frédéric Huet
- Centre de compétence maladies métaboliques, Hôpital d'Enfants; Dijon France
| | - Yannis Duffourd
- FHU TRANSLAD, Centre Hospitalier Universitaire et Université de Bourgogne-Franche Comté; Dijon France
- Equipe GAD (Génétique des Anomalies du Développement), UMR INSERM 1231, Université de Bourgogne; Dijon France
| | - François Feillet
- Centre de référence Maladies Métaboliques, CHU Nancy; Nancy France
| | - Christel Thauvin-Robinet
- Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du Développement’ de l'Interrégion Est; Hôpital d'Enfants, CHU; Dijon France
- FHU TRANSLAD, Centre Hospitalier Universitaire et Université de Bourgogne-Franche Comté; Dijon France
- Equipe GAD (Génétique des Anomalies du Développement), UMR INSERM 1231, Université de Bourgogne; Dijon France
| | - Sandrine Marlin
- Centre de référence des Surdités Génétiques, Institut Imagine, Hôpital Necker Enfants Malades, APHP; Paris France
- INSERM UMR_S1163, IHU Imagine - Institut des Maladies Génétiques - Université Paris Descartes; Paris France
| | - Laurence Faivre
- Centre de Génétique et Centre de Référence Maladies Rares ‘Anomalies du Développement’ de l'Interrégion Est; Hôpital d'Enfants, CHU; Dijon France
- FHU TRANSLAD, Centre Hospitalier Universitaire et Université de Bourgogne-Franche Comté; Dijon France
- Equipe GAD (Génétique des Anomalies du Développement), UMR INSERM 1231, Université de Bourgogne; Dijon France
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Matlach J, Zindel T, Amraoui Y, Arash-Kaps L, Hennermann JB, Pitz S. Retinal and optic nerve degeneration in α-mannosidosis. Orphanet J Rare Dis 2018; 13:88. [PMID: 29859105 PMCID: PMC5984778 DOI: 10.1186/s13023-018-0829-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 05/21/2018] [Indexed: 01/17/2023] Open
Abstract
Background α-mannosidosis is a rare, autosomal-recessive, lysosomal storage disease caused by a deficient activity of α-mannosidase. Typical symptoms include intellectual, motor and hearing impairment, facial coarsening, and musculoskeletal abnormalities. Ocular pathologies reported previously were mainly opacities of the cornea and lens, strabismus, and ocular motility disorders. However, retinal and optic nerve degeneration have been rarely described. Methods We report ocular findings of 32 patients with α-mannosidosis. We particularly concentrated on retinal abnormalities which we supported by posterior segment examination, fundus photography, and Spectral-Domain optical coherence tomography (SD-OCT) imaging. Results Tapeto-retinal degeneration with bone spicule formations in the peripheral retina or macular changes were seen in three patients (9.4%) on funduscopy; of these, two with optic nerve atrophy. Eight retinal images could be obtained by OCT or fundus photography; of these, six showed thinning of the outer retinal layers on OCT. Overall, optic nerve atrophy was seen in six patients (18.8%); of these, four with partial atrophy. Two patients had partial optic nerve atrophy with no retinal abnormalities on funduscopy. Cataract was seen in two (6.3%), corneal haze also in two patients (6.3%). Six patients (18.8%) had manifest strabismus, four (12.5%) nystagmus, and in five patients (15.6%) impaired smooth pursuit eye movements were seen. Conclusion Ocular pathologies are not exclusively confined to opacities of the cornea and lens or strabismus and ocular motility disorders but tapeto-retinal degeneration and optic nerve atrophy may be a common feature in α-mannosidosis. OCT technology helps detecting early outer retinal thinning which can progress with age and potentially leads to vision loss over time.
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Affiliation(s)
- Juliane Matlach
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
| | - Thea Zindel
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Yasmina Amraoui
- Department of Pediatrics, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Laila Arash-Kaps
- Department of Pediatrics, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Julia B Hennermann
- Department of Pediatrics, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Susanne Pitz
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.,Orbital Center, Ophthalmic Clinic, Bürgerhospital, Frankfurt, Germany
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12
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Ceccarini MR, Codini M, Conte C, Patria F, Cataldi S, Bertelli M, Albi E, Beccari T. Alpha-Mannosidosis: Therapeutic Strategies. Int J Mol Sci 2018; 19:E1500. [PMID: 29772816 PMCID: PMC5983820 DOI: 10.3390/ijms19051500] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 05/04/2018] [Accepted: 05/15/2018] [Indexed: 01/16/2023] Open
Abstract
Alpha-mannosidosis (α-mannosidosis) is a rare lysosomal storage disorder with an autosomal recessive inheritance caused by mutations in the gene encoding for the lysosomal α-d-mannosidase. So far, 155 variants from 191 patients have been identified and in part characterized at the biochemical level. Similarly to other lysosomal storage diseases, there is no relationship between genotype and phenotype in alpha-mannosidosis. Enzyme replacement therapy is at the moment the most effective therapy for lysosomal storage disease, including alpha-mannosidosis. In this review, the genetic of alpha-mannosidosis has been described together with the results so far obtained by two different therapeutic strategies: bone marrow transplantation and enzyme replacement therapy. The primary indication to offer hematopoietic stem cell transplantation in patients affected by alpha-mannosidosis is preservation of neurocognitive function and prevention of early death. The results obtained from a Phase I⁻II study and a Phase III study provide evidence of the positive clinical effect of the recombinant enzyme on patients with alpha-mannosidosis.
