231 results on '"alpha-Mannosidosis"'
Search Results
2. Mortality in patients with alpha-mannosidosis: a review of patients’ data and the literature
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Julia B. Hennermann, Eva M. Raebel, Francesca Donà, Marie-Line Jacquemont, Graziella Cefalo, Andrea Ballabeni, and Dag Malm
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MAN2B1 ,Alpha-mannosidosis ,Mortality ,Cause of death ,Natural history ,Medicine - Abstract
Abstract Background Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder (LSD) caused by reduced activity of alpha-mannosidase. Clinical manifestations include skeletal dysmorphism, mental impairment, hearing loss and recurrent infections. The severe type of the disease leads to early childhood death, while patients with milder forms can live into adulthood. There are no mortality studies to date. This study aimed to investigate the age at death and the causes of death of patients with alpha-mannosidosis who had not received disease-modifying treatment. Methods Clinicians and LSD patient organisations (POs) from 33 countries were invited to complete a questionnaire between April–May 2021. Cause of death and age at death was available for 15 patients. A literature review identified seven deceased patients that met the inclusion criteria. Results Median age at death for patients reported by clinicians/POs was 45 years (mean 40.3 ± 13.2, range 18–56, n = 15); 53% were female. One death occurred during the patient’s second decade of life, and 14 out of 15 deaths (93.3%) during or after the patients’ third decade, including four (26.7%) during their sixth decade. Median age at death for patients identified from the literature was 4.3 years (mean 15.7 ± 17.0, range 2.2–41, n = 7); two were female. Four of the seven patients (57.1%) died within the first decade of life. Seven of 15 deaths (46.7%) reported by clinicians/POs were recorded as pneumonia and three (20.0%) as cancer. Other causes of death included acute renal failure due to sepsis after intestinal perforation, decrease of red blood cells of unknown origin, kidney failure with systemic lupus erythematosus, aortic valve insufficiency leading to heart failure, and dehydration due to catatonia. Three out of seven causes of death (42.9%) reported in the literature were associated with septicaemia, two (28.6%) with respiratory failure and one to pneumonia following aspiration. Conclusions This study suggests that pneumonia has been the primary cause of death during recent decades in untreated patients with alpha-mannosidosis, followed by cancer. Determining the causes of mortality and life expectancy in these patients is crucial to further improve our understanding of the natural history of alpha-mannosidosis.
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- 2022
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3. The SPARKLE registry: protocol for an international prospective cohort study in patients with alpha-mannosidosis
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Julia B. Hennermann, Nathalie Guffon, Federica Cattaneo, Ferdinando Ceravolo, Line Borgwardt, Allan M. Lund, Mercedes Gil-Campos, Anna Tylki-Szymanska, and Nicole M. Muschol
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Alpha-mannosidosis ,Recombinant alpha-mannosidase ,Velmanase alfa ,Patient registry ,Enzyme-replacement therapy ,Medicine - Abstract
Abstract Background Alpha-mannosidosis is a lysosomal storage disorder caused by reduced enzymatic activity of alpha-mannosidase. SPARKLE is an alpha-mannosidosis registry intended to obtain long-term safety and effectiveness data on the use of velmanase alfa during routine clinical care in patients with alpha-mannosidosis. It is a post-approval commitment to European marketing authorization for Velmanase alfa (Lamzede®), the first enzyme replacement therapy for the treatment of non-neurologic manifestations in patients with mild to moderate alpha-mannosidosis. In addition, SPARKLE will expand the current understanding of alpha-mannosidosis by collecting data on the clinical manifestations, progression, and natural history of the disease in treated and untreated patients, respectively. Results The SPARKLE registry is designed as a multicenter, multinational, noninterventional, prospective cohort study of patients with alpha-mannosidosis, starting patient enrollment in 2020. Patients will be followed for up to 15 years. Safety and effectiveness as post-authorization outcomes under routine clinical care in patients with treatment will be evaluated. The primary safety outcomes are the rate of adverse events (anti-velmanase alfa-immunoglobulin G antibody development, infusion-related reactions, and hypersensitivity). Secondary safety outcomes include the evaluation of medical events, change in vital signs, laboratory tests, physical examination, and electrocardiogram results. The primary effectiveness outcome is a global treatment response rate, evaluated as the individual aggregate of single endpoints from pharmacodynamic, functional, and quality-of-life effectiveness outcomes; secondary effectiveness outcomes are to characterize the population of patients with alpha-mannosidosis with regard to clinical manifestation, progression, and natural history of the disease. Any patient in the European Union with a diagnosis of alpha-mannosidosis who is willing to participate will likely be eligible for inclusion in the registry. Publications to disseminate scientific insights from the registry are planned. Conclusion This study will provide real-world data on the long-term safety and effectiveness of velmanase alfa in patients with alpha-mannosidosis during routine clinical care and increase the understanding of the natural course, clinical manifestations, and progression of this ultra-rare disease.
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- 2020
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4. White matter alteration and cerebellar atrophy are hallmarks of brain MRI in alpha-mannosidosis
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Petr Dusek, Troy C. Lund, Paul J. Orchard, Katarina Jurickova, Jitka Majovska, Manuela Vaneckova, David Nascene, Martin Magner, Anna Hlavatá, Amy Paulson, Jiri Zeman, and Igor Nestrasil
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Adult ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Neuroimaging ,030105 genetics & heredity ,Nervous System Malformations ,Corpus callosum ,Cisterna magna ,Biochemistry ,White matter ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Cerebellum ,Basal ganglia ,Genetics ,medicine ,Humans ,Perivascular space ,Child ,Molecular Biology ,business.industry ,Brain ,Infant ,medicine.disease ,Magnetic Resonance Imaging ,White Matter ,Hypoplasia ,medicine.anatomical_structure ,Child, Preschool ,alpha-Mannosidosis ,Female ,Cerebellar atrophy ,Atrophy ,business ,030217 neurology & neurosurgery - Abstract
Objective Despite profound neurological symptomatology there are only few MRI studies focused on the brain abnormalities in alpha-mannosidosis (AM). Our aim was to characterize brain MRI findings in a large cohort of AM patients along with clinical manifestations. Methods Twenty-two brain MRIs acquired in 13 untreated AM patients (8 M/5F; median age 17 years) were independently assessed by three experienced readers and compared to 16 controls. Results Focal and/or diffuse hyperintense signals in the cerebral white matter were present in most (85%) patients. Cerebellar atrophy was common (62%), present from the age of 5 years. Progression was observed in two out of 6 patients with follow-up scans. Cortical atrophy (62%) and corpus callosum thinning (23%) were already present in a 13-month-old child. The presence of low T2 signal intensity in basal ganglia and thalami was excluded by the normalized signal intensity profiling. The enlargement of perivascular spaces in white matter (38%), widening of perioptic CSF spaces (62%), and enlargement of cisterna magna (85%) were also observed. Diploic space thickening (100%), mucosal thickening (69%) and sinus hypoplasia (54%) were the most frequent non-CNS abnormalities. Conclusion White matter changes and cerebellar atrophy are proposed to be the characteristic brain MRI features of AM. The previously reported decreased T2 signal intensity in basal ganglia and thalami was not detected in this quantitative study. Rather, this relative MR appearance seems to be related to the diffuse high T2 signal in the adjacent white matter and not the gray matter iron deposition that has been hypothesized.
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- 2021
5. Case report of a novel homozygous variant in a Saudi patient with alpha mannosidosis
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Omhani Malibari and Rehab Al Jawad
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Pediatrics ,medicine.medical_specialty ,business.industry ,Mucopolysaccharidosis ,Alpha-mannosidosis ,Urinary system ,medicine.disease ,Short stature ,Umbilical hernia ,Cataracts ,OMIM : Online Mendelian Inheritance in Man ,Medicine ,Global developmental delay ,medicine.symptom ,business - Abstract
Background: Alpha-mannosidosis [Online Mendelian Inheritance in Man (OMIM): 248500] is an autosomal recessive disorder due to a deficiency of the lysosomal enzyme alpha-mannosidase. It is an ultra-orphan disease. In this paper, we report a case of alpha-mannosidosis in a Saudi boy of consanguineous parents, who was referred to our hospital to be worked up for possible mucopolysaccharidosis. Case Presentation: The patient was presented with dysmorphic features, global developmental delay, hearing defect, and recurrent respiratory tract infections. On examination, he had short stature, a short neck, cataracts, hearing impairment, chest deformity, hepatomegaly, umbilical hernia, right inguinal hernia, and two Mongolian spots in the back. He had normal peripheral blood smear: urinary oligosaccharide and dry blood spot for mucopolysaccharide enzyme assay founded to be negative. Definitive diagnosis was performed by directly sequencing the MAN2B1 gene of the peripheral blood leukocytes. It showed a homozygous variant c.1065delC; p.Ala356fs*7 (NM_001173498.1) as likely pathogenic. Conclusion: We report a novel variant mutation in MAN2B1 gene mutation. Also, to the best of authors' knowledge, this is the first reported case of alpha-mannosidosis in a Saudi patient.
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- 2021
6. Alpha-mannosidosis in children: analysis of the observations and treatment options
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A. N. Semyachkina, E. A. Nikolaeva, E. Yu. Voskoboeva, M. A. Dantseva, and E. Yu. Zakharova
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Proband ,medicine.medical_specialty ,clinical manifestations ,business.industry ,Genetic counseling ,Alpha-mannosidosis ,man2b1 gene ,Low activity ,velmanase alpha ,Disease ,Enzyme replacement therapy ,medicine.disease ,rare (orphan) diseases ,Pediatrics ,Peripheral blood ,RJ1-570 ,children ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,alpha-mannosidosis ,Hurler syndrome ,business ,lysosomal storage diseases ,enzyme replacement therapy - Abstract
The article is devoted to a rare (orphan) disease from the group of lysosomal storage diseases — alpha-mannosidosis, associated with the accumulation of mannose-containing oligosaccharides in the tissues and cells of the body. The authors analyze the literature data and proposals of the International working group for the diagnosis of alpha-mannosidosis. The article presents the examination results of 15 patients with alpha-mannosidosis aged from 1 to 12 years. The diagnosis was based on the combination of phenotypic traits and extremely low activity of the lysosomal enzyme of alpha-mannosidase in peripheral blood lymphocytes. The molecular genetic verification of the diagnosis was performed in 14 probands. The authors found that all the patients under observation had a typical Hurler-like phenotype, lighter than patients with Hurler syndrome. The children were divided into 2 groups according to the severity of the disease: severe (1 child) and moderate (14 children) forms. The disease had a progressive course. The enzyme replacement therapy with velmanase alpha (recombinant human alpha-mannosidase), developed and registered in the European countries, is not used in Russia due to the absence of registration. Early diagnosis and early start of enzyme replacement therapy is the best way to limit the progression of the disease, and effective genetic counseling helps to prevent it.
