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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 -
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 -
Orphanet Journal of Rare Diseases Jun 2015Alpha-mannosidosis is caused by mutations in MAN2B1, leading to loss of lysosomal alpha-mannosidase activity. Symptoms include intellectual disabilities, hearing... (Clinical Trial)
Clinical Trial
BACKGROUND
Alpha-mannosidosis is caused by mutations in MAN2B1, leading to loss of lysosomal alpha-mannosidase activity. Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities.
METHODS
To study the genotype-phenotype relationship for alpha-mannosidosis 66 patients were included. Based on the predicted effect of the mutations and the subcellular localisation of mutant MAN2B1 in cultured cells, the patients were divided into three subgroups. Clinical and biochemical data were collected. Correlation analyses between each of the three subgroups of genotype/subcellular localisation and the clinical and biochemical data were done to investigate the potential relationship between genotype and phenotype in alpha-mannosidosis. Statistical analyses were performed using the SPSS software. Analyses of covariance were performed to describe the genotype-phenotype correlations. The phenotype parameters were modelled by the mutation group and age as a covariate. P values of <0.05 were considered as statistically significant.
RESULTS
Complete MAN2B1 genotypes were established for all patients. We found significantly higher scores in the Leiter-R test, lower concentrations of CSF-oligosaccharides, higher point scores in the Bruininks-Oseretsky Test of Motor Proficiency subtests (BOT-2); Upper limb coordination and Balance, and a higher FVC% in patients in subgroup 3, harbouring at least one variant that allows localisation of the mutant MAN2B1 protein to the lysosomes compared to subgrou 2 and/or subgroup 1 with no lysosomal localization of the mutant MAN2B1 protein.
CONCLUSION
Our results indicate a correlation between the MAN2B1 genotypes and the cognitive function, upper limb coordination, balance, FVC% and the storage of oligosaccharides in CSF. This correlation depends on the subcellular localisation of the mutant MAN2B1 protein.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Genetic Association Studies; Genotype; Humans; Male; Mannosidases; Oligosaccharides; Phenotype; Young Adult; alpha-Mannosidosis
PubMed: 26048034
DOI: 10.1186/s13023-015-0286-x -
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 -
Molecular Genetics and Metabolism Jul 2019Multiplex tandem mass spectrometry (MS/MS)-based enzyme activity assays for newborn screening (NBS) and diagnosis of lysosomal storage diseases (LSDs) in newborns, using...
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.
Topics: Enzyme Assays; Fucosidosis; Humans; Infant, Newborn; Lysosomal Storage Diseases; Neonatal Screening; Tandem Mass Spectrometry; alpha-Mannosidosis
PubMed: 31235216
DOI: 10.1016/j.ymgme.2019.05.016 -
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 -
Molecular Genetics and Metabolism Apr 2019Alpha-mannosidosis is an ultra-rare progressive lysosomal storage disorder caused by deficiency of alpha-mannosidase. Timely diagnosis of the disease has the potential...
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.
Topics: Adolescent; Adult; Age Factors; Algorithms; Child; Child, Preschool; Consensus; Disease Progression; Humans; Internationality; Middle Aged; Young Adult; alpha-Mannosidosis
PubMed: 30792122
DOI: 10.1016/j.ymgme.2019.01.024 -
Molecular Genetics and Metabolism... Mar 2022Alpha-mannosidosis (AM) is a rare autosomal recessive lysosomal storage disease which the natural history has not been exhaustively described yet. The aim of this study...
INTRODUCTION
Alpha-mannosidosis (AM) is a rare autosomal recessive lysosomal storage disease which the natural history has not been exhaustively described yet. The aim of this study was to present the long-term follow-up of 12 Polish patients with AM, evaluate the clinical, biochemical, and molecular findings and progression of the disease.
MATERIAL AND METHODS
The article presents a long-term (over 30 years) observational, retrospective, single-center study of patients with AM.
RESULTS
The hearing loss, as one of the first symptoms, was detected in childhood (mean age of 2 years and 6 months) in 10 patients. The other symptoms include: recurrent infections (all patients), inguinal hernias (6 patients), craniosynostosis (1 patient). The mean age at AM diagnosis was 6 years while median was 4 years (age range: 1 year and 8 months - 12 years). The most commonly identified variant in the 1 gene was c.2245C > T, p.(Arg749Trp). The mean time of follow-up in our study was approximately 14 years (range: 1 year - 26 years). Following birth, children with AM grow slowly, finally reaching the 3rd percentile (or values below the 3rd percentile). Hearing loss was not progressive while a gradual exacerbation of intellectual disability with no developmental regression was observed in all patients. Ataxia was diagnosed in 6 patients in the second decade of life (age range 15-20 years).
CONCLUSIONS
Our study revealed the sensorineural hearing loss as one of the first noted symptom in AM which was congenital and non-progressive during the natural course of disease. A detailed anthropometric phenotype of AM patients was provided with observation of the growth decline during the long-term follow-up. Our study confirmed the existence of two distinguished clinical phenotypes of AM (mild and moderate), and also the lack of clear genotype-phenotype correlation.
PubMed: 35242565
DOI: 10.1016/j.ymgmr.2021.100826 -
Cureus Apr 2024Alpha-mannosidosis is a rare lysosomal storage disorder with progressive impairments in motor functions, skeletal deformities, and immunodeficiency. Enzyme replacement...
Prenatal Diagnosis of c.437-1G>A Mutation in the MAN2B1 Gene in a Family With Alpha-Mannosidosis: Unraveling Clinical Presentation and Treatment Outcomes in a Novel Prenatal Case.
Alpha-mannosidosis is a rare lysosomal storage disorder with progressive impairments in motor functions, skeletal deformities, and immunodeficiency. Enzyme replacement therapy (ERT) should be initiated early to achieve optimal outcomes. This report describes how alpha-mannosidosis diagnosis in a seven-year-old girl led to a successful prenatal diagnosis in the subsequent pregnancy and pre-symptomatic treatment at the early disease stage. The index patient was a seven-year-old girl who was referred with a confirmed diagnosis of alpha-mannosidosis based on the presence of homozygous c.437-1G>A mutation in the MAN2B1 gene. A prenatal diagnosis was made in the subsequent pregnancy through molecular analysis, which revealed the same homozygous variant. The patient was treated at the fifth week of age and showed mild skeletal involvement and normal development at ERT initiation. At 11 months of age, the ERT level increased to 15.8 µmol/l/h. The motor assessment showed that the patient was developmentally normal and was able to maintain her sitting and walking for a few steps only. Prenatal molecular screening in affected families can allow for the early identification and implementation of appropriate management strategies for alpha-mannosidosis.
PubMed: 38800253
DOI: 10.7759/cureus.58922 -
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