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Affiliation(s)
- Maria Rachele Ceccarini
- Department of Pharmaceutical Sciences; University of Perugia, Via Fabretti 48, 06123 Perugia, Italy.
| | - Michela Codini
- Department of Pharmaceutical Sciences; University of Perugia, Via Fabretti 48, 06123 Perugia, Italy.
| | - Carmela Conte
- Department of Pharmaceutical Sciences; University of Perugia, Via Fabretti 48, 06123 Perugia, Italy.
| | - Federica Patria
- Department of Pharmaceutical Sciences; University of Perugia, Via Fabretti 48, 06123 Perugia, Italy.
| | - Samuela Cataldi
- Department of Pharmaceutical Sciences; University of Perugia, Via Fabretti 48, 06123 Perugia, Italy.
| | - Matteo Bertelli
- MAGI Human Medical Genetics Institute; laboratory of genetic diagnosis of rare diseases, 38068 Rovereto, Italy.
| | - Elisabetta Albi
- Department of Pharmaceutical Sciences; University of Perugia, Via Fabretti 48, 06123 Perugia, Italy.
| | - Tommaso Beccari
- Department of Pharmaceutical Sciences; University of Perugia, Via Fabretti 48, 06123 Perugia, Italy.
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13
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Catabolism of N-glycoproteins in mammalian cells: Molecular mechanisms and genetic disorders related to the processes. Mol Aspects Med 2016; 51:89-103. [DOI: 10.1016/j.mam.2016.05.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 05/11/2016] [Accepted: 05/24/2016] [Indexed: 11/17/2022]
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14
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Engin A, Gonul II, Engin AB, Karamercan A, Sepici Dincel A, Dursun A. Relationship between indoleamine 2,3-dioxygenase activity and lymphatic invasion propensity of colorectal carcinoma. World J Gastroenterol 2016; 22:3592-601. [PMID: 27053851 PMCID: PMC4814645 DOI: 10.3748/wjg.v22.i13.3592] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 01/31/2016] [Accepted: 03/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate whether serum and tumor indoleamine 2,3-dioxygenase activities can predict lymphatic invasion (LI) or lymph node metastasis in colorectal carcinoma. METHODS The study group consisted of 44 colorectal carcinoma patients. The patients were re-grouped according to the presence or absence of LI and lymph node metastasis. Forty-three cancer-free subjects without any metabolic disturbances were included into the control group. Serum neopterin was measured by enzyme linked immunosorbent assay. Urinary neopterin and biopterin, serum tryptophan (Trp) and kynurenine (Kyn) concentrations of all patients were determined by high performance liquid chromatography. Kyn/Trp was calculated and its correlation with serum neopterin was determined to estimate the serum indoleamine 2,3-dioxygenase activity. Tissue sections from the studied tumors were re-examined histopathologically and were stained by immunohistochemistry with indoleamine-2,3-dioxygenase antibodies. RESULTS Neither serum nor urinary neopterin was significantly different between the patient and control groups (both P > 0.05). However, colorectal carcinoma patients showed a significant positive correlation between the serum neopterin levels and Kyn/Trp (r = 0.450, P < 0.01). Urinary biopterin was significantly higher in cancer cases (P < 0.05). Serum Kyn/Trp was significantly higher in colorectal carcinoma patients (P < 0.01). Lymphatic invasion was present in 23 of 44 patients, of which only 12 patients had lymph node metastasis. Eleven patients with LI had no lymph node metastasis. Indoleamine-2,3-dioxygenase intensity score was significantly higher in LI positive cancer group (44.56% ± 6.11%) than negative colorectal cancer patients (24.04% ± 6.90%), (P < 0.05). Indoleamine 2,3-dioxygenase expression correlated both with the presence of LI and lymph node metastasis (P < 0.01 and P < 0.05, respectively). A significant difference between the accuracy of diagnosis by using either total indoleamine-2,3-dioxygenase immunostaining score or of lymph node metastasis was found during the evaluation of cancer patients. CONCLUSION Indoleamine-2,3-dioxygenase expression may predict the presence of unrecognized LI and lymph node metastasis and may be included in the histopathological evaluation of colorectal carcinoma cases.
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15
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Avenarius DFM, Svendsen JS, Malm D. Proton nuclear magnetic resonance spectroscopic detection of oligomannosidic n glycans in alpha-mannosidosis: a method of monitoring treatment. J Inherit Metab Dis 2011; 34:1023-7. [PMID: 21541723 PMCID: PMC3173639 DOI: 10.1007/s10545-011-9331-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2010] [Revised: 03/22/2011] [Accepted: 03/31/2011] [Indexed: 11/12/2022]
Abstract
In Alpha-mannosidosis (MIM 248500) the patients accumulate mainly unbranched oligosaccharide chains in the lysosomes in all body tissues, including the brain. With ensuing therapeutic modalities in man (BMT and ERT) non-invasive methods of monitoring the effect of treatment are needed. Paramount is the possible effect of the treatment on the brain, since this organ is regarded as difficult to reach because of the blood-brain barrier. We therefore performed proton nuclear magnetic resonance spectroscopy (MRS) of the brain in two untreated patients, and a 16-year-old patient treated with BMT at the age of 10 to assess whether this non-invasive method could be applied in the monitoring of the accumulation of abnormal chemicals in the brain of patients. We found an abnormal peak that was not present in the treated patient. A similar pattern was also found in MRS of urine from patients, reflecting the concentration of oligosaccharides in serum and tissues. We therefore conclude that MRS can be a useful method to monitor the effect of treatment for Alpha-Mannosidosis.