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- 2020
7. Global CNS correction in a large brain model of human alpha-mannosidosis by intravascular gene therapy
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Manoj Kumar, Dana L. Clarke, Charles H. Vite, Caitlyn Molony, Patricia O'Donnell, Sanjeev Chawla, Harish Poptani, John H. Wolfe, Sea Young Yoon, Jessica H. Bagel, and Jacqueline E Hunter
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0301 basic medicine ,Reporter gene ,Pathology ,medicine.medical_specialty ,business.industry ,Alpha-mannosidosis ,Genetic enhancement ,Original Articles ,medicine.disease_cause ,medicine.disease ,Viral vector ,White matter ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Cerebral cortex ,medicine ,Lysosomal storage disease ,Neurology (clinical) ,business ,Adeno-associated virus ,030217 neurology & neurosurgery - Abstract
Intravascular injection of certain adeno-associated virus vector serotypes can cross the blood–brain barrier to deliver a gene into the CNS. However, gene distribution has been much more limited within the brains of large animals compared to rodents, rendering this approach suboptimal for treatment of the global brain lesions present in most human neurogenetic diseases. The most commonly used serotype in animal and human studies is 9, which also has the property of being transported via axonal pathways to distal neurons. A small number of other serotypes share this property, three of which were tested intravenously in mice compared to 9. Serotype hu.11 transduced fewer cells in the brain than 9, rh8 was similar to 9, but hu.32 mediated substantially greater transduction than the others throughout the mouse brain. To evaluate the potential for therapeutic application of the hu.32 serotype in a gyrencephalic brain of larger mammals, a hu.32 vector expressing the green fluorescent protein reporter gene was evaluated in the cat. Transduction was widely distributed in the cat brain, including in the cerebral cortex, an important target since mental retardation is an important component of many of the human neurogenetic diseases. The therapeutic potential of a hu.32 serotype vector was evaluated in the cat homologue of the human lysosomal storage disease alpha-mannosidosis, which has globally distributed lysosomal storage lesions in the brain. Treated alpha-mannosidosis cats had reduced severity of neurological signs and extended life spans compared to untreated cats. The extent of therapy was dose dependent and intra-arterial injection was more effective than intravenous delivery. Pre-mortem, non-invasive magnetic resonance spectroscopy and diffusion tensor imaging detected differences between the low and high doses, and showed normalization of grey and white matter imaging parameters at the higher dose. The imaging analysis was corroborated by post-mortem histological analysis, which showed reversal of histopathology throughout the brain with the high dose, intra-arterial treatment. The hu.32 serotype would appear to provide a significant advantage for effective treatment of the gyrencephalic brain by systemic adeno-associated virus delivery in human neurological diseases with widespread brain lesions.
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- 2020
8. Early biochemical effects of velmanase alfa in a 7‐month‐old infant with alpha‐mannosidosis
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Lucia Padella, Andrea Dardis, Rosanna Cordiali, Lucia Zampini, Lucia Santoro, Stefania Zampieri, Chiara Monachesi, Tiziana Galeazzi, and Carlo Catassi
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medicine.medical_specialty ,lcsh:QH426-470 ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,medicine.medical_treatment ,Alpha (ethology) ,Case Report ,Hematopoietic stem cell transplantation ,Normal values ,Urine ,Case Reports ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Gastroenterology ,alpha mannosidosis ,oligosaccharides ,Internal medicine ,Internal Medicine ,medicine ,chemistry.chemical_classification ,liquid chromatography coupled with tandem mass spectrometry ,lcsh:RC648-665 ,Hematopoietic cell transplantation ,business.industry ,Velmanase alfa ,thin layer chromatography ,Enzyme replacement therapy ,medicine.disease ,lcsh:Genetics ,Enzyme ,chemistry ,business ,enzyme replacement therapy - Abstract
Alpha mannosidosis is an ultrarare pathology with variable phenotypic manifestations, characterized by the deficiency of lysosomal alpha mannosidase which causes accumulation of neutral oligosaccharides. Until recently, the hematopoietic stem cell transplantation was the only clinical feasible therapeutic option. Only in 2018, the European Medicines Agency's committee approved the recombinant enzyme velmanase alfa for long‐term treatment of non‐neurological manifestations in mild and moderate forms of alpha‐mannosidosis. In this study, the very early biochemical effects of enzyme replacement therapy in in a 7‐month‐old patient with alpha‐mannosidosis were described. Velmanase alpha was administered as supporting therapy awaiting for hematopoietic stem cell transplantation, the treatment chosen for the patient because of the early onset form. The results showed that the enzyme replacement therapy was able to reduce the content of three different mannosyl‐oligosaccharides monitored by tandem mass spectrometry after 2 months of treatment. In particular, the mean relative changes from baseline values were −67% in urine and −53% in serum at the latest observation. The study also showed that the enzymatic activity detected in serum 1 week after the first infusion was four times higher than the normal values and constant in the following points of observation. These findings led us to assume that velmanase alfa might be biologically active in this young patient.
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- 2020
9. Alpha-mannosidosis caused by toxic plants in ruminants of Argentina
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María Elena Pistán, Agustin Martinez, Carlos Alejandro Robles, Luciana Andrea Cholich, Juan Francisco Micheloud, Enrique Nicolas Garcia, Eduardo Juan Gimeno, and Hugo Hector Ortega
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neuronal vacuolation ,Astragalus ,Alpha-mannosidosis ,Science ,Guinea Pigs ,Argentina ,Zoology ,Ipomoea ,chemistry.chemical_compound ,Alfa-manosidosis ,guinea pig model ,medicine ,Animals ,Immunodeficiency ,poisonous plants ,swainsonine ,Plantas Tóxicas ,Plant Poisoning ,Inmunodeficiencia ,Multidisciplinary ,Ipomoea carnea ,biology ,business.industry ,Poisoning ,Ruminants ,Fabaceae ,biology.organism_classification ,medicine.disease ,Envenenamiento ,livestock ,Plants, Toxic ,Swainsonine ,chemistry ,alpha-Mannosidosis ,Livestock ,business ,Convolvulaceae - Abstract
It is well known that several of the swainsonine-containing plant species found widespread around the world have a negative economic impact in each country. In Argentina, most of the information on the poisonous plant species that produce α-mannosidosis is published in Spanish and thus not available to most English speaking researchers interested in toxic plants. Therefore, the aim of this review is to summarize the information about swainsonine-containing plants in Argentina, which are extensively distributed throughout different ecoregions of the country. To date, five species from three genera have been shown to induce α-mannosidosis in livestock in Argentina: Ipomoea carnea subsp. fi stulosa, Ipomoea hieronymi subsp. calchaquina (Convolvulaceae), Astragalus garbancillo, Astragalus pehuenches (Fabaceae), and Sida rodrigoi (Malvaceae). These species contain the indolizidine alkaloid swainsonine, which inhibits the lysosomal enzyme α-mannosidase and consequently affects glycoprotein metabolism, resulting in partially metabolized sugars. The prolonged consumption of these poisonous plants produces progressive weight loss and clinical signs related to a nervous disorder, characterized by tremors of head and neck, abnormalities of gait, difficulty in standing, ataxia and wide-based stance. Histological lesions are mainly characterized by vacuolation of different cells, especially neurons of the central nervous system. The main animal model used to study α-mannosidosis is the guinea pig because, when experimentally poisoned, it exhibits many of the characteristics of naturally intoxicated livestock. Estación Experimental Agropecuaria Bariloche Fil: Cholich, Luciana Andrea. Universidad Nacional del Nordeste. Facultad de Ciencias Veterinarias; Argentina Fil: Cholich, Luciana Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Martinez, Agustin. Instituto Nacional de Tecnologia Agropecuaria (INTA). Estacion Experimental Agropecuaria Bariloche. Grupo de Sanidad Animal; Argentina Fil: Micheloud, Juan Francisco. Universidad Católica de Salta. Facultad de Ciencias Veterinarias y Agronomía; Argentina Fil: Micheloud, Juan Francisco. Instituto Nacional de Tecnologia Agropecuaria (INTA). Instituto de Investigación Animal del Chaco Semiárido. Área de Sanidad Animal; Argentina Fil: Pistán, Maria Elena. Universidad Nacional del Nordeste. Facultad de Ciencias Veterinarias; Argentina Fil: Garcia, Enrique Nicolas. Universidad Nacional del Nordeste. Facultad de Ciencias Veterinarias; Argentina Fil: Robles, Carlos Alejandro. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Grupo de Sanidad Animal; Argentina Fil: Ortega, Hugo Hector. Universidad Nacional del Litoral. Instituto de Ciencias Veterinarias del Litoral; Argentina Fil: Ortega, Hugo Hector. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Gimeno, Eduardo Juan. Universidad Nacional de la Plata. Facultad de Ciencias Veterinarias; Argentina Fil: Gimeno, Eduardo Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
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- 2021
10. Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment
- Author
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Soumeya Bekri, Olfa Messaoud, Cherine Charfeddine, Hela Boudabbous, Amel Tounsi, Meriem Hechmi, Lotfi Zekri, Rahma Mkaouar, Ghazi Besbes, Ahlem Ben Hmid, Christine Petit, R. M’rad, Neji Tebib, Sami Bouchoucha, Fabrice Giraudet, Rym Kefi, J. Marrakchi, Crystel Bonnet, Imen Chelly, Ichraf Kraoua, Hamza Dallali, Ilhem Turki Ben Youssef, Sonia Abdelhak, Nadia Zitouna, Zied Riahi, Sonia Maalej, Mediha Trabelsi, Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory (LR11IPT05), Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Faculté des Sciences Mathématiques, Physiques et Naturelles de Tunis (FST), Université de Tunis El Manar (UTM), Department of Gastroenterology, Habib Bougatfa Hospital, Bizerte, Tunisia, Hôpital La Rabta [Tunis], Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Abderahman Mami Hospital, Laboratoire d'immunologie clinique [Institut Pasteur de Tunis], Institut Pasteur de Tunis, Faculté de Médecine de Tunis, Université Clermont Auvergne (UCA), University of Tunis El Manar, RM is a recipient of a MOBIDOC (http://www.anpr.tn/resultat-mobidoc-session-2017/) fellowship, funded by the EU through the EMORI program and managed by the ANPR., and We would like to thank the patients and their families for their participation in this work. The authors also thank Mrs. Rowan Ben Dakhlia for her critical reading of the manuscript.
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Male ,MESH: Geography ,[SDV]Life Sciences [q-bio] ,Otology ,Deafness ,MESH: Base Sequence ,MESH: Cognitive Dysfunction ,MESH: Membrane Transport Proteins ,Consanguinity ,Database and Informatics Methods ,Medical Conditions ,MESH: Audiometry ,Gene duplication ,Medicine and Health Sciences ,Missense mutation ,Cognitive decline ,Hearing Disorders ,Exome ,Cognitive Impairment ,Sanger sequencing ,Genetics ,Multidisciplinary ,Geography ,Cognitive Neurology ,MESH: Genetic Predisposition to Disease ,Genomics ,Genomic Databases ,Pedigree ,Phenotype ,Neurology ,symbols ,Medicine ,Female ,Cellular Structures and Organelles ,MESH: Tunisia ,Research Article ,Tunisia ,MESH: Mutation ,MESH: Exome Sequencing ,MESH: Pedigree ,Science ,Cognitive Neuroscience ,Disabilities ,Alpha-mannosidosis ,MESH: Carrier Proteins ,MESH: alpha-Mannosidosis ,Biology ,Research and Analysis Methods ,MESH: Phenotype ,Frameshift mutation ,symbols.namesake ,Audiometry ,Intellectual Disability ,Exome Sequencing ,medicine ,Humans ,Cognitive Dysfunction ,Family ,Genetic Predisposition to Disease ,MESH: Family ,MESH: Consanguinity ,MESH: Humans ,Base Sequence ,Membrane Transport Proteins ,Biology and Life Sciences ,Computational Biology ,Human Genetics ,Cell Biology ,Genome Analysis ,medicine.disease ,Human genetics ,MESH: Male ,Biological Databases ,Otorhinolaryngology ,Mutation ,alpha-Mannosidosis ,Mutation Databases ,Cognitive Science ,Carrier Proteins ,Lysosomes ,MESH: Female ,Neuroscience - Abstract
Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy.
