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Frontiers in Bioscience (Landmark... Feb 2023Alpha-mannosidosis is a rare lysosomal storage disorder, caused by decreased activity of α-D-mannosidase. This enzyme is involved in the hydrolysis of mannosidic...
BACKGROUND
Alpha-mannosidosis is a rare lysosomal storage disorder, caused by decreased activity of α-D-mannosidase. This enzyme is involved in the hydrolysis of mannosidic linkages in N-linked oligosaccharides. Due to the mannosidase defect, undigested mannose-rich oligosaccharides (Man2GlcNAc - Man9GlcNAc) accumulating in cells are excreted in large quantities in urine.
METHODS
In this work, we determined the levels of urinary mannose-rich oligosaccharides in a patient subjected to novel enzyme replacement therapy. Urinary oligosaccharides were extracted using solid phase extraction (SPE), labeled by fluorescent tag 2-aminobenzamide, and quantified by high-performance liquid chromatography (HPLC) with fluorescence detector (FLD). The identity of peaks was determined by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF) mass spectrometry. In addition, the levels of urinary mannose-rich oligosaccharides were also quantified by 1H nuclear magnetic resonance (NMR) spectroscopy. The data were analyzed using one-tailed paired -test and Pearson's correlation tests.
RESULTS
Compared to levels before the administration of therapy, an approximately two-folds decrease in total mannose-rich oligosaccharides after one month of treatment was observed by NMR and HPLC. After four months, an approximately ten-folds significant decrease in total urinary mannose-rich oligosaccharides was detected, suggesting therapy effectiveness. A significant decrease in the levels of oligosaccharides with 7-9 mannose units was detected by HPLC.
CONCLUSIONS
The application of both HPLC-FLD and NMR in quantification of oligosaccharide biomarkers is a suitable approach for monitoring of therapy efficacy in alpha-mannosidosis patients.
Topics: Humans; Chromatography, High Pressure Liquid; alpha-Mannosidosis; Mannose; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy
PubMed: 36866557
DOI: 10.31083/j.fbl2802039 -
Journal of Inherited Metabolic Disease Jul 2023Alpha-mannosidosis (AM) is a rare, autosomal recessive, lysosomal storage disorder caused by alpha-mannosidase deficiency that leads to the accumulation of mannose-rich...
Alpha-mannosidosis (AM) is a rare, autosomal recessive, lysosomal storage disorder caused by alpha-mannosidase deficiency that leads to the accumulation of mannose-rich oligosaccharides. AM symptoms and severity vary among individuals; consequently, AM is often not diagnosed until late childhood. Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase product, is the first enzyme replacement therapy indicated to treat non-neurological symptoms of AM in Europe. Previous studies suggested that early VA treatment in children may produce greater clinical benefit over the disease course than starting treatment in adolescents or adults; however, long-term studies in children are limited, and very few studies include children under 6 years of age. The present phase 2, multicenter, open-label study evaluated the safety and efficacy of long-term VA treatment in children under 6 years of age with AM. Five children (three males) received VA weekly for ≥24 months, and all children completed the study. Four children experienced adverse drug reactions (16 events) and two experienced infusion-related reactions (12 events). Most (99.5%) adverse events were mild or moderate, and none caused study discontinuation. Four children developed antidrug antibodies (three were neutralizing). After VA treatment, all children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreases), hearing, immunological profile, and quality of life, suggesting a beneficial effect of early treatment. Although the small study size limits conclusions, these results suggest that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to patients with AM under 6 years of age.
Topics: Male; Adult; Adolescent; Humans; Child; Child, Preschool; alpha-Mannosidosis; Quality of Life; alpha-Mannosidase; Lysosomes; Antibodies
PubMed: 36849760
DOI: 10.1002/jimd.12602 -
Molecular Genetics and Metabolism... Sep 2019Alpha-mannosidosis is an ultra-rare lysosomal storage disorder resulting from the deficient activity of lysosomal alpha-mannosidase. Alpha-mannosidosis presents as a...
INTRODUCTION
Alpha-mannosidosis is an ultra-rare lysosomal storage disorder resulting from the deficient activity of lysosomal alpha-mannosidase. Alpha-mannosidosis presents as a highly heterogenous condition with large variations in symptom severity and disease progression rates. Quantitative and qualitative data for alpha-mannosidosis patients and their caregivers provide important insights into their daily experiences.