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16
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Desai AS, Dramis A, Board TN, Kay PR. Cemented total hip arthroplasty in a patient with alpha-mannosidosis: a case report. Hip Int 2009; 19:151-4. [PMID: 19462374 DOI: 10.1177/112070000901900213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Mannosidosis is an extremely rare genetic disease occurring due to deficiency of the lysosomal enzyme, alpha-mannosidase. Patients with this disorder often suffer from musculoskeletal abnormalities and muscular weakness leading to joint destruction and severe morbidity along with other major systems involvement. We present here such a case of a 27-year-old male that highlights the challenges in management of hip joint destruction secondary to Mannosidosis.
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17
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Zhou J, Lin CZ, Zheng XZ, Lin XJ, Sang WJ, Wang SH, Wang ZH, Ebbole D, Lu GD. Functional analysis of an α-1,2-mannosidase from Magnaporthe oryzae. Curr Genet 2009; 55:485-96. [DOI: 10.1007/s00294-009-0261-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2009] [Revised: 06/28/2009] [Accepted: 07/03/2009] [Indexed: 11/25/2022]
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Abstract
Alpha-mannosidosis is an inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual disability. It occurs in approximately 1 of 500,000 live births. The children are often born apparently normal, and their condition worsens progressively. Some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life), skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum), hearing impairment (moderate-to-severe sensorineural hearing loss), gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia. The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common. The clinical variability is significant, representing a continuum in severity. The disorder is caused by lysosomal alpha-mannosidase deficiency. Alpha-mannosidosis is inherited in an autosomal recessive fashion and is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12). Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic. Differential diagnoses are mainly the other lysosomal storage diseases like the mucopolysaccharidoses. Genetic counseling should be given to explain the nature of the disease and to detect carriers. Antenatal diagnosis is possible, based on both biochemical and genetic methods. The management should be pro-active, preventing complications and treating manifestations. Infections must be treated frequently. Otolaryngological treatment of fluid in the middle ear is often required and use of hearing aids is invariably required. Early educational intervention for development of social skills is needed and physiotherapy is important to improve bodily function. Orthopedic surgery may be necessary. The long-term prognosis is poor. There is an insidiously slow progression of neuromuscular and skeletal deterioration over several decades, making most patients wheel-chair dependent. No patients manage to be completely socially independent. Many patients are over 50 years of age.
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Faid V, Michalski JC, Morelle W. A mass spectrometric strategy for profiling glycoproteinoses, Pompe disease, and sialic acid storage diseases. Proteomics Clin Appl 2008; 2:528-42. [PMID: 21136856 DOI: 10.1002/prca.200780097] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2007] [Indexed: 11/07/2022]
Abstract
Glycoproteinoses, Pompe disease, and sialic acid storage diseases are characterized by a massive accumulation of unprocessed oligosaccharides and/or glycoconjugates in urine. The identification of these glycocompounds is essential for a proper diagnosis. In this study, we investigated the potential of MALDI-TOF-MS to identify glycocompounds present in urine from patients with different inborn errors of glycan metabolism. Urinary glycocompounds were permethylated, and analyzed using GC-MS and MALDI-TOF-MS. In order to confirm tentative assignments, a second aliquot of urine was purified on a C18 Sep-Pak cartridge and glycocompounds were desalted on a column of nonporous graphitized carbon. The glycocompounds were then sequentially on-plate digested using an array of exoglycosidases. A range of disease-specific oligosaccharides as well as glycopeptides was identified for all oligosacchariduria models. In addition, free sialic acid accumulated in urine from a patient suffering from French-type sialuria, has been detected by a GC-MS approach, which could be applied to other sialic acid storage diseases. This procedure is simple, and can be performed in few simple steps in less than 24 h. This current method can be applied for newborn screening for other inherited metabolic diseases as well as for assessing treatments in clinical trials.
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Affiliation(s)
- Valegh Faid
- Unité Mixte de Recherche CNRS/USTL 8576, Glycobiologie Structurale et Fonctionnelle, IFR 147, Université des Sciences et Technologies de Lille 1, Villeneuve d'Ascq, France
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20
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Conzelmann E, Sandhoff K. Glycolipid and glycoprotein degradation. ADVANCES IN ENZYMOLOGY AND RELATED AREAS OF MOLECULAR BIOLOGY 2006; 60:89-216. [PMID: 3310533 DOI: 10.1002/9780470123065.ch3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- E Conzelmann
- Institut für Organische Chemie und Biochemie, Universität Bonn, Federal Republic of Germany
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21
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Ries M, Moore DF, Robinson CJ, Tifft CJ, Rosenbaum KN, Brady RO, Schiffmann R, Krasnewich D. Quantitative dysmorphology assessment in Fabry disease. Genet Med 2006; 8:96-101. [PMID: 16481892 DOI: 10.1097/01.gim.0000200950.25118.dd] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
PURPOSE 1) To identify morphometric characteristics in hemizygous patients with Fabry disease a treatable lysosomal storage disorder caused by the deficiency of alpha-galactosidase A where morphological abnormalities have occasionally been mentioned, but have never been investigated systematically. 2) To devise a quantitative method to evaluate dysmorphic abnormalities in Fabry disease. METHOD Cross-sectional, single center, independent dysmorphology assessment by a panel of three clinical geneticists, based on standardized medical photography. POPULATION consecutive hemizygous patients with Fabry disease (N = 38) unselected for the features assessed, mean age 38 +/- 10.8 years (range: 10-60), recruited for neuropathic pain into enzyme replacement therapy trials. RESULTS The following dysmorphic features were identified (in order of descending frequency): periorbital fullness, prominent lobules of the ears, bushy eyebrows, recessed forehead, pronounced nasal angle, generous nose/bulbous nasal tip, prominent supraorbital ridges, shallow midface, full lips, prominent nasal bridge, broad alar base, coarse features, posteriorly rotated ears, and prognathism. Extremity features included broad fingertips, short fingers, prominent superficial vessels of hands, 5 digit brachydactyly, and 5 digit clinodactyly. Narrow anterior-posterior chest diameter was noted. Ten core features were statistically defined. Cronbach's alpha measuring internal consistency was 0.62. Light's kappa for global inter-rater variability was 0.26 while Cohen's kappa allowing pair-wise rater comparison varied between 0.08-0.48. CONCLUSIONS Patients with Fabry disease share common morphological characteristics of the face, trunk, and extremities. Some of these features are subtle as documented by the inter-rater variability. Awareness of these features may facilitate the diagnosis of patients with Fabry disease, and identification of affected family members.