- Published
- 2021
11. Gene therapy for global brain diseases: one small step for mice, one giant leap for humans
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Ahad A. Rahim and Paul Gissen
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0301 basic medicine ,Alpha-mannosidosis ,Genetic enhancement ,Genetic Vectors ,Bioinformatics ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Transduction, Genetic ,Animals ,Humans ,Medicine ,Gene ,Brain Diseases ,Brain model ,business.industry ,Gene Transfer Techniques ,Brain ,Genetic Therapy ,Dependovirus ,Scientific Commentaries ,medicine.disease ,Corrigenda ,humanities ,Disease Models, Animal ,030104 developmental biology ,alpha-Mannosidosis ,Cats ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Intravascular injection of certain adeno-associated virus vector serotypes can cross the blood-brain barrier to deliver a gene into the CNS. However, gene distribution has been much more limited within the brains of large animals compared to rodents, rendering this approach suboptimal for treatment of the global brain lesions present in most human neurogenetic diseases. The most commonly used serotype in animal and human studies is 9, which also has the property of being transported via axonal pathways to distal neurons. A small number of other serotypes share this property, three of which were tested intravenously in mice compared to 9. Serotype hu.11 transduced fewer cells in the brain than 9, rh8 was similar to 9, but hu.32 mediated substantially greater transduction than the others throughout the mouse brain. To evaluate the potential for therapeutic application of the hu.32 serotype in a gyrencephalic brain of larger mammals, a hu.32 vector expressing the green fluorescent protein reporter gene was evaluated in the cat. Transduction was widely distributed in the cat brain, including in the cerebral cortex, an important target since mental retardation is an important component of many of the human neurogenetic diseases. The therapeutic potential of a hu.32 serotype vector was evaluated in the cat homologue of the human lysosomal storage disease alpha-mannosidosis, which has globally distributed lysosomal storage lesions in the brain. Treated alpha-mannosidosis cats had reduced severity of neurological signs and extended life spans compared to untreated cats. The extent of therapy was dose dependent and intra-arterial injection was more effective than intravenous delivery. Pre-mortem, non-invasive magnetic resonance spectroscopy and diffusion tensor imaging detected differences between the low and high doses, and showed normalization of grey and white matter imaging parameters at the higher dose. The imaging analysis was corroborated by post-mortem histological analysis, which showed reversal of histopathology throughout the brain with the high dose, intra-arterial treatment. The hu.32 serotype would appear to provide a significant advantage for effective treatment of the gyrencephalic brain by systemic adeno-associated virus delivery in human neurological diseases with widespread brain lesions.
- Published
- 2020
12. Intellectual functioning in alpha‐mannosidosis
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Gordon Kimbrell, Lucia Horowitz, Katie Pietris, Callum Wilson, David Sillence, Sara M. Sarasua, Sara Cathey, and Richard J. Simensen
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Research Report ,alpha‐mannosidosis ,lcsh:QH426-470 ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Alpha-mannosidosis ,Hematopoietic stem cell transplantation ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,03 medical and health sciences ,0302 clinical medicine ,Borderline intellectual functioning ,Intellectual disability ,Internal Medicine ,medicine ,Cognitive skill ,030304 developmental biology ,0303 health sciences ,lcsh:RC648-665 ,business.industry ,Metabolic disorder ,glycoproteinoses ,Cognition ,Research Reports ,medicine.disease ,lcsh:Genetics ,intellectual disability ,IQ ,business ,030217 neurology & neurosurgery ,Clinical psychology ,Rare disease - Abstract
Alpha‐mannosidosis is a rare inherited metabolic disorder (OMIM #248500) caused by mutations in the enzyme α‐mannosidase encoded by the gene MAN2B1. Patients have distinct physical and developmental features, but only limited information regarding standardized cognitive functioning of patients has been published. Here we contribute intellectual ability scores (IQ) on 12 patients with alpha‐mannosidosis (ages 8‐59 years, 10 males, 2 females). In addition, a pooled analysis was performed with data collected from this investigation and 31 cases obtained from the literature, allowing a comprehensive analysis of intellectual functioning in this rare disease. The initial and pooled analyses show that patients with alpha‐mannosidosis have variable degrees of intellectual disability but show decline in IQ with age, particularly during the first decade of life. Patients treated with hematopoietic stem cell transplantation tend to show stabilized cognitive abilities.
- Published
- 2019
13. Tandem mass spectrometry-based multiplex assays for α-mannosidosis and fucosidosis
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Arun Kumar, Fan Yi, Tim Wood, Xinying Hong, and Michael H. Gelb
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Fucosidosis ,0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Endocrinology, Diabetes and Metabolism ,030105 genetics & heredity ,Tandem mass spectrometry ,Biochemistry ,Article ,03 medical and health sciences ,Neonatal Screening ,0302 clinical medicine ,Endocrinology ,Tandem Mass Spectrometry ,Genetics ,Humans ,Medicine ,Multiplex ,Dried blood ,Molecular Biology ,Enzyme Assays ,Newborn screening ,biology ,business.industry ,Infant, Newborn ,α mannosidosis ,nutritional and metabolic diseases ,medicine.disease ,Molecular biology ,Enzyme assay ,Lysosomal Storage Diseases ,Bone transplantation ,alpha-Mannosidosis ,biology.protein ,business ,030217 neurology & neurosurgery - Abstract
Multiplex tandem mass spectrometry (MS/MS)-based enzyme activity assays for newborn screening (NBS) and diagnosis of lysosomal storage diseases (LSDs) in newborns, using dried blood spots (DBS) on newborn screening cards, have garnered much attention due to its sensitivity, high precision, and the capability to screen for an unprecedented number of diseases in a single assay. Herein we report the development of MS/MS-based enzyme assays for the diagnosis of α-mannosidosis and fucosidosis. These new protocols are able to distinguish untreated patients from random newborns, carriers and a post-bone marrow transplant patient. We have successfully multiplexed the α-mannosidosis assay with a multiplex MS/MS assay for the screening and diagnosis of other LSDs, namely Fabry, Pompe, MPS I, Gaucher, Niemann-Pick-A/B, and Krabbe diseases. Additionally, we also multiplexed the fucosidosis NBS assay with a 5-plex assay that tests for MPS-II, MPS-IIIB, MPS-IVA, MPS-VI and MPS-VII.
- Published
- 2019
14. Elevated Dipeptidyl Peptidase IV (DPP-IV) Activity in Plasma from Patients with Various Lysosomal Diseases
- Author
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Barbara Perkowska-Sumiła, Jolanta Wierzba, Anna Tylki-Szymańska, Jolanta Kubalska, Krystyna Szymańska, Ałła Graban, Galina Baydakova, Alex Ilyushkina, Agnieszka Ługowska, Hanna Mierzewska, Ekaterina Zakharova, Tomasz Kmieć, and Małgorzata Bednarska-Makaruk
- Subjects
0301 basic medicine ,mucolipidosis II/III ,medicine.medical_specialty ,diagnosis ,Alpha-mannosidosis ,Lymphocyte ,Clinical Biochemistry ,Gangliosidosis ,Article ,Dipeptidyl peptidase ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,lysosomal diseases ,Internal medicine ,Medicine ,alpha-mannosidosis ,lcsh:R5-920 ,business.industry ,Mucolipidosis ,screening ,medicine.disease ,mucopolysaccharidoses ,Metachromatic leukodystrophy ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,DPP-IV ,030220 oncology & carcinogenesis ,business ,lcsh:Medicine (General) - Abstract
Increased activity of dipeptidyl peptidase IV (DPP-IV) was reported earlier in patients with different types of mucopolysaccharidoses. DPP-IV (also known as CD26 lymphocyte T surface antigen) is a transmembrane protein showing protease activity. This enzyme displays various functions in the organism and plays an important role in multiple processes like glucose metabolism, nociception, cell-adhesion, psychoneuroendocrine regulation, immune response and cardiovascular adaptation. In order to evaluate DPP-IV in lysosomal storage diseases (LSD), we examined its activity in plasma samples from 307 patients affected with 24 different LSDs and in 75 control persons. Our results revealed elevated DPP-IV activity especially in individuals affected with mucolipidosis II/III, alpha-mannosidosis, and mucopolysaccharidoses types III, II, and I (p <, 0.05). In other LSDs the DPP-IV activity was still significantly increased, but to a lesser extent. In patients with Gaucher disease, ceroid lipofuscinosis type 1 (CLN1), Niemann–Pick disease type C and A, Krabbe and Pompe diseases, gangliosidosis GM2 and metachromatic leukodystrophy discreet or no changes in DPP-IV activity were observed. DPP-IV may serve as a first-tier diagnostic procedure or additional biochemical analysis in recognizing patients with some LSDs. DPP-IV may become an object of basic research for a better understanding of LSDs.