METHODS
A survey of nine alpha-mannosidosis patients was carried out in the UK between August 2017 and January 2018. Patient demographics, health-related quality of life (HRQoL), and qualitative data from patients and carers relating to clinical characteristics and impact of the disease and treatment were analysed.
RESULTS
At the time of survey completion, patient age ranged from 7 to 37 years. Five patients were described as 'walking unassisted', one as 'walking with assistance', one as 'wheelchair-dependent', and two as 'severely immobile'. In addition to best supportive care, three patients had received haematopoietic stem cell transplantation (HSCT) and one had received velmanase alfa enzyme replacement therapy (ERT). Patient HRQoL results for the EQ-5D-5 L questionnaire and the Health Utilities Index-3 showed that patients with more severe ambulatory health states reported lower utility values than patients who were more mobile. Patients who received HSCT or ERT experienced improved HRQoL. Carer HRQoL results for the Hospital Anxiety and Depression Scale and Caregiver Strain Index demonstrated that carers experience high levels of stress and anxiety from their caregiving responsibilities.
CONCLUSIONS
This survey confirmed the heterogeneity of alpha-mannosidosis and the large impact of the disease and treatment on patients, carers, and families. Early diagnosis and access to treatment offers the best chance of slowing the disease progression and may provide some relief to patients and carers.
PubMed: 31198684
DOI: 10.1016/j.ymgmr.2019.100480 -
Journal of Pediatric Endocrinology &... Dec 2023Alpha-mannosidosis is a rare genetic lysosomal storage condition leading to the systemic buildup of oligomannoside. Clinical presentation and associated conditions, as...
OBJECTIVES
Alpha-mannosidosis is a rare genetic lysosomal storage condition leading to the systemic buildup of oligomannoside. Clinical presentation and associated conditions, as well as the full extent of histopathologic changes associated with this disease process, are not fully understood.
CASE PRESENTATION
We present the case of an 8-year-1-month old patient with persistent anemia and who was initially diagnosed with Celiac disease before ultimately being diagnosed with alpha-mannosidosis. As part of his diagnostic work-up, duodenal and bone marrow biopsies were examined by pathology. Duodenal biopsies showed foamy plasma cells expanding the lamina propria which triggered a workup for a genetic storage disease; features suggestive of Celiac disease which resolved on gluten-free diet were also noted by pathology. Bone marrow analysis via electron microscopy showed cytoplasmic granules and inclusions in multiple immune cell lines.
CONCLUSIONS
Alpha-mannosidosis can occur with Celiac disease and milder forms may only be suspected from incidental pathology findings. The ultrastructural bone marrow findings from this case, the first to be reported from human, show numerous disease-associated changes in multiple immune cell lines whose contribution to disease-associated immunodeficiency is unclear.
Topics: Humans; Infant; alpha-Mannosidosis; Microscopy; Celiac Disease; Lysosomal Storage Diseases
PubMed: 37979187
DOI: 10.1515/jpem-2023-0357 -
The Canadian Journal of Neurological... Sep 2022
Topics: Contrast Media; Humans; Magnetic Resonance Imaging; Thalamus; alpha-Mannosidosis
PubMed: 34486965
DOI: 10.1017/cjn.2021.208 -
American Journal of Medical Genetics.... Jul 2023We describe the first case of bridge therapy in alpha-mannosidosis (AM) in an infant diagnosed at only 5 months of life who underwent enzyme replacement therapy (ERT)...
We describe the first case of bridge therapy in alpha-mannosidosis (AM) in an infant diagnosed at only 5 months of life who underwent enzyme replacement therapy (ERT) in the pre- and peri-transplant phases. Eight ERT infusions were administered before hematopoietic stem cell transplantation (HSCT) and continued for additional 90 days until complete engraftment. The clinical and laboratory data after 3 years post-HSCT show that the early combined intervention may reduce the disease progression and the urine and plasma content of mannosyl-oligosaccharides (OS) monitored by liquid chromatography tandem mass spectrometry (LC-MS/MS). This report highlights that early diagnosis and prompt initiation of such treatments in AM are the best chance to minimize the progression of symptoms.