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Affiliation(s)
- Markus Ries
- Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1260, USA
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22
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Springer C, Gutschalk A, Meinck HM, Rohrschneider K. Late-onset retinal dystrophy in α-mannosidosis. Graefes Arch Clin Exp Ophthalmol 2005; 243:1277-9. [PMID: 16075219 DOI: 10.1007/s00417-004-1084-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2004] [Accepted: 11/04/2004] [Indexed: 10/25/2022] Open
Abstract
alpha-Mannosidosis is a rare lysosomal storage disease that is caused by an inherited deficiency of the lysosomal alpha-mannosidase. Clinical symptoms include coarse facial features, skeletal involvement (dysostosis multiplex), hearing disabilities, mental retardation and hepatosplenomegaly. Only few cases with ocular symptoms have been reported, mainly with lenticular opacities. We report on two brothers with complex neurological symptoms who presented with late-onset retinal dystrophy and were followed up for 6 years.
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23
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Michalski JC, Klein A. Glycoprotein lysosomal storage disorders: alpha- and beta-mannosidosis, fucosidosis and alpha-N-acetylgalactosaminidase deficiency. BIOCHIMICA ET BIOPHYSICA ACTA 1999; 1455:69-84. [PMID: 10571005 DOI: 10.1016/s0925-4439(99)00077-0] [Citation(s) in RCA: 95] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Glycoproteinoses belong to the lysosomal storage disorders group. The common feature of these diseases is the deficiency of a lysosomal protein that is part of glycan catabolism. Most of the lysosomal enzymes involved in the hydrolysis of glycoprotein carbohydrate chains are exo-glycosidases, which stepwise remove terminal monosaccharides. Thus, the deficiency of a single enzyme causes the blockage of the entire pathway and induces a storage of incompletely degraded substances inside the lysosome. Different mutations may be observed in a single disease and in all cases account for the nonexpression of lysosomal glycosidase activity. Different clinical phenotypes generally characterize a specific disorder, which rather must be described as a continuum in severity, suggesting that other biochemical or environmental factors influence the course of the disease. This review provides details on clinical features, genotype-phenotype correlations, enzymology and biochemical storage of four human glycoprotein lysosomal storage disorders, respectively alpha- and beta-mannosidosis, fucosidosis and alpha-N-acetylgalactosaminidase deficiency. Moreover, several animal disorders of glycoprotein metabolism have been found and constitute valuable models for the understanding of their human counterparts.
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Affiliation(s)
- J C Michalski
- Laboratoire de Chimie Biologique, UMR 8576 CNRS (UMR 111 CNRS), Université des Sciences et Technologies de Lille, Villeneuve d'Ascq, France.
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Riise HM, Berg T, Nilssen O, Romeo G, Tollersrud OK, Ceccherini I. Genomic structure of the human lysosomal alpha-mannosidase gene (MANB). Genomics 1997; 42:200-7. [PMID: 9192839 DOI: 10.1006/geno.1997.4668] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Lysosomal alpha-mannosidase (LAMAN) (EC 3.2.1.24) is an exoglycosidase involved in the ordered degradation of N-linked oligosaccharides. Lack of LAMAN activity leads to the lysosomal storage disorder alpha-mannosidosis (MIM No. 248500). We determined the genomic organization of the human lysosomal alpha-mannosidase gene (laman; HGMW-approved symbol MANB) by using oligonucleotide primers designed from the human laman cDNA sequence as part of a PCR-based strategy. The gene spanned 21.5 kb and contained 24 exons. By primer extension analysis, the major transcription initiation sites were mapped to positions -309, -196, and -191 relative to the first in-frame ATG. No CAAT or TATA sequences could be identified within 134 bp upstream of the transcription initiation sites, but the 5' flanking region contained several GC-rich regions with putative binding sites for the transcription factors SP-1, AP-2, and ETF.
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Affiliation(s)
- H M Riise
- Department of Medical Biochemistry, Institute of Medical Biology, University of Tromsø, Norway.
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Chapter 1b Normal and pathological catabolism of glycoproteins. ACTA ACUST UNITED AC 1996. [DOI: 10.1016/s0167-7306(08)60279-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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Seow WK, Needleman HL, Smith LE, Holtzman D, Najjar S. Enamel hypoplasia, bilateral cataracts, and aqueductal stenosis: a new syndrome? AMERICAN JOURNAL OF MEDICAL GENETICS 1995; 58:371-3. [PMID: 8533849 DOI: 10.1002/ajmg.1320580414] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We report on a 12-year-old girl who presented with generalized enamel hypoplasia, cataracts, and enlargement of the cerebral ventricles secondary to aqueductal stenosis. Previously described syndromes of enamel defects with or without cataracts were excluded on the basis of clinical criteria and appearance of the dentition. Metabolic conditions which could have caused cataracts were excluded clinically and by biochemical tests. The combination of signs in this patient may represent a new syndrome.