- Published
- 2021
15. Effect of velmanase alfa (human recombinant alpha-mannosidase) enzyme-replacement therapy on quality of life and disease burden of patients with alpha-mannosidosis: Results from caregiver feedback
- Author
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Luc Régal, Line Borgwardt, Nathalie Guffon, Bénédicte Héron, Allan M. Lund, Anna Tylki-Szymańska, Frederica Cattaneo, Duncan Cole, Julia B. Hennermann, Mercedes Gil-Campos, and Pediatrics
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Velmanase alfa ,Enzyme replacement therapy ,medicine.disease ,alpha-Mannosidase ,Biochemistry ,law.invention ,Endocrinology ,Quality of life ,law ,Internal medicine ,Genetics ,medicine ,Recombinant DNA ,business ,Molecular Biology ,Disease burden - Published
- 2021
16. Evaluation of 2 patients with alpha-mannosidosis and history of conductive hearing impairment participating in a placebo-controlled, phase 3 program receiving velmanase alfa (human recombinant alpha-mannosidase)
- Author
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Frederica Cattaneo, Allan M. Lund, Luc Régal, Line Borgwardt, and Pediatrics
- Subjects
medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Velmanase alfa ,alpha-Mannosidase ,Placebo ,medicine.disease ,Biochemistry ,law.invention ,Conductive hearing impairment ,Endocrinology ,law ,Internal medicine ,Genetics ,Recombinant DNA ,Medicine ,business ,Molecular Biology - Published
- 2021
17. Alpha-Mannosidosis: A Novel Cause of Bilateral Thalami and Dentate Nuclei Hyperintensity
- Author
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Maria João Malaquias, João Parente Freixo, Carla Caseiro, Marina Magalhães, Eduarda Pinto, and Jorge Oliveira
- Subjects
Pathology ,medicine.medical_specialty ,Alpha-mannosidosis ,Thalamus ,Contrast Media ,General Medicine ,Biology ,medicine.disease ,Magnetic Resonance Imaging ,Hyperintensity ,Dentate nucleus ,Neurology ,alpha-Mannosidosis ,medicine ,Humans ,Neurology (clinical) - Published
- 2021
18. Alpha-mannosidosis in a family: natural history with an uncommon retinal dystrophy
- Author
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Ratna Dua Puri, Tinku Bali Razdan, Apurba Ghosh, S.K. Dubey, Jyotsna Verma, Sapna Sandal, and Renu Saxena
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Retinal dystrophy ,Alpha-mannosidosis ,DNA Mutational Analysis ,Pathology and Forensic Medicine ,Consanguinity ,alpha-Mannosidase ,Retinal Dystrophies ,medicine ,Humans ,Genetic Predisposition to Disease ,Fluorescein Angiography ,Genetics (clinical) ,Alleles ,Genetic Association Studies ,business.industry ,Facies ,General Medicine ,medicine.disease ,Pedigree ,Natural history ,Phenotype ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Mutation ,alpha-Mannosidosis ,Female ,Anatomy ,Symptom Assessment ,business - Published
- 2020
19. Caregivers' and Physicians' Perspectives on Alpha-Mannosidosis: A Report from Italy
- Author
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Elena Verrecchia, Silvia Rossi, Maria Grazia Massaro, Rossana Rocco, Gabriella Silvestri, Ludovico Luca Sicignano, and Raffaele Manna
- Subjects
Adult ,Male ,030213 general clinical medicine ,medicine.medical_specialty ,Recurrent infections ,Lysosomal storage disorder ,Disease ,Recombinant human alpha-mannosidase ,03 medical and health sciences ,0302 clinical medicine ,Multidisciplinary approach ,Residential care ,alpha-Mannosidase ,Physicians ,medicine ,Humans ,Pharmacology (medical) ,Early childhood ,Preschool ,Large city ,Child ,Velmanase alfa ,Health professionals ,business.industry ,Settore MED/09 - MEDICINA INTERNA ,General Medicine ,Caregivers ,Italy ,Enzyme replacement therapy ,030220 oncology & carcinogenesis ,Family medicine ,Child, Preschool ,alpha-Mannosidosis ,Female ,Rural area ,business - Abstract
Alpha-mannosidosis is a rare lysosomal storage disorder that generally presents in early childhood. It is a progressive, highly heterogeneous disease that is difficult to recognize, and a diagnosis is usually reached after referrals to multiple specialists. It is important to understand the challenges faced by patients and their caregiver up to and after a diagnosis of alpha-mannosidosis. In this report, we describe the process of alpha-mannosidosis diagnosis and treatment from the caregivers’ and physicians’ perspectives. For the caregivers’ perspective, the mothers of two patients with alpha-mannosidosis (‘Adele’ aged 35 years and ‘Amedeo’ aged 40 years) were interviewed in their homes in Italy, and anonymized transcripts were used to describe their experiences. Adele lived in a large city with access to hospitals and specialized centers and was diagnosed with alpha-mannosidosis before 3 years of age. Amedeo was from a small village and was diagnosed when he was 10–11 years old. In both cases, their mothers sought help from pediatricians and other specialists for recurrent infections and delayed speech and motor development in the first years of their lives, but diagnosis was delayed. Although the diagnostic pathway was concerning and frustrating for her mother, Adele was able to live at home and receive multidisciplinary care and psychosocial support locally, but the transition from pediatric to adult services was difficult. She is currently waiting for access to enzyme replacement therapy. Amedeo had to travel widely and frequently to receive a diagnosis and access supportive treatment. The cumulative morbidity resulting from the delays and poor access to care necessitated long-term residential care. From the physicians’ perspective, greater awareness of alpha-mannosidosis is required among healthcare professionals and more support is needed for patients and caregivers, particularly those living in rural areas or small centers.
- Published
- 2020
20. Comprehensive cardiopulmonary assessment in α mannosidosis
- Author
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Ronen Bar-Yoseph, Anat Ilivitzki, Galit Tal, Guy Gut, Merav Zucker-Toledano, Michal Gur, Vered Nir, Moneera Hanna, Lea Bentur, and Yazeed Toukan
- Subjects
Pulmonary and Respiratory Medicine ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Alpha-mannosidosis ,Air trapping ,Pulmonary function testing ,Young Adult ,Internal medicine ,medicine ,Lysosomal storage disease ,Humans ,Child ,Bone Marrow Transplantation ,business.industry ,Coarse facial features ,VO2 max ,medicine.disease ,Respiratory Function Tests ,Pediatrics, Perinatology and Child Health ,alpha-Mannosidosis ,Cardiology ,Disease Progression ,Exercise Test ,Female ,medicine.symptom ,business ,Complication ,Tomography, X-Ray Computed ,Rare disease - Abstract
Introduction α Mannosidosis is an extremely rare, progressive, and complex lysosomal storage disease, characterized by mental retardation, hearing impairment, coarse facial features, skeletal abnormalities, and pulmonary involvement. While bone marrow transplantation has been the only therapeutic option to date, nowadays new treatment options are being explored, which may affect pulmonary and exercise capacity. Aim and methods To assess cardiopulmonary involvement in patients with α mannosidosis by pulmonary function tests, cardiopulmonary exercise testing, and low irradiation chest computed tomography (CT). Results Five patients aged 11 to 28 years were followed in our Respiratory-Metabolic Clinic. All five had pulmonary symptoms and received inhaled therapy. Three patients underwent bone marrow transplantation. Parenchymal lung disease was evident in 3/5 chest CT tests. Pulmonary function tests were abnormal in all patients and showed obstructive/restrictive impairment with air trapping. All five patients showed reduced peak oxygen uptake (median 23.1; range 20.4-32.2 mL/minute/kg, median %predicted 62; range %predicted 59-79). Conclusions Pulmonary involvement is a known complication in this rare disease. Comprehensive cardiopulmonary evaluation is feasible among these patients and may help in assessing disease progression and response to new treatment modalities.
- Published
- 2020
21. α-Mannosidosis - An underdiagnosed lysosomal storage disease in individuals with an 'MPS-like' phenotype
- Author
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Thomas P. Mechtler, Berthold Streubel, Thomas Wiesinger, David C. Kasper, Markus Schwarz, and Sandra Liebmann-Reindl
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Mucopolysaccharidosis ,Pilot Projects ,Disease ,030105 genetics & heredity ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,alpha-Mannosidase ,Internal medicine ,Genetics ,medicine ,Lysosomal storage disease ,Humans ,Molecular Biology ,Genetic testing ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Phenotype ,Dried blood spot ,Cohort ,Mutation ,alpha-Mannosidosis ,Dried Blood Spot Testing ,business ,030217 neurology & neurosurgery ,Rare disease - Abstract
Individuals affected by alpha-Mannosidosis suffer from similar clinical symptoms such as respiratory infections, skeletal changes as patients with mucopolysaccharidoses (MPS). α-Mannosidosis is considered as an ultra-rare disorders and also diagnostic testing is often limited. With the availability of novel therapies and easy-to-access diagnostic tests (e.g. Tandem mass spectrometry) using dried blood spots for both enzymatic and genetic testing, the chance for the development of a better understanding of disease and awareness may be triggered. In a pilot study, we have investigated 1010 residual dried blood spot samples from individuals suspicious to MPS. In these study cohort, 158/1010 individuals were genetically confirmed for MPS. Additional biochemical and genetic confirmatory testing for α-mannosidases revealed four individuals with a final diagnosis of α-mannosidosis. This unexpected high number of individuals with α-mannosidosis demonstrated the urgent need of taking this rare disorder in clinical and diagnostic consideration particularly in patients suspicious to MPS.
- Published
- 2020
22. Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis
- Author
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Line Borgwardt, Diego Ardigò, Silvia Geraci, Allan M. Lund, Nathalie Guffon, Christian J. Hendriksz, Federica Cattaneo, Paul Harmatz, and Julia B. Hennermann
- Subjects
Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Disease ,alpha-Mannosidase ,Placebo ,Biochemistry ,law.invention ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Quality of life ,law ,Internal medicine ,Genetics ,medicine ,Humans ,Enzyme Replacement Therapy ,Child ,Molecular Biology ,business.industry ,Enzyme replacement therapy ,Prognosis ,medicine.disease ,Recombinant Proteins ,030104 developmental biology ,Child, Preschool ,Pharmacodynamics ,alpha-Mannosidosis ,Quality of Life ,Recombinant DNA ,Female ,business ,030217 neurology & neurosurgery - Abstract
Alpha-mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for alpha-mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to ≥2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n = 15) compared with 30% of patients receiving placebo (n = 10). Longer-term data from all patients in the clinical program (n = 33) showed 88% of patients were global responders, including all (100%) pediatric patients (n = 19) and the majority (71%) of adult patients (n = 14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with alpha-mannosidosis with this ERT.
- Published
- 2018
23. Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial
- Author
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J. M. Hannerieke Van den Hout, Allan M. Lund, Nathalie Guffon, Line Borgwardt, Federica Cattaneo, Simon Jones, Linda De Meirleir, Yasmina Amraoui, Christine í Dali, Jens Fogh, Diego Ardigò, Ulla Haugsted, Silvia Geraci, Anna Tylki-Szymańska, Bénédicte Héron, Mercedes Gil-Campos, M Beck, and Pediatrics
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Placebo-controlled study ,Placebo ,Severity of Illness Index ,law.invention ,03 medical and health sciences ,Young Adult ,Randomized controlled trial ,Double-Blind Method ,law ,alpha-Mannosidase ,Internal medicine ,Severity of illness ,Post-hoc analysis ,Genetics ,Medicine ,Humans ,Genetics(clinical) ,Enzyme Replacement Therapy ,Young adult ,Child ,Genetics (clinical) ,business.industry ,Confidence interval ,Recombinant Proteins ,3. Good health ,Clinical trial ,Europe ,030104 developmental biology ,Treatment Outcome ,Child, Preschool ,alpha-Mannosidosis ,Quality of Life ,Original Article ,Female ,business - Abstract
Introduction This phase III, double-blind, randomised, placebo-controlled trial (and extension phase) was designed to assess the efficacy and safety of velmanase alfa (VA) in alpha-mannosidosis (AM) patients. Methods Twenty-five patients were randomised to weekly 1 mg/kg VA or placebo for 52 weeks. At study conclusion, placebo patients switched to VA; 23 patients continued receiving VA in compassionate-use/follow-on studies and were evaluated in the extension phase [last observation (LO)]. Co-primary endpoints were changes in serum oligosaccharide (S-oligo) and in the 3-min stair-climb test (3MSCT). Results Mean relative change in S-oligo in the VA arm was −77.6% [95% confidence interval (CI) −81.6 to −72.8] at week 52 and −62.9% (95% CI −85.8 to −40.0) at LO; mean relative change in the placebo arm was −24.1% (95% CI −40.3 to −3.6) at week 52 and −55.7% (95% CI −76.4 to −34.9) at LO after switch to active treatment. Mean relative change in 3MSCT at week 52 was −1.1% (95% CI −9.0 to 7.6) and − % (95% CI −13.4 to 6.5) for VA and placebo, respectively. At LO, the mean relative change was 3.9% (95% CI −5.5 to 13.2) in the VA arm and 9.0% (95% CI −10.3 to 28.3) in placebo patients after switch to active treatment. Similar improvement pattern was observed in secondary parameters. A post hoc analysis investigated whether some factors at baseline could account for treatment outcome; none of those factors were predictive of the response to VA, besides age. Conclusions These findings support the utility of VA for the treatment of AM, with more evident benefit over time and when treatment is started in the paediatric age. Electronic supplementary material The online version of this article (10.1007/s10545-018-0185-0) contains supplementary material, which is available to authorized users.