Topics: Infant; Humans; alpha-Mannosidosis; Enzyme Replacement Therapy; Chromatography, Liquid; Tandem Mass Spectrometry; Hematopoietic Stem Cell Transplantation
PubMed: 37045799
DOI: 10.1002/ajmg.a.63210 -
Clinical Dysmorphology Jan 2024Alpha-mannosidosis (MIM #248500) is an ultra-rare autosomal recessive lysosomal storage disease with multi-system involvement and a wide phenotypic spectrum. Information...
Alpha-mannosidosis (MIM #248500) is an ultra-rare autosomal recessive lysosomal storage disease with multi-system involvement and a wide phenotypic spectrum. Information on long-term outcomes remains poor. We present the long-term outcomes (median, 19 years) of nine patients with alpha-mannosidosis, three females and six males, followed at a single center. The findings of the nine patients were collected from medical records and reported as mean ± SD or median, and range. The age of onset of the first symptoms ranged from 0-1 to 10 years. The diagnostic delay ranged from 2 to 22 years (median= 11 years). Coarse face, hearing, heart valves, joints, gait, language, dysarthria, psychiatric symptoms, I.Q., MRI, walking disabilities, orthopedic disturbances and surgeries showed a slow worsening over the decades. Our patients showed a slowly worsening progressive outcome over the decades. Psychiatric symptoms were present in 100% of our population and improved with the appropriate pharmacological intervention. This aspect requires attention when following up on these patients. Our description of the long-term evolution of alpha-mannosidosis patients may provide basic knowledge for understanding the effects of specific treatments.
Topics: Male; Female; Humans; Infant, Newborn; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; alpha-Mannosidosis; Delayed Diagnosis; Mental Disorders; Inheritance Patterns; Italy
PubMed: 37791705
DOI: 10.1097/MCD.0000000000000474 -
Journal of Inherited Metabolic Disease Mar 2023Oligosaccharidoses, sphingolipidoses and mucolipidoses are lysosomal storage disorders (LSDs) in which defective breakdown of glycan-side chains of glycosylated proteins...
Oligosaccharidoses, sphingolipidoses and mucolipidoses are lysosomal storage disorders (LSDs) in which defective breakdown of glycan-side chains of glycosylated proteins and glycolipids leads to the accumulation of incompletely degraded oligosaccharides within lysosomes. In metabolic laboratories, these disorders are commonly diagnosed by thin-layer chromatography (TLC) but more recently also mass spectrometry-based approaches have been published. To expand the possibilities to screen for these diseases, we developed an ultra-high-performance liquid chromatography (UHPLC) with a high-resolution accurate mass (HRAM) mass spectrometry (MS) screening platform, together with an open-source iterative bioinformatics pipeline. This pipeline generates comprehensive biomarker profiles and allows for extensive quality control (QC) monitoring. Using this platform, we were able to identify α-mannosidosis, β-mannosidosis, α-N-acetylgalactosaminidase deficiency, sialidosis, galactosialidosis, fucosidosis, aspartylglucosaminuria, GM1 gangliosidosis, GM2 gangliosidosis (M. Sandhoff) and mucolipidosis II/III in patient samples. Aberrant urinary oligosaccharide excretions were also detected for other disorders, including NGLY1 congenital disorder of deglycosylation, sialic acid storage disease, MPS type IV B and GSD II (Pompe disease). For the latter disorder, we identified heptahexose (Hex7), as a potential urinary biomarker, in addition to glucose tetrasaccharide (Glc4), for the diagnosis and monitoring of young onset cases of Pompe disease. Occasionally, so-called "neonate" biomarker profiles were observed in young patients, which were probably due to nutrition. Our UHPLC/HRAM-MS screening platform can easily be adopted in biochemical laboratories and allows for simple and robust screening and straightforward interpretation of the screening results to detect disorders in which aberrant oligosaccharides accumulate.