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Affiliation(s)
- W K Seow
- Department of Pediatric Dentistry, Children's Hospital, Boston, Massachusetts, USA
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27
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Gaikwad SM, Keskar SS, Khan MI. Purification and characterization of alpha-D-mannosidase from Aspergillus sp. BIOCHIMICA ET BIOPHYSICA ACTA 1995; 1250:144-8. [PMID: 7632718 DOI: 10.1016/0167-4838(95)00082-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
alpha-D-Mannosidase from Aspergillus sp. was purified to homogeneity by preparative polyacrylamide gel electrophoresis (PAGE). The native enzyme of molecular mass 412 kDa (gel filtration) is made up of six identical subunits of molecular mass 69.2 kDa (SDS-PAGE) The enzyme is acidic (pI 4.5) and a glycoprotein with a carbohydrate content of 3.8%. The pH and temperature optima of the enzyme were in the range 6.0-6.5 and 50-55 degrees C, respectively. At pH 6.0 the enzyme was stable for 30 min at 50 degrees C. The Km and Vmax for p-nitrophenyl-alpha-D-mannopyranoside were 83 microM and 0.2 mumol/min per mg of the enzyme, respectively. The enzyme was strongly inhibited by 1 mM Hg2+ and Cu2+ and partially by 30 mM glucose and mannose. The enzyme hydrolysed Man-alpha-(1-3)Man at a very high rate followed by Man-alpha-(1-2)Man, while the rate of hydrolysis was low for Man-alpha-(1-6)Man. The rate of hydrolysis for high mannose oligosaccharide Man-6 was higher than for Man-9 and yeast mannan was not hydrolysed at all.
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Affiliation(s)
- S M Gaikwad
- Division of Biochemical Sciences, National Chemical Laboratory, Pune, India
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28
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Grabb PA, Albright AL, Zitelli BJ. Multiple suture synostosis, macrocephaly, and intracranial hypertension in a child with alpha-D-mannosidase deficiency. Case report. J Neurosurg 1995; 82:647-9. [PMID: 7897530 DOI: 10.3171/jns.1995.82.4.0647] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The authors present an unusual case in which increased intracranial pressure developed because of multiple-suture craniosynostosis and megaloencephaly in a child with a previously undiagnosed lysosomal storage disease, alpha-D-mannosidase deficiency. This 3-year-old boy presented with a history of frequent naps, headaches, florid papilledema, enlarged head (> 95th percentile), elevated opening pressure by lumbar puncture, a "beaten copper" appearance on skull radiographs, and no hydrocephalus. Multiple synostectomies were performed. Postoperatively, the child's headaches and papilledema resolved and his level of physical activity increased dramatically. The authors discuss the paradoxical presentation of prematurely fused sutures and macrocrania in light of this lysosomal storage disease and its subsequent management.
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Affiliation(s)
- P A Grabb
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pennsylvania
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29
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Ishigami T, Schmidt-Westhausen A, Philipsen HP, Baiborodin SI, Gelderblom H, Reichart PA. Oral manifestations of alpha-mannosidosis: report of a case with ultrastructural findings. J Oral Pathol Med 1995; 24:85-8. [PMID: 7745547 DOI: 10.1111/j.1600-0714.1995.tb01144.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Alpha-mannosidosis is a rare storage disease with distinct biochemical, clinical, histological and ultrastructural features. The oro-facial findings in a 26-year-old man are described. Gingival and oral mucosal hyperplasias were studied using histology and transmission electron microscopy (TEM). The TEM findings were comparable to those of other tissues examined in previous reports, consisting of histiocytic cells containing storage vacuoles with fine reticulo-granular material.
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Affiliation(s)
- T Ishigami
- First Department of Oral and Maxillofacial Surgery, Kagoshima, University Dental School, Japan
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30
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Bennet JK, Dembure PP, Elsas LJ. Clinical and biochemical analysis of two families with type I and type II mannosidosis. AMERICAN JOURNAL OF MEDICAL GENETICS 1995; 55:21-6. [PMID: 7702090 DOI: 10.1002/ajmg.1320550108] [Citation(s) in RCA: 28] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
We report on two unrelated patients with different presentations of mannosidosis. One patient was affected in early childhood with a severe phenotype characteristic of type I mannosidosis. The other was diagnosed with type II mannosidosis only after the onset of progressive neurologic deterioration in late adulthood. Both were detected by non-invasive urinary screening of oligosaccharides. Lymphoblasts transformed from both patients' blood cells had markedly reduced lysosomal alpha-mannosidase activity. Kinetic analyses showed that alpha-mannosidase from the type I patient had a 400-fold reduction in affinity while that from the type II patient was reduced 40-fold. Lymphoblasts from all 4 parents had reduced alpha-mannosidase activity, but there were overlapping activities among these type I and type II obligate heterozygotes. We conclude that screening urinary oligosaccharides will detect mannosidosis over a wide range of phenotypes, that lymphoblasts transformed from affected heterozygotes have decreased enzymatic activity, and that the severity of clinical expression is related to the degree of enzyme impairment.
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Affiliation(s)
- J K Bennet
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA
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31
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Keskar SS, Gaikwad SM, Khire JM, Khan MI. Production and properties of ∝-mannosidase from aspergillus sp. Biotechnol Lett 1993. [DOI: 10.1007/bf01080140] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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32
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Wong LT, Vallance H, Savage A, Davidson AG, Applegarth D. Oral zinc therapy in the treatment of alpha-mannosidosis. AMERICAN JOURNAL OF MEDICAL GENETICS 1993; 46:410-4. [PMID: 8357013 DOI: 10.1002/ajmg.1320460413] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Human alpha-mannosidosis is a lysosomal storage disorder characterized by mental retardation, dysostosis multiplex, and hepatosplenomegaly. Deficiency of the enzyme leads to accumulation of mannose-rich glycoconjugates in tissues. Zinc sulphate has been shown to stimulate alpha-mannosidase activity in vitro. Oral zinc therapy was attempted on a 4-year-old boy with alpha-mannosidosis for 3 years. After almost 10 years of follow-up on and off zinc therapy, we must conclude that oral zinc does not substantially affect the clinical course of alpha-mannosidosis.