- Published
- 2018
24. Intestinal Epithelial Cell-specific Deletion of α-Mannosidase II Ameliorates Experimental Colitis
- Author
-
Koichiro Suzuki, Masato Hirota, Takahiro G. Yamada, Koji Hase, Daisuke Takahashi, Narumi Ishihara, Hideki Iijima, Keiko Yamazaki, and Mizuki Sakamoto
- Subjects
0301 basic medicine ,Candidate gene ,Chemokine ,Cell type ,Glycosylation ,Colon ,Physiology ,Down-Regulation ,Polymorphism, Single Nucleotide ,digestive system ,Inflammatory bowel disease ,Pathogenesis ,Mice ,03 medical and health sciences ,Mannosidases ,Gene expression ,medicine ,Animals ,Humans ,Intestinal Mucosa ,Colitis ,Molecular Biology ,Mice, Knockout ,Gastrointestinal tract ,biology ,Dextran Sulfate ,Epithelial Cells ,Cell Biology ,General Medicine ,Inflammatory Bowel Diseases ,medicine.disease ,digestive system diseases ,Gastrointestinal Microbiome ,Mice, Inbred C57BL ,030104 developmental biology ,Neutrophil Infiltration ,alpha-Mannosidosis ,Cancer research ,biology.protein ,Chemokines ,Genome-Wide Association Study - Abstract
Inflammatory bowel disease (IBD) is a refractory disease of the gastrointestinal tract that is believed to develop in genetically susceptible individuals. Glycosylation, a type of post-translational modification, is involved in the development of a wide range of diseases, including IBD, by modulating the function of various glycoproteins. To identify novel genes contributing to the development of IBD, we analyzed single nucleotide polymorphisms (SNPs) of glycosylation-related genes in IBD patients and identified MAN2A1, encoding alpha-mannosidase II (α-MII), as a candidate gene. α-MII plays a crucial, but not exclusive, role in the maturation of N-glycans. We also observed that intestinal epithelial cells (IECs), which establish the first-line barrier and regulate gut immunity, selectively expressed α-MII with minimal expression of its isozyme, alpha-mannosidase IIx (α-MIIx). This led us to hypothesize that IEC-intrinsic α-MII is implicated in the pathogenesis of IBD. To test this hypothesis, we generated IEC-specific α-MII-deficient (α-MIIΔIEC) mice. Although α-MII deficiency has been shown to have a minimal effect on N-glycan maturation in most cell types due to the compensation by α-MIIx, ablation of α-MII impaired the maturation of N-glycans in IECs. α-MIIΔIEC mice were less susceptible to dextran sulfate sodium-induced colitis compared with control littermates. In accordance with this, neutrophil infiltration in the colonic mucosa was attenuated in α-MIIΔIEC mice. Furthermore, gene expression levels of neutrophil-attracting chemokines were downregulated in the colonic tissue. These results suggest that IEC-intrinsic α-MII promotes intestinal inflammation by facilitating chemokine expression. We propose SNPs in MAN2A1 as a novel genetic factor for IBD.Key words: inflammatory bowel disease, alpha-mannosidase II, intestinal epithelial cell, N-glycosylation.
- Published
- 2018
25. Swainsonine-induced lysosomal storage disease in goats caused by the ingestion of Sida rodrigoi Monteiro in North-western Argentina
- Author
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Dale R. Gardner, Eduardo Juan Gimeno, Luis Adrián Colque-Caro, Raul E. Marin, Juan Francisco Micheloud, and Olga Gladys Martínez
- Subjects
Central Nervous System ,0301 basic medicine ,medicine.medical_specialty ,Ataxia ,040301 veterinary sciences ,Argentina ,SWAINSONINE ,Biology ,STORAGE DISEASE ,Toxicology ,Microbiology ,0403 veterinary science ,03 medical and health sciences ,chemistry.chemical_compound ,Agglutinin ,POISONOUS PLANTS ,Otras Ciencias Veterinarias ,medicine ,Lysosomal storage disease ,Animals ,Ingestion ,Sida ,Malvaceae ,Plant Poisoning ,Goat Diseases ,Swainsonine ,Ciencias Veterinarias ,Goats ,030111 toxicology ,food and beverages ,04 agricultural and veterinary sciences ,ARGENTINIAN NORTHEASTERN ,medicine.disease ,biology.organism_classification ,Animal Feed ,Diet ,Plants, Toxic ,chemistry ,Vacuolization ,CIENCIAS AGRÍCOLAS ,alpha-Mannosidosis ,Immunology ,Histopathology ,Plant Lectins ,medicine.symptom - Abstract
There are numerous poisonous plants that can induce intralysosomal accumulation of glycoproteins and neurologic syndromes. Here we describe for the first time, a disease caused by ingesting Sida rodrigoi Monteiro in goats in North-western Argentina. The animals showed weight loss, indifference to the environment, unsteady gait and ataxia. Histopathologic studies showed vacuolization in cells of various organs, mainly in the CNS. The material deposited in the cells was positive for LCA (Lens culinaris agglutinin), WGA (Triticum vulgaris agglutinin), sWGA (succinyl-Triticum vulgaris agglutinin) and Con-A (Concanavalia ensiformis agglutinin) lectins. Finally, toxic levels of swansonine were identified in the plant. The present investigation allowed to recognize S. rodrigoi Monteiro poisoning as a plant induced α-mannosidosis. Fil: Micheloud, Juan Francisco. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias. Instituto de Investigación Animal del Chaco Semiárido; Argentina. Universidad Católica de Salta; Argentina Fil: Marin, Raúl. Universidad Nacional de Jujuy; Argentina Fil: Colque Caro, Luis Adrián. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias. Instituto de Investigación Animal del Chaco Semiárido; Argentina. Universidad Católica de Salta; Argentina Fil: Martinez, Olga Gladys. Universidad Nacional de Salta; Argentina Fil: Gardner, Dale. United States Department of Agriculture. Agriculture Research Service; Estados Unidos Fil: Gimeno, Eduardo Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Cátedra de Patología General Veterinaria; Argentina
- Published
- 2017
26. Lysosomal alpha-mannosidase and alpha-mannosidosis
- Author
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Silvia Paciotti, Michela Codini, Bernard Fioretti, Samuela Cataldi, Maria Rachele Ceccarini, Tommaso Beccari, Elisabetta Albi, Cataldo Arcuri, and Anna Tasegian
- Subjects
0301 basic medicine ,Alpha-mannosidosis ,Mannose ,alpha-mannosidase, alpha-mannosidosis, lysosomes ,Biology ,medicine.disease_cause ,alpha-Mannosidase ,law.invention ,Mannosidosis ,03 medical and health sciences ,chemistry.chemical_compound ,lysosomes ,law ,Chromosome 19 ,medicine ,Animals ,Humans ,Enzyme Replacement Therapy ,alpha-mannosidase ,alpha-mannosidosis ,Mutation ,Enzyme replacement therapy ,medicine.disease ,Molecular biology ,Recombinant Proteins ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Recombinant DNA - Abstract
Lysosomal alpha-mannosidase with acidic pH optimum is ubiquitous in human tissues where is expressed in two major forms, A and B that are the product of a single gene located on chromosome 19. Mutations in the gene encoding for alpha-mannosidase cause alpha- mannosidosis, an autosomal recessive disease, resulting in the accumulation of unprocessed mannose containing oligosaccharide material. This rare disease has an estimated incidence of 1/500.0.00 live births and clinically is divided into three subgroups. Today the most promising therapy for this disease is the enzyme replacement therapy. To develop this strategy a mouse model for alpha-mannosidosis has been generated and a recombinant human alpha-mannosidase has been produced from Chinese-hamster ovary cells. Interestingly it has been shown that the recombinant enzyme, used in high dose, can cross the blood brain barrier. This recombinant enzyme has been tested in the first randomized study investigating the efficacy of enzyme replacement therapy in patients with alpha-mannosidosis. This review contains the scientific progresses on lysosomal alpha-mannosidase from the cloning to the beginning of the therapy.
- Published
- 2017
27. Velmanase alfa enzyme replacement therapy for alpha-mannosidosis improves patient outcomes over standard of care both in terms of clinically relevant improvement and disease stabilization
- Author
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Federica Cattaneo, Sofie Geelissen, Christian J. Hendriksz, Irene Rastelletti, Diego Ardigò, and Paul Harmatz
- Subjects
medicine.medical_specialty ,Standard of care ,business.industry ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Velmanase alfa ,Disease ,Enzyme replacement therapy ,medicine.disease ,Biochemistry ,Endocrinology ,Internal medicine ,Genetics ,medicine ,business ,Molecular Biology - Published
- 2020
28. A Cross-sectional Quantitative Analysis of the Natural History of Alpha-mannosidosis
- Author
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Georg F. Hoffmann, Markus Ries, Sven F. Garbade, Stefan Kölker, and Matthias Zielonka
- Subjects
Natural history ,business.industry ,Alpha-mannosidosis ,medicine ,Computational biology ,medicine.disease ,business ,Quantitative analysis (chemistry) - Published
- 2019
29. Large animal models contribute to the development of therapies for central and peripheral nervous system dysfunction in patients with lysosomal storage diseases
- Author
-
Brittney L. Gurda and Charles H. Vite
- Subjects
Alpha-mannosidosis ,Disease ,Gangliosidosis ,Biology ,Bioinformatics ,Fucosidosis ,03 medical and health sciences ,0302 clinical medicine ,Nervous system disease ,Genetics ,medicine ,Animals ,Humans ,Enzyme Replacement Therapy ,Molecular Biology ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Leukodystrophy ,Hematopoietic Stem Cell Transplantation ,Disease Management ,General Medicine ,Enzyme replacement therapy ,Genetic Therapy ,medicine.disease ,Combined Modality Therapy ,Lysosomal Storage Diseases ,Disease Models, Animal ,Treatment Outcome ,Neuronal ceroid lipofuscinosis ,Nervous System Diseases ,030217 neurology & neurosurgery - Abstract
Lysosomal storage diseases (LSDs) are a group of 70 monogenic disorders characterized by the lysosomal accumulation of a substrate. As a group, LSDs affect ~1 in 5000 live births; however, each individual storage disease is rare, limiting the ability to perform natural history studies or to perform clinical trials. Perhaps in no other biomedical field have naturally occurring large animal (canine, feline, ovine, caprine, and bovine) models been so essential for understanding the fundamentals of disease pathogenesis and for developing safe and effective therapies. These models were critical for the development of hematopoietic stem cell transplantation in α- and β- mannosidosis, fucosidosis, and the mucopolysaccharidoses; enzyme replacement therapy for fucosidosis, the mucopolysaccharidoses, and neuronal ceroid lipofuscinosis; and small molecule therapy in Niemann–Pick type C disease. However, their most notable contributions to the biomedical field are in the development of gene therapy for LSDs. Adeno-associated viral vectors to treat nervous system disease have been evaluated in the large animal models of α-mannosidosis, globoid cell leukodystrophy, GM1 and GM2 gangliosidosis, the mucopolysaccharidoses, and neuronal ceroid lipofuscinosis. This review article will summarize the large animal models available for study as well as their contributions to the development of central and peripheral nervous system dysfunction in LSDs.