Topics: Humans; Chromatography, High Pressure Liquid; Glycogen Storage Disease Type II; Lysosomal Storage Diseases; Mucolipidoses; Tandem Mass Spectrometry; Oligosaccharides; Mucopolysaccharidosis IV
PubMed: 36752951
DOI: 10.1002/jimd.12597 -
Molecular Genetics and Metabolism May 2024Alpha-mannosidosis is an ultra-rare lysosomal disease that is caused by variants of the MAN2B1 gene on chromosome 19p13. These variants result in faulty or absent... (Review)
Review
Alpha-mannosidosis is an ultra-rare lysosomal disease that is caused by variants of the MAN2B1 gene on chromosome 19p13. These variants result in faulty or absent alpha-mannosidase in lysosomes, which leads to intracellular accumulation of mannose-containing oligosaccharides. Diagnosis of alpha-mannosidosis is often delayed, in part because of the rarity of the disease, its gradual onset and heterogeneity of presentation, but also because of the similarity of many signs and symptoms of the disease to those of other lysosomal diseases. Treatment of alpha-mannosidosis was previously limited to hematopoietic stem cell transplantation, but outcomes are variable and not all patients are eligible or have a suitable donor. Recently, an enzyme replacement therapy, recombinant human alpha-mannosidase (velmanase alfa), was approved for the treatment of non-neurological manifestations in adult and pediatric patients with alpha-mannosidosis. Treatment with velmanase alfa reduces serum levels of oligosaccharides, increases levels of immunoglobulin G, and improves patients' functional capacity and quality of life, although it is not effective for the neurologic phenotype because it does not cross the blood-brain barrier. Since the effects of velmanase alfa are more marked in children than adults, early diagnosis to allow early initiation of treatment has become more important. To support this, patient, parent/caregiver, and clinician awareness and education is imperative. A number of approaches can be taken to meet this goal, such as the development of disease registries, validated diagnostic algorithms, and screening tools, improved under-/post-graduate clinician education, easily accessible and reliable information for patients/families (such as that made available on the internet), and the formation of patient advocacy groups. Such approaches may raise awareness of alpha-mannosidosis, reduce the diagnostic delay and thus improve the lives of those affected.
Topics: Humans; alpha-Mannosidosis; Enzyme Replacement Therapy; alpha-Mannosidase; Delayed Diagnosis; Rare Diseases
PubMed: 38555683
DOI: 10.1016/j.ymgme.2024.108444 -
JIMD Reports Mar 2023Alpha-mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the gene, leads to lysosomal alpha-mannosidase deficiency and...
Relationship between genotype/subcellular localization subgroups, antidrug antibody detection, and long-term velmanase alfa treatment outcomes in patients with alpha-mannosidosis.
Alpha-mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the gene, leads to lysosomal alpha-mannosidase deficiency and accumulation of mannose-rich oligosaccharides. Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase, is the first enzyme replacement therapy for non-neurological symptoms of AM. Previously, a potential relationship was identified between three genotype/subcellular localization subgroups (G1, G2, and G3) and AM disease severity. In VA-treated patients with AM, it is unknown if a relationship exists between genotype/subcellular localization subgroups, antidrug antibodies (ADAs), and infusion-related reactions (IRRs). This pooled analysis evaluated data from 33 VA-treated patients with AM to investigate this relationship. Overall, 10 patients were positive for ADAs, 4 of whom had treatment-emergent ADAs (G1: 3/7 [43%]; G2: 1/17 [6%]; G3: 0/9). Treatment-emergent ADA-positive patients with relatively high titers ( = 2; G1: 1012 U/ml and G2: 440 U/ml) experienced mild/moderate IRRs that were well-managed; patients with lower titers ( = 2) experienced no IRRs. Overall, changes from baseline in serum oligosaccharides and immunoglobulin G levels did not vary between ADA-positive and ADA-negative patients, suggesting a similar effect of VA treatment regardless of ADA status in most patients. Clinical outcomes (3MSCT and 6MWT) were also similar in most patients regardless of ADA status. While further studies are needed, these data suggest a relationship between genotype/subcellular localization subgroups and ADA development, with G1 and G2 subgroups more likely to develop ADAs and IRRs. Regardless, this study suggests that ADAs have limited effect on the clinical impact of VA in most patients with AM.
PubMed: 36873087
DOI: 10.1002/jmd2.12349