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Affiliation(s)
- L T Wong
- Department of Pediatrics, B.C.'s Children's Hospital, Vancouver, Canada
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33
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Hård K, Mekking A, Kamerling JP, Dacremont GA, Vliegenthart JF. Different oligosaccharides accumulate in the brain and urine of a cat with alpha-mannosidosis: structure determination of five brain-derived and seventeen urinary oligosaccharides. Glycoconj J 1991; 8:17-28. [PMID: 1668528 DOI: 10.1007/bf00731639] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Five brain-derived and 17 urinary oligomannose-type oligosaccharides were isolated by ion-exchange chromatography on Mono Q or Dowex, followed by HPLC on Lichrosorb-NH2 from a Persian cat suffering from alpha-mannosidosis. The structures of the carbohydrate chains were determined by 500- or 600-MHz 1H-NMR spectroscopy. Different oligosaccharide patterns were found in brain and urine. 99% of the urinary oligosaccharides possess an alpha(1-6)-linked mannose residue attached to beta-mannose, whereas only 5% of the brain-derived oligosaccharides contain such a residue. Furthermore, of the urinary carbohydrate chains 71% end with Man beta 1-4GlcNAc beta 1-4GlcNAc and 29% end with Man beta 1-4GlcNAc, whereas the corresponding amounts are 23% and 77%, respectively, for the brain-derived oligosaccharides.
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Affiliation(s)
- K Hård
- Department of Bio-Organic Chemistry, Utrecht University, The Netherlands
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Dietemann JL, Filippi de la Palavesa MM, Tranchant C, Kastler B. MR findings in mannosidosis. Neuroradiology 1990; 32:485-7. [PMID: 2287376 DOI: 10.1007/bf02426460] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
MR findings are reported in three patients presenting mannosidosis. Among a family of 8 children, 4 presented typical clinical and biological abnormalities related to mannosidosis. Brain MR examinations including sagittal T1 and axial T2 sections were obtained in three patients of this family (one 25-year-old male, one 34-year-old female, and one 35-year-old female). MR scans demonstrate seven types of modifications: (1) brachycephaly, (2) thick calvaria, (3) verticalization of the chiasmatic sulcus, (4) poor pneumatization of the sphenoid body, (5) partial empty sella turcica (6) cerebellar atrophy, and (7) white matter signal modifications. High signal abnormalities involving the parieto-occipital white matter are identified on axial T2-weighted scans in the three patients and are probably related to demyelination and associated gliosis as described previously by several authors on specimens.
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Affiliation(s)
- J L Dietemann
- Service de Radiologie Médico-Chirurgicale B, Hôpital Central, Strasbourg, France
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35
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Abstract
The intracellular degradation of glycoproteins occurs predominantly in the lysosomes through the concerted action of proteases and glycosidases. Genetic defects in any of the enzymes cleaving the oligosaccharide side chains lead to specific diseases because of an excessive lysosomal accumulation of partially degraded material, mostly oligosaccharides. This paper presents an overview of the biochemistry and the clinical spectrum of this group of diseases including sialidosis, galactosialidosis, alpha- and beta-mannosidosis, fucosidosis, aspartylglucosaminuria, and alpha-N-acetylgalactosaminidase deficiency (Schindler disease). In addition, the sialic acid storage disorder (Salla disease) which is caused by a defect in the lysosomal transport of this acidic monosaccharide is included because of functional and clinical correlations.
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Affiliation(s)
- M Cantz
- Institute of Pathochemistry and General Neurochemistry, University of Heidelberg, FRG
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36
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Abstract
In addition to the already recognized metabolic diseases which have been associated with cataract formation, e.g. galactosaemia, galactokinase deficiency, Lowe's syndrome and diabetes, several other disorders can also lead to the development of cataracts. They are sorbitol dehydrogenase deficiency, uridine diphosphate galactose-4-epimerase deficiency, marginal maternal transferase and galactokinase deficiency, galactitol and sorbitol accumulation of unknown origin, heterozygosity for galactosaemia and galactokinase deficiency as well as the carrier state for Lowe's syndrome. In this review these metabolic disorders have been divided into five groups according to the age at the first appearance of lens clouding and the possible means of treatment have been discussed.
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Affiliation(s)
- W Endres
- Universitäts-Kinderklinik, München, FRG
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37
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Abstract
Clinical, pathological and biochemical findings in the mannosidoses are described. Family studies showed granulocyte-rich white cell fractions to be the tissue of choice for carrier detection in beta-mannosidosis. Metabolic labelling studies using [3H] mannose demonstrated accumulation of Man beta 1-4GlcNAc in cultured skin fibroblasts from a patient with this condition. Alternative methods of egress from lysosomes were suggested for this compound by its secretion into culture medium and apparent reduction of storage with time in cultures. beta-mannosidase deficient goats are not thought to be a true animal model of the human condition, as although they showed a similar enzyme deficiency, the clinical presentation is much more severe and the major storage material (Man beta 1-4GlcNAc beta 1-4GlcNAc) is different.