- Published
- 2019
30. Ultra-orphan lysosomal storage diseases: A cross-sectional quantitative analysis of the natural history of alpha-mannosidosis
- Author
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Matthias Zielonka, Stefan Kölker, Markus Ries, Sven F. Garbade, and Georg F. Hoffmann
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Disease onset ,Delayed Diagnosis ,Adolescent ,Alpha-mannosidosis ,Young Adult ,Genetics ,Medicine ,media_common.cataloged_instance ,Humans ,Enzyme Replacement Therapy ,European union ,Age of Onset ,Child ,Genetics (clinical) ,media_common ,Retrospective Studies ,business.industry ,Infant ,Enzyme replacement therapy ,medicine.disease ,Survival Analysis ,Natural history ,Cross-Sectional Studies ,Phenotype ,Child, Preschool ,Cohort ,alpha-Mannosidosis ,Female ,Age of onset ,business ,Median survival ,Biomarkers - Abstract
Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disorder caused by a deficiency of the enzyme alpha-mannosidase. Recently, enzyme replacement therapy was approved in the European Union for the treatment of alpha-mannosidosis, but evaluation regarding long-term efficacy and safety is hard to assess due to missing quantitative natural history data, in particular survival. We performed a quantitative analysis of published cases (N = 111) with alpha-mannosidosis. Main outcome measures were age of disease onset, diagnostic delay and survival (overall and by subgroup exploration). Residual alpha-mannosidase activity and age of onset were explored as potential predictors of survival. STROBE criteria were respected. Median age of onset was 12 months. Median diagnostic delay was 6 years. At the age of 41 years 72.3% of patients were alive (N = 111). Residual alpha-mannosidase activity (N = 34) predicted survival: Patients with a residual alpha-mannosidase activity below or equal to 4.5% of normal in fibroblasts had a median survival of 3.5 years, whereas patients with alpha-mannosidase activity above this threshold all survived during the observation period reported. Patients with age of onset above 7 years survived significantly longer than patients with age of onset below or equal to 7 years. Patient distribution was panethnic with hotspots in the United States and Germany. We defined age of onset, diagnostic delay, and survival characteristics in a global cohort of 111 patients with alpha-mannosidosis by retrospective quantitative natural history modeling. These data expand the quantitative understanding of the clinical phenotype.
- Published
- 2019
31. Health Related Quality of Life, Disability, and Pain in Alpha Mannosidosis: Long-Term Data of Enzyme Replacement Therapy With Velmanase Alfa (Human Recombinant Alpha Mannosidase)
- Author
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Dawn Phillips, Yasmina Amraoui, Linda De Meirleir, Diego Ardigò, Federica Cattaneo, Paul Harmatz, Johanna M. P. Van den Hout, Line Borgwardt, Anna Tylki-Szymańska, Nathalie Guffon, Mercedes Gil-Campos, Simon Jones, Allan M. Lund, and Silvia Geraci
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,recombinant human alpha-mannosidase ,alpha-Mannosidase ,law.invention ,HRQoL ,03 medical and health sciences ,0302 clinical medicine ,law ,Internal medicine ,Medicine ,alpha-mannosidosis ,Genetics (clinical) ,chemistry.chemical_classification ,Health related quality of life ,business.industry ,Enzyme replacement therapy ,medicine.disease ,CHAQ ,030104 developmental biology ,Enzyme ,Endocrinology ,EQ-5D-5L ,chemistry ,disability ,Pediatrics, Perinatology and Child Health ,Long term data ,Recombinant DNA ,business ,Glycoprotein ,030217 neurology & neurosurgery - Abstract
Alpha-mannosidosis, a rare lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha-mannosidase, results in accumulation of mannose-rich glycoproteins in the tissues and sequelae leading to intellectual disability, ataxia, impaired hearing and speech, recurrent infections, skeletal abnormalities, muscular pain, and weakness. This study aimed to investigate disability, pain, and overall health using the Childhood Health Assessment Questionnaire (CHAQ) and the EuroQol 5 Dimension-5 Level Questionnaire (EQ-5D-5L) in patients with alpha-mannosidosis participating in rhLAMAN-10, a phase III open-label, clinical trial of velmanase alfa, a recombinanthumanlysosomalalpha-mannosidase. Long-termprognosesformost patients withuntreatedalpha-mannosidosisarepoor due to progressive neuromuscular, skeletal, and intellectual deterioration, leading to increased dependence in mobility and activities of daily living and increased caregiver and health-care burden. Long-term CHAQ and EQ-5D-5L data highlight improvement trends in health-related quality of life and a reduction in disability and pain in patients receiving up to 48 months of velmanase alfa treatment.
- Published
- 2019
32. Recognition of alpha-mannosidosis in paediatric and adult patients: Presentation of a diagnostic algorithm from an international working group
- Author
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Mercedes Gil-Campos, Anna Tylki-Szymańska, Julia B. Hennermann, Allan M. Lund, Rossella Parini, Line Borgwardt, and Nathalie Guffon
- Subjects
0301 basic medicine ,Adult ,Consensus ,Internationality ,Referral ,Lysosomal storage disorder ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Disease ,030105 genetics & heredity ,Biochemistry ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Endocrinology ,Nominal group technique ,Diagnosis ,Genetics ,medicine ,Humans ,Stage (cooking) ,Child ,Molecular Biology ,business.industry ,Age Factors ,International working group ,Middle Aged ,medicine.disease ,Algorithm ,Child, Preschool ,Speech delay ,Symptoms ,alpha-Mannosidosis ,Disease Progression ,Presentation (obstetrics) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Algorithms - Abstract
Alpha-mannosidosis is an ultra-rare progressive lysosomal storage disorder caused by deficiency of alpha-mannosidase. Timely diagnosis of the disease has the potential to influence patient outcomes as preventive therapies can be initiated at an early stage. However, no internationally-recognised algorithm is currently available for the diagnosis of the disease. With the aim of developing a diagnostic algorithm for alpha-mannosidosis an international panel of experts met to reach a consensus by applying the nominal group technique. Two proposals were developed for diagnostic algorithms of alpha-mannosidosis, one for patients ≤10 years of age and one for those >10 years of age. In younger patients, hearing impairment and/or speech delay are the cardinal symptoms that should prompt the clinician to look for additional symptoms that may provide further diagnostic clues. Older patients have different clinical presentations, and the presence of mental retardation and motor impairment progression and/or psychiatric manifestations should prompt the clinician to assess for other symptoms. In both younger and older patients, either additional metabolic monitoring or referral for testing is warranted upon suspicion of disease. Oligosaccharides in urine (historically performed) or serum were considered as an initial screening procedure, while enzymatic activity may also be considered as first choice in some centres. Molecular testing should be performed as a final confirmatory step. The developed algorithms can easily be applied in a variety of settings, and may help to favour early diagnosis of alpha mannosidosis and treatment.
- Published
- 2019
33. Hearing impairment as an early sign of alpha-mannosidosis in children with a mild phenotype: Report of seven new cases
- Author
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Sebastien Moutton, Aurore Garde, Laurence Faivre, François Feillet, Christel Thauvin-Robinet, Paul Kuentz, Antonio Vitobello, Frédéric Huet, Arthur Sorlin, Roberto Colombo, Nada Houcinat, Yannis Duffourd, Caroline Racine, Julian Delanne, Christophe Philippe, Daphné Lehalle, Michael J. O'Grady, Julien Thevenon, Frédéric Tran Mau-Them, Bénédicte Héron, Sandrine Marlin, and Sophie Nambot
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Hearing loss ,Alpha-mannosidosis ,Urinary system ,Young Adult ,alpha-Mannosidase ,Intellectual Disability ,Intellectual disability ,Exome Sequencing ,Genetics ,medicine ,Humans ,Child ,Hearing Loss ,Genetics (clinical) ,Exome sequencing ,Coarse facial features ,business.industry ,Siblings ,Enzyme replacement therapy ,medicine.disease ,Hypotonia ,Phenotype ,Child, Preschool ,alpha-Mannosidosis ,Female ,medicine.symptom ,business ,Lysosomes - Abstract
Alpha-mannosidosis (AM) is a very rare (prevalence: 1/500000 births) autosomal recessive lysosomal storage disorder. It is characterized by multi-systemic involvement associated with progressive intellectual disability, hearing loss, skeletal anomalies, and coarse facial features. The spectrum is wide, from very severe and lethal to a milder phenotype that usually progresses slowly. AM is caused by a deficiency of lysosomal alpha-mannosidase. A diagnosis can be established by measuring the activity of lysosomal alpha-mannosidase in leucocytes and screening for abnormal urinary excretion of mannose-rich oligosaccharides. Genetic confirmation is obtained with the identification of MAN2B1 mutations. Enzyme replacement therapy (LAMZEDER ) was approved for use in Europe in August 2018. Here, we describe seven individuals from four families, diagnosed at 3-23 years of age, and who were referred to a clinical geneticist for etiologic exploration of syndromic hearing loss, associated with moderate learning disabilities. Exome sequencing had been used to establish the molecular diagnosis in five cases, including a two-sibling pair. In the remaining two patients, the diagnosis was obtained with screening of urinary oligosaccharides excretion and the association of deafness and hypotonia. These observations emphasize that the clinical diagnosis of AM can be challenging, and that it is likely an underdiagnosed rare cause of syndromic hearing loss. Exome sequencing can contribute significantly to the early diagnosis of these nonspecific mild phenotypes, with advantages for treatment and management.