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Affiliation(s)
- A Cooper
- Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Pendlebury, UK
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38
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Kawai H, Yoneda K, Takeda M, Nishida Y, Nishino H, Masuda K, Saito S. Isozyme pattern of leukocyte alpha-D-mannosidase in patients with mannosidosis. JINRUI IDENGAKU ZASSHI. THE JAPANESE JOURNAL OF HUMAN GENETICS 1988; 33:1-7. [PMID: 3392840 DOI: 10.1007/bf01891236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Will A, Cooper A, Hatton C, Sardharwalla IB, Evans DI, Stevens RF. Bone marrow transplantation in the treatment of alpha-mannosidosis. Arch Dis Child 1987; 62:1044-9. [PMID: 3314721 PMCID: PMC1778651 DOI: 10.1136/adc.62.10.1044] [Citation(s) in RCA: 30] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Bone marrow transplantation was performed in a patient with alpha-mannosidosis. To our knowledge this is the first time such treatment has been attempted. The patient died 18 weeks after successful grafting and specimens of tissues were obtained at necropsy. Alpha-mannosidase activity in spleen and liver was just below normal (spleen 102 mumol/g/hour, control 113-330; liver 29 mumol/g/hour, control 30-131). Splenic alpha-mannosidase activity was indistinguishable from the control enzyme with respect to the Michaelis constant, heat stability, and inhibition by cobalt ions, as was 86% of the liver enzyme. In brain tissue alpha-mannosidase activity was 7% of controls, and less than one third had the properties of the normal enzyme. Oligosaccharides were present only in small amounts in liver and spleen, whereas they were greatly increased in brain tissue. Electron microscopic pictures of liver and spleen tissue showed normal morphology, but brain tissue showed definite vacuolation. These findings suggest that transplantation reversed the somatic changes of alpha-mannosidosis but did not affect lysosomal storage within brain tissue. It is concluded that marrow transplantation may not be a suitable treatment for alpha-mannosidosis.
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Affiliation(s)
- A Will
- Department of Haematology, Royal Manchester Children's Hospital
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40
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Jansen PH, Schoonderwaldt HC, Renier WO, Wevers RA, Gabreëls FJ. Mannosidosis: a study of two patients, presenting clinical heterogeneity. Clin Neurol Neurosurg 1987; 89:185-92. [PMID: 3665292 DOI: 10.1016/s0303-8467(87)80053-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Two unrelated patients suffering from mannosidosis, aged 9 and 33 years, are reported, presenting two extremes in the phenotypic expression of this lysosomal storage disorder. Clinical, radiological, biochemical and therapeutical aspects of the disease are discussed. Our patients support the concept that mannosidosis is not a homogeneous syndrome but manifests wide clinical heterogeneity.
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Affiliation(s)
- P H Jansen
- Institute of Child Neurology, St. Radboud Hospital, Catholic University of Nijmegen, The Netherlands
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41
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42
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Abstract
Mannosidosis was diagnosed in four stillborn Galloway calves and an autolyzed full-term fetus from experimental matings of carrier animals. Gross lesions were moderate internal hydrocephalus, and pallor and enlargement of the liver and kidneys and arthrogryposis. Histologic changes in the central nervous system of each calf were marked foamy vacuolation of the cytoplasm of neurones in the cerebral cortex, thalamus and brainstem, and vacuolation of the Purkinje cells of the cerebellum. Spheroids were common throughout the brain and there was also consistent severe foamy cytoplasmic vacuolation of renal tubular epithelial cells and hepatocytes. The activities of alpha-mannosidase, the lysosomal enzyme whose activity is deficient in mannosidosis, and activities of five other lysosomal enzymes were compared in brain, liver, and kidney tissues of three mannosidosis-affected calves and normal calf tissues. Tissues from the affected calves had a marked deficiency of alpha-mannosidase activity compared with the normal tissues; the greatest deficiency was in the liver (99%) and brain (98%). Activities of the other lysosomal enzymes were elevated in the affected tissues compared with normal. Mannosidosis is a lysosomal storage disease that results from a defect in glycoprotein metabolism and affects man, Angus and Angus-related breeds of cattle, such as Murray greys, and the cat. The congenital disease is caused by an inherited deficiency of the lysosomal enzyme alpha-mannosidase, and is inherited in an autosomal recessive manner. Mannosidosis was recently reported in a number of aborted and stillborn Australian Galloway calves from an experimental breeding trial. This is more detailed account of the histological and biochemical results obtained during the trial.
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43
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Coles E, Reinhold VN, Carr SA. Fluorescent labeling of carbohydrates and analysis by liquid chromatography. Comparison of derivatives using mannosidosis oligosaccharides. Carbohydr Res 1985; 139:1-11. [PMID: 4040810 DOI: 10.1016/0008-6215(85)90001-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
To enhance resolution and detectability of carbohydrates by liquid chromatography, two fluorescent labels, introduced into oligosaccharides by reductive amination, were compared by use of standard sugars and a complex, biological sample of D-mannose oligomers obtained from the urine of a mannosidosis patient. Both labels, 2-aminopyridine and 7-amino-1-naphthol, improved the chromatographic efficiency and detection sensitivity. However, reductive amination with the pyridinylamine derivative was incomplete. The Schiff-base intermediates left in the mixtures were only partially resolved by chromatography and complicate the patterns. In contrast, the naphtholamine derivatives were completely reduced and, in addition, possess enhanced fluorescence.