- Published
- 2019
34. Pharmacological Chaperones for the Treatment of α-Mannosidosis
- Author
-
Katsumi Higaki, Carmen Ortiz Mellet, Fernando Ortega-Caballero, Reimi Matsumoto, José M. García Fernández, Rocío Rísquez-Cuadro, Eiji Nanba, Universidad de Sevilla. Departamento de Química orgánica, Ministerio de Economía y Competitividad (MINECO). España, Junta de Andalucía, and Japan Society for the Promotion of Science
- Subjects
Mutant ,Amino Acid Motifs ,01 natural sciences ,Cell Line ,03 medical and health sciences ,Glycomimetic ,alpha-Mannosidase ,Lysosome ,Drug Discovery ,medicine ,Humans ,Glycosides ,Enhancer ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,biology ,Chemistry ,Transfection ,Fibroblasts ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,Enzyme ,Biochemistry ,Chaperone (protein) ,Drug Design ,alpha-Mannosidosis ,biology.protein ,Molecular Medicine ,Protein folding ,Imino Pyranoses - Abstract
α-Mannosidosis (AM) results from deficient lysosomal α-mannosidase (LAMAN) activity and subsequent substrate accumulation in the lysosome, leading to severe pathology. Many of the AM-causative mutations compromise enzyme folding and could be rescued with purpose-designed pharmacological chaperones (PCs). We found that PCs combining a LAMAN glycone-binding motif based on the 5N,6O-oxomethylidenemannojirimycin (OMJ) glycomimetic core and different aglycones, in either mono- or multivalent displays, elicit binding modes involving glycone and nonglycone enzyme regions that reinforce the protein folding and stabilization potential. Multivalent derivatives exhibited potent enzyme inhibition that generally prevailed over the chaperone effect. On the contrary, monovalent OMJ derivatives with LAMAN aglycone binding area-fitting substituents proved effective as activity enhancers for several mutant LAMAN forms in AM patient fibroblasts and/or transfected MAN2B1-KO cells. This translated into a significant improvement in endosomal/lysosomal function, reverting not only the primary LAMAN substrate accumulation but also the additional downstream consequences such as cholesterol accumulation. Ministerio de Economía y Competitividad SAF2016-76083-R, CTQ2015-64425-C2-1-R Junta de Andalucía FQM2012-1467 Japan Society for the Promotion of Science 17K10051
- Published
- 2019
35. Intranasal dexmedetomidine and intravenous ketamine for procedural sedation in a child with alpha-mannosidosis: A magic bullet?
- Author
-
Giorgio Cozzi, Matteo Trevisan, Flora Maria Murru, Sara Romano, Irene Bruno, Egidio Barbi, Trevisan, M., Romano, S., Barbi, E., Bruno, I., Murru, F. M., and Cozzi, G.
- Subjects
Male ,Intravenous ketamine ,Sedation ,Alpha-mannosidosis ,Case Report ,Spinal Puncture ,03 medical and health sciences ,0302 clinical medicine ,Dexmedetomidine ,Ketamine ,Procedural sedation ,030225 pediatrics ,medicine ,Humans ,Hypnotics and Sedatives ,030212 general & internal medicine ,Infusions, Intravenous ,Administration, Intranasal ,Anesthetics, Dissociative ,business.industry ,Maternal and child health ,lcsh:RJ1-570 ,lcsh:Pediatrics ,medicine.disease ,Alpha-mannosidosi ,Magnetic Resonance Imaging ,Child, Preschool ,Anesthesia ,Nasal administration ,medicine.symptom ,Magic bullet ,business ,medicine.drug - Abstract
Background Procedural sedation is increasingly needed in pediatrics. Although different drugs or drugs association are available, which is the safest and most efficient has yet to be defined, especially in syndromic children with increased sedation-related risk factors. Case report we report the case of a five-year-old child affected by alpha-mannosidosis who required procedural sedation for an MRI scan and a lumbar puncture. We administered intranasal dexmedetomidine (4 μg/kg) 45 min before intravenous cannulation, followed by one bolus of ketamine (1 mg/kg) for each procedure. The patient maintained spontaneous breathing and no desaturation or any complication occurred. Conclusion intranasal dexmedetomidine and intravenous ketamine could be a feasible option for MRI and lumbar puncture in children with alpha-mannosidosis needing sedation.
- Published
- 2019
36. Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis
- Author
-
Dawn Phillips, Mercedes Gil-Campos, Diego Ardigò, Simon Jones, Paul Harmatz, Yasmina Amraoui, Nathalie Guffon, Philippe Dolhem, Linda De Meirleir, Christine í Dali, Duncan Cole, Federica Cattaneo, Encarna Guillén-Navarro, Silvia Geraci, Allan M. Lund, Anna Tylki-Szymańska, Bénédicte Héron, Jens Fogh, Cecile Laroche, Nicole Muschol, J. M. Hannerieke Van den Hout, Line Borgwardt, Monica Lopez-Rodriguez, and Pediatrics
- Subjects
0301 basic medicine ,Male ,Integrated analysis ,Lysosomal storage disorder ,Severity of Illness Index ,Activities of Daily Living ,genetics ,Genetics(clinical) ,Child ,Genetics (clinical) ,Genetics & Heredity ,education.field_of_study ,Velmanase alfa ,Enzyme replacement therapy ,16. Peace & justice ,Recombinant Human Alpha Mannosidase ,Recombinant Proteins ,3. Good health ,Europe ,Treatment Outcome ,6.1 Pharmaceuticals ,Original Article ,Female ,Adult ,medicine.medical_specialty ,Adolescent ,Alpha-mannosidosis ,Population ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Recombinant human alpha-mannosidase ,03 medical and health sciences ,Young Adult ,Clinical Research ,alpha-Mannosidase ,Internal medicine ,medicine ,Humans ,In patient ,Adverse effect ,education ,business.industry ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,Discontinuation ,030104 developmental biology ,alpha-Mannosidosis ,Quality of Life ,business ,Follow-Up Studies - Abstract
Introduction Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM). Methods Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and the 3-minute stair climb test (3MSCT). Results Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the overall population at 12 months (mean change: –72.7%, P
- Published
- 2018
37. Clinical outcomes in an adult patient with alpha-mannosidosis treated with velmanase alfa for 5 years
- Author
-
Duncan Cole and Katie J. Maw
- Subjects
Pediatrics ,medicine.medical_specialty ,Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Velmanase alfa ,Genetics ,medicine ,medicine.disease ,business ,Molecular Biology ,Biochemistry - Published
- 2021
38. Alpha-mannosidosis from India due to a novel pathogenic variant in MAN2B1 gene
- Author
-
VykuntarajuKammasandra Gowda, AshwinV Sardesai, VarunvenkatM Srinivasan, and SanjayK Shivappa
- Subjects
Genetics ,MAN2B1 gene ,business.industry ,General Neuroscience ,Alpha-mannosidosis ,Pediatrics, Perinatology and Child Health ,medicine ,medicine.disease ,business - Published
- 2021
39. A new randomized placebo-controlled study to establish the safety and efficacy of velmanase alfa (human recombinant alpha-mannosidase) enzyme replacement therapy for the treatment of alpha-mannosidosis
- Author
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Barbara K. Burton, Ferdinando Ceravolo, Loren D M Pena, Federica Cattaneo, Nicola Longo, Ylenia Paleari, Paul Harmatz, Parul Jayakar, and Vernon R. Sutton
- Subjects
business.industry ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Velmanase alfa ,Placebo-controlled study ,Enzyme replacement therapy ,Pharmacology ,alpha-Mannosidase ,medicine.disease ,Biochemistry ,law.invention ,Endocrinology ,law ,Genetics ,Recombinant DNA ,medicine ,business ,Molecular Biology - Published
- 2020
40. Global treatment response analysis of velmanase alfa long term enzyme replacement therapy for alpha-mannosidosis shows treatment benefit across ages
- Author
-
Nathalie Guffon, Linda De Meirleir, Simon Jones, Allan M. Lund, Yasmina Amraoui, Mercedes Gil-Campos, Christine í Dali, Frits A. Wijburg, Federica Cattaneo, Silvia Geraci, Diego Ardigò, Paul Harmatz, Johanna M. P. Van den Hout, Anna Tylki-Szymańska, Nicole Muschol, Line Borgwardt, Reproduction and Genetics, Neurogenetics, Clinical sciences, and Pediatrics
- Subjects
Oncology ,medicine.medical_specialty ,Treatment response ,business.industry ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Velmanase alfa ,Enzyme replacement therapy ,medicine.disease ,Biochemistry ,Term (time) ,Endocrinology ,Internal medicine ,Genetics ,medicine ,business ,Molecular Biology - Published
- 2018
41. Global treatment responder analysis demonstrates clinically relevant effect of velmanase alfa long term enzyme replacement therapy for alpha mannosidosis, in a phase III randomized placebo controlled trial
- Author
-
Simon Jones, Mercedes Gil-Campos, Nicole Muschol, Paul Harmatz, Linda De Meirleir, Federica Cattaneo, Nathalie Guffon, Diego Ardigò, Frits A. Wijburg, Line Borgwardt, Anna Tylki-Szymańska, Yasmina Amraoui, Silvia Geraci, Christine í Dali, Johanna M. P. Van den Hout, Allan M. Lund, Reproduction and Genetics, Neurogenetics, Clinical sciences, and Pediatrics
- Subjects
medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Velmanase alfa ,Placebo-controlled study ,Enzyme replacement therapy ,medicine.disease ,Biochemistry ,Gastroenterology ,Endocrinology ,Internal medicine ,Genetics ,medicine ,business ,Molecular Biology - Published
- 2018
42. The SPARKLE study: Shedding light on alpha mannosidosis
- Author
-
Mercedes Gil-Campos, Nathalie Guffon, Julia B. Hennermann, Stefania Pirondi, Allan M. Lund, Federica Cattaneo, Anna Tylki-Szymańska, Nicole Muschol, and Line Borgwardt
- Subjects
0301 basic medicine ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Incidence (epidemiology) ,Alpha-mannosidosis ,Antibiotics ,Enzyme replacement therapy ,030105 genetics & heredity ,medicine.disease ,Biochemistry ,Pulmonary function testing ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Disease registry ,Quality of life ,Internal medicine ,Genetics ,medicine ,business ,Prospective cohort study ,Molecular Biology ,030217 neurology & neurosurgery - Abstract
Alpha-mannosidosis (AM) is a lysosomal storage disorder caused by reduced activity of the enzyme alpha-mannosidase, leading to intracellular accumulation of mannose-rich oligosaccharides in various organs. Velmanase alfa (VA) is a human recombinant alpha-mannosidase approved in Europe in 2018 as enzyme replacement therapy for the treatment of non-neurological manifestations in mild to moderate AM patients. A post-authorization safety and efficacy registry called SPARKLE was designed as a multi-centre, multi-national, non-interventional, prospective cohort study. SPARKLE has two objectives. The first is to assess post-marketing safety and effectiveness of VA (product registry) the second is to gain new understanding of the natural course of AM (disease registry). In terms of effectiveness, the primary focus is to estimate the treatment response rate based on a multi-parametric response model. The effectiveness assessment includes the measurement of serum oligosaccharides, serum immunoglobulin G levels, endurance, pulmonary function, hearing tests, incidence of infections, use of antibiotics, psychotic events, questionnaires on quality of life and burden of disease for caregivers, among others. All patients affected by AM can participate into the registry, regardless of their treatment. Based on the current protocol, the study will be opened for participation for an indefinite time and each patient will be followed up for 15 years. The protocol does not foresee a pre-specified sample size and aims at including most of the patients treated with VA in clinical practice. The SPARKLE study will start in Europe in the second half of 2019.