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44
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Kawai H, Nishino H, Nishida Y, Yoneda K, Yoshida Y, Inui T, Masuda K, Saito S. Skeletal muscle pathology of mannosidosis in two siblings with spastic paraplegia. Acta Neuropathol 1985; 68:201-4. [PMID: 4082921 DOI: 10.1007/bf00690195] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Deficiency of alpha-D-mannosidase was found in two siblings with muscle weakness and spastic paraplegia. A biopsy of the vastus lateralis muscle was studied by light and electron microscopy. Cryostat sections showed mild fiber size variation but no necrosis. Semithin Epon sections revealed many vacuoles in the muscle cells and fibroblasts. Electron microscopy showed that the vacuoles, presumably lysosomal, had a single limiting membrane and contained finely granular or granulo-reticular material, membranous structures, and electron-dense ovoids. The vacuoles were identical with those in lymphocytes and other cells of patients with mannosidosis. Disorganization of sarcomere alignment and widening of intermyofibrillar spaces were also observed. Deficiency of alpha-D-mannosidase is considered to cause slowly progressing degeneration of muscle fibers.
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Jardine I, Matsuura F, Sweeley CC. Electron ionization mass spectra of reduced and permethylated urinary oligosaccharides from patients with mannosidosis. BIOMEDICAL MASS SPECTROMETRY 1984; 11:562-8. [PMID: 6525412 DOI: 10.1002/bms.1200111104] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The electron ionization mass spectra of reduced and permethylated isomeric mixtures of the major urinary tri- to deca-oligosaccharides of patients with mannosidosis are reported. Many of the oligosaccharide isomers can be differentiated in the mixtures on the basis of their distinct fragmentation patterns.
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46
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Warner TG, Mock AK, Nyhan WL, O'Brien JS. Alpha-mannosidosis: analysis of urinary oligosaccharides with high performance liquid chromatography and diagnosis of a case with unusually mild presentation. Clin Genet 1984; 25:248-55. [PMID: 6705257 DOI: 10.1111/j.1399-0004.1984.tb01985.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Mannose containing oligosaccharides (OS) excreted in the urine of patients with alpha-mannosidosis have been analyzed with high performance liquid chromatography (HPLC). The HPLC method provides a highly sensitive assay for detection of the urinary oligosaccharides and was employed for diagnosis of a fifteen-year-old female with an unusually mild presentation of the disease. Dysostosis multiplex and coarse facies were absent; mental impairment was particularly mild. The elution profile of the urinary OS from this patient and two, more severely affected, patients with mannosidosis were nearly identical, containing nine major OS fractions. The concentrations of the OS were eight fold lower in our patient but, when calculated relative to creatinine, the levels of the urinary OS of all patients were similar.
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47
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Pohlmann R, Hasilik A, Cheng S, Pemble S, Winchester B, von Figura K. Synthesis of lysosomal alpha-mannosidase in normal and mannosidosis fibroblasts. Biochem Biophys Res Commun 1983; 115:1083-9. [PMID: 6626219 DOI: 10.1016/s0006-291x(83)80046-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The biosynthesis and secretion of lysosomal alpha-mannosidase was studied in metabolically labelled fibroblasts from controls and two patients with mannosidosis. Normal fibroblasts secrete alpha-mannosidase as a 110kDa polypeptide. Intracellularly alpha-mannosidase is represented by several polypeptides with apparent Mrs ranging from 40 to 67kDa. In two mannosidosis cell lines none of intra- and extracellular polypeptides of alpha-mannosidase were detectable. The mannosidosis fibroblasts secreted acid alpha-mannosidase activity at one third of the normal rate. In contrast to normal cells the secretion was not enhanced by NH4C1 and the secreted activity was not immunoprecipitable, indicating that the acid alpha-mannosidase activity secreted by mannosidosis fibroblasts is not related to the lysosomal alpha-mannosidase.
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48
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Abstract
The genetics of hemolymph alpha-mannosidase was investigated in the silkworm, Bombyx mori. By selecting individuals showing either high or low enzyme activities, homozygotes were separated, with activities varying about five-fold. No differences in the activities of beta-galactosidase and beta-N-acetylglucosaminidase were observed. Thus, it seems that high- and low-enzyme silkworms (High and Low Lines) share the same genetic background except for the gene concerning the activity of alpha-mannosidase. The synthesis of the enzyme is controlled by an autosomal allele. Furthermore, expression of the gene varies from tissue to tissue, and there is no correlation between enzyme activity and growth rate. The difference in activity between High and Low lines is due to the amount of active enzyme, not to an endogeneous activator or inhibitor. There was no isozymic difference in alpha-mannosidase.
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49
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Abstract
The first linkage of disease traits on the human X-chromosome was reported in 1937, and the first assignment of a human disease to an autosome was made 26 years later in 1963. Now, after only 19 years, there are at least 338 assignments to loci on the human chromosome map. This amazing expansion of information extends to eye diseases. In this review, basic mechanisms of mutation are discussed, and the basic methodologies used for gene assignments are explained. All of the eye-related, definite, autosomal assignments are presented. The diseases that have regional assignments on the X-chromosome are discussed, and the remaining X-linked eye diseases are listed in table form.
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50
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Patton MA, Barnes IC, Young ID, Harper PS, Pennock CA. Mannosidosis in two brothers: prolonged survival in the severe phenotype. Clin Genet 1982; 22:284-9. [PMID: 7151314 DOI: 10.1111/j.1399-0004.1982.tb01447.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Two cases of mannosidosis are reported in brothers, one aged 41 years at death, the other aged 40 years and still alive. These patients are the oldest reported in the literature. Prolonged survival has previously been associated with the milder Type II phenotype. In addition to the characteristic clinical and radiological features of mannosidosis, both had severe joint destruction, which may be related to abnormal lysosomal enzymes in cartilage. The activity of acidic alpha-mannosidase was markedly reduced in plasma, leucocytes and fibroblasts, and the altered kinetic and physical properties are described.
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