- Published
- 2019
43. Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice
- Author
-
Renate Lüllmann-Rauch, Markus Damme, Annika Ericsson, Judith Blanz, Paul Saftig, Michelle Rothaug, Rudi D'Hooge, Claes Andersson, Jens Fogh, Hans Christian Beck, Meike Lüdemann, Stijn Stroobants, and Neurology
- Subjects
mice ,Chronic enzyme replacement therapy ,brain ,Transgene ,Alpha-mannosidosis ,LAMAN ,Neuropathology ,Pharmacology ,Immune system ,Lysosomal storage disease ,medicine ,Medicine(all) ,biology ,business.industry ,General Neuroscience ,Enzyme replacement therapy ,medicine.disease ,3. Good health ,Immunology ,Knockout mouse ,lysosomal storage disease alpha-mannosidosis ,biology.protein ,Neurology (clinical) ,business ,Acid hydrolase ,Research Article - Abstract
OBJECTIVE: The lysosomal storage disease alpha-mannosidosis is caused by the deficiency of the lysosomal acid hydrolase alpha-mannosidase (LAMAN) leading to lysosomal accumulation of neutral mannose-linked oligosaccharides throughout the body, including the brain. Clinical findings in alpha-mannosidosis include skeletal malformations, intellectual disabilities and hearing impairment. To date, no curative treatment is available. We previously developed a beneficial enzyme replacement therapy (ERT) regimen for alpha-mannosidase knockout mice, a valid mouse model for the human disease. However, humoral immune responses against the injected recombinant human alpha-mannosidase (rhLAMAN) precluded long-term studies and chronic treatment. METHODS: Here, we describe the generation of an immune-tolerant alpha-mannosidosis mouse model that allowed chronic injection of rhLAMAN by transgenic expression of a catalytically inactive variant of human LAMAN in the knockout background. RESULTS: Chronic ERT of rhLAMAN revealed pronounced effects on primary substrate storage throughout the brain, normalization of lysosomal enzyme activities and morphology as well as a decrease in microglia activation. The positive effect of long-term ERT on neuronal lysosomal function was reflected by an improvement of cognitive deficits and exploratory activity. in vivo and in vitro uptake measurements indicate rapid clearance of rhLAMAN from circulation and a broad uptake into different cell types of the nervous system. INTERPRETATION: Our data contribute to the understanding of neurological disorders treatment by demonstrating that lysosomal enzymes such as rhLAMAN can penetrate into the brain and is able to ameliorate neuropathology. ispartof: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY vol:2 issue:11 pages:987-1001 ispartof: location:United States status: published
- Published
- 2015
44. Alpha-mannosidosis: characterization of CNS pathology and correlation between CNS pathology and cognitive function
- Author
-
N. Taouatas, Christine í Dali, E.R. Danielsen, A. M. Thuesen, Carsten Thomsen, Allan M. Lund, K. J. Olsen, Jan-Eric Månsson, Jens Fogh, and Line Borgwardt
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Glial fibrillary acidic protein ,biology ,medicine.diagnostic_test ,Alpha-mannosidosis ,Central nervous system ,Magnetic resonance imaging ,medicine.disease ,White matter ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Cerebrospinal fluid ,Gliosis ,Genetics ,medicine ,biology.protein ,Lysosomal storage disease ,medicine.symptom ,030217 neurology & neurosurgery ,Genetics (clinical) - Abstract
Alpha-mannosidosis (AM) (OMIM 248500) is a rare lysosomal storage disease. The understanding of the central nervous system (CNS) pathology is limited. This study is the first describing the CNS pathology and the correlation between the CNS pathology and intellectual disabilities in human AM. Thirty-four patients, aged 6-35 years, with AM were included. Data from 13 healthy controls were included in the analysis of the magnetic resonance spectroscopy (MRS). Measurements of CNS neurodegeneration biomarkers in cerebrospinal fluid (CSF), CSF-oligosaccharides, and performance of cerebral magnetic resonance imaging (MRI) and MRS were carried out. On MRI, 5 of 10 patients had occipital white matter (WM) signal abnormalities, and 6 of 10 patients had age-inappropriate myelination. MRS demonstrated significantly elevated mannose complex in gray matter and WM. We found elevated concentrations of tau-protein, glial fibrillary acidic protein and neurofilament light protein in 97 patients, 74% and 41% of CSF samples, respectively. A negative correlation between CSF-biomarkers and cognitive function and CSF-oligosaccharides and cognitive function was found. The combination of MRS/MRI changes, elevated concentrations of CSF-biomarkers and CSF-oligosaccharides suggests gliosis and reduced myelination, as part of the CNS pathology in AM. Our data demonstrate early neuropathological changes, which may be taken into consideration when planning initiation of treatment.
- Published
- 2015
45. amamutdb.no: A Relational Database for MAN2B1 Allelic Variants that Compiles Genotypes, Clinical Phenotypes, and Biochemical and Structural Data of Mutant MAN2B1 in -Mannosidosis
- Author
-
Pirkko Heikinheimo, Elina Kuokkanen, Øivind Nilssen, Helle Bagterp Klenow, Elisabeth Kjeldsen Buvang, Hilde Monica Frostad Riise Stensland, Dag Malm, and Gabrio Frantzen
- Subjects
Genotype ,Protein Conformation ,Relational database ,Alpha-mannosidosis ,Mutant ,Biology ,Structure-Activity Relationship ,alpha-Mannosidase ,Databases, Genetic ,Genetics ,medicine ,Missense mutation ,Allele ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,Immunodeficiency ,ta1182 ,medicine.disease ,Phenotype ,Mutation ,alpha-Mannosidosis ,Software - Abstract
α-Mannosidosis is an autosomal recessive lysosomal storage disorder caused by mutations in the MAN2B1 gene, encoding lysosomal α-mannosidase. The disorder is characterized by a range of clinical phenotypes of which the major manifestations are mental impairment, hearing impairment, skeletal changes, and immunodeficiency. Here, we report an α-mannosidosis mutation database, amamutdb.no, which has been constructed as a publicly accessible online resource for recording and analyzing MAN2B1 variants (http://amamutdb.no). Our aim has been to offer structured and relational information on MAN2B1 mutations and genotypes along with associated clinical phenotypes. Classifying missense mutations, as pathogenic or benign, is a challenge. Therefore, they have been given special attention as we have compiled all available data that relate to their biochemical, functional, and structural properties. The α-mannosidosis mutation database is comprehensive and relational in the sense that information can be retrieved and compiled across datasets; hence, it will facilitate diagnostics and increase our understanding of the clinical and molecular aspects of α-mannosidosis. We believe that the amamutdb.no structure and architecture will be applicable for the development of databases for any monogenic disorder.
- Published
- 2015
46. Improvement in fine and gross motor proficiency after long-term enzyme replacement therapy with velmanase alfa (human recombinant alpha mannosidase) in alpha-mannosidosis patients
- Author
-
Oluf Andersen, Linda De Meirleir, Nathalie Guffon, Anna Tylki-Szymańska, Diego Ardigò, Christoffer Lindberg, Federica Cattaneo, Line Borgwardt, Yasmine Amraoui, Frits A. Wijburg, Ans T. van der Ploeg, Philippe Dolhem, Silvia Geraci, Lindsey Welling, Thorsten Marquardt, Simon Jones, Bénédicte Héron, Dawn Phillips, Cecile Laroche, Mercedes Gil Campos, Nicole Muschol, Allan M. Lund, Jens Fogh, Elisabeth Jameson, Karl-Eugene Mengel, Johanna M. P. Van den Hout, Reproduction and Genetics, Neurogenetics, Clinical sciences, and Pediatrics
- Subjects
0301 basic medicine ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Gross motor skill ,Velmanase alfa ,Enzyme replacement therapy ,medicine.disease ,alpha-Mannosidase ,Biochemistry ,law.invention ,03 medical and health sciences ,030104 developmental biology ,Endocrinology ,law ,Internal medicine ,Genetics ,medicine ,Recombinant DNA ,business ,Molecular Biology - Published
- 2017
47. Long-term enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase) improves mobility in alpha-mannosidosis patients
- Author
-
Lindsey Welling, Ans T. van der Ploeg, Thorsten Marquardt, Karl-Eugene Mengel, Johanna M. P. Van den Hout, Cecile Laroche, Frits A. Wijburg, Linda De Meirleir, Federica Cattaneo, Diego Ardigò, Yasmina Amraoui, Allan M. Lund, Philippe Dolhem, Jens Fogh, Silvia Geraci, Mercedes Gil Campos, Nathalie Guffon, Oluf Andersen, Nicole Muschol, Elisabeth Jameson, Line Borgwardt, Christoffer Lindberg, Simon Jones, Anna Tylki-Szymańska, Bénédicte Héron, Reproduction and Genetics, Neurogenetics, and Clinical sciences
- Subjects
0301 basic medicine ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Velmanase alfa ,Enzyme replacement therapy ,medicine.disease ,alpha-Mannosidase ,Biochemistry ,law.invention ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,law ,030220 oncology & carcinogenesis ,Internal medicine ,Genetics ,medicine ,Recombinant DNA ,business ,Molecular Biology - Published
- 2017
48. Early onset alpha-mannosidosis: A Turkish case
- Author
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Deniz Kor, Derya Bulut, Sevcan Erdem, Sebile Kılavuz, Neslihan Önenli Mungan, Berna Şeker Yılmaz, and Çukurova Üniversitesi
- Subjects
business.industry ,Turkish ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,education ,medicine.disease ,Biochemistry ,humanities ,language.human_language ,Endocrinology ,Immunology ,Genetics ,medicine ,language ,business ,Molecular Biology ,reproductive and urinary physiology ,health care economics and organizations ,Early onset - Abstract
We're Organizing Research for Lysosomal Diseases (WORLD) Symposium -- FEB 05-09, 2018 -- San Diego, CA WOS: 000424963800258 …
- Published
- 2018
49. Gender, mutations and residual enzymatic activity: Investigation of predictive factors of alpha-mannosidosis phenotypic presentation and of response to velmanase alfa long term enzyme replacement therapy
- Author
-
Christine I. Dali, Line Borgwardt, Allan M. Lund, Federica Cattaneo, Diego Ardigò, Silvia Geraci, Nicole Muschol, Yasmina Amraoui, Anna Tylki-Szymanska, Frits Wijburg, Johanna M.P. Van den Hout, Mercedes Gil-Campos, Nathalie Guffon, Simon A. Jones, and Paul Harmatz
- Subjects
chemistry.chemical_classification ,business.industry ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Velmanase alfa ,Enzyme replacement therapy ,medicine.disease ,Bioinformatics ,Biochemistry ,Phenotype ,Endocrinology ,Enzyme ,chemistry ,Genetics ,Medicine ,Presentation (obstetrics) ,business ,Molecular Biology - Published
- 2018
50. The first study investigating safety and efficacy of velmanase alfa (human recombinant alpha mannosidase) in alpha-mannosidosis patients below six years of age
- Author
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Line Borgwardt, Elisabetta Gelmetti, Nicole Muschol, Allan M. Lund, Vassiliki Konstantopoulou, Federica Cattaneo, Nathalie Guffon, Albina Tummolo, Irene Bruno, and Julia B. Hennermann
- Subjects
business.industry ,Endocrinology, Diabetes and Metabolism ,Alpha-mannosidosis ,Velmanase alfa ,Pharmacology ,medicine.disease ,alpha-Mannosidase ,Biochemistry ,law.invention ,Endocrinology ,law ,Genetics ,Recombinant DNA ,Medicine ,business ,Molecular Biology - Published
- 2019
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