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International Journal of Surgery... Sep 2023Alpha-mannosidosis (AM) is an autosomal recessive lysosomal storage disorder caused by reduced activity of the enzyme alpha-mannosidase. The disease is characterized by...
Alpha-mannosidosis (AM) is an autosomal recessive lysosomal storage disorder caused by reduced activity of the enzyme alpha-mannosidase. The disease is characterized by immunodeficiency, facial and skeletal abnormalities, impaired hearing, and intellectual disability. The clinical subtype of AM shows considerable variability in an individual, and at present, at least three clinical subtypes are suggested. Diagnosis is made by identification of deficiency of α-mannosidase activity in nucleated cells, like fibroblasts. The children are often born apparently normal as the disease is insidiously progressive, hence making early diagnosis essential. Along with supportive care, long-term therapeutic options include hematopoietic stem cell transplant, bone marrow transplantation, and enzyme replacement therapy. The possible benefits of these procedures must be weighed against the overall risk of procedure-related morbidity and mortality. Velmanase alfa is the first human recombinant form of alpha-mannosidase licensed and available for long-term enzyme replacement therapy. It is approved for treating non-neurologic manifestations of mild to moderate AM. The results obtained from different clinical trials provide evidence of the positive clinical effect of the recombinant enzyme on patients with AM. Different routes of diagnosis and unspecific initial symptoms of the disease lead to a delay in the initiation of treatment, resulting in accumulative morbidity. Thus, there is a dire necessity to create more awareness. Furthermore, additional multiple large-scale trials are needed to evaluate the long-term safety and efficacy of velmanase alfa.
Topics: Child; Humans; alpha-Mannosidosis; alpha-Mannosidase; Bone Marrow Transplantation; Cognition; Enzyme Replacement Therapy
PubMed: 37352513
DOI: 10.1097/JS9.0000000000000528 -
Orphanet Journal of Rare Diseases Jun 2018α-mannosidosis is a rare, autosomal-recessive, lysosomal storage disease caused by a deficient activity of α-mannosidase. Typical symptoms include intellectual, motor...
BACKGROUND
α-mannosidosis is a rare, autosomal-recessive, lysosomal storage disease caused by a deficient activity of α-mannosidase. Typical symptoms include intellectual, motor and hearing impairment, facial coarsening, and musculoskeletal abnormalities. Ocular pathologies reported previously were mainly opacities of the cornea and lens, strabismus, and ocular motility disorders. However, retinal and optic nerve degeneration have been rarely described.
METHODS
We report ocular findings of 32 patients with α-mannosidosis. We particularly concentrated on retinal abnormalities which we supported by posterior segment examination, fundus photography, and Spectral-Domain optical coherence tomography (SD-OCT) imaging.
RESULTS
Tapeto-retinal degeneration with bone spicule formations in the peripheral retina or macular changes were seen in three patients (9.4%) on funduscopy; of these, two with optic nerve atrophy. Eight retinal images could be obtained by OCT or fundus photography; of these, six showed thinning of the outer retinal layers on OCT. Overall, optic nerve atrophy was seen in six patients (18.8%); of these, four with partial atrophy. Two patients had partial optic nerve atrophy with no retinal abnormalities on funduscopy. Cataract was seen in two (6.3%), corneal haze also in two patients (6.3%). Six patients (18.8%) had manifest strabismus, four (12.5%) nystagmus, and in five patients (15.6%) impaired smooth pursuit eye movements were seen.
CONCLUSION
Ocular pathologies are not exclusively confined to opacities of the cornea and lens or strabismus and ocular motility disorders but tapeto-retinal degeneration and optic nerve atrophy may be a common feature in α-mannosidosis. OCT technology helps detecting early outer retinal thinning which can progress with age and potentially leads to vision loss over time.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Male; Middle Aged; Nerve Degeneration; Optic Atrophy; Retina; Retinal Degeneration; Tomography, Optical Coherence; Young Adult; alpha-Mannosidosis
PubMed: 29859105
DOI: 10.1186/s13023-018-0829-z -
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 -
Orphanet Journal of Rare Diseases Aug 2020The Roma are a European ethnic minority threatened by several recessive diseases. Variants in MANBA cause a rare lysosomal storage disorder named beta-mannosidosis whose...
Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant.
BACKGROUND
The Roma are a European ethnic minority threatened by several recessive diseases. Variants in MANBA cause a rare lysosomal storage disorder named beta-mannosidosis whose clinical manifestation includes deafness and mental retardation. Since 1986, only 23 patients with beta-mannosidosis and biallelic MANBA variants have been described worldwide.
RESULTS
We now report on further 10 beta-mannosidosis patients of Roma origin from eight families in the Czech and Slovak Republics with hearing loss, mental retardation and homozygous pathogenic variants in MANBA. MANBA variant c.2158-2A>G screening among 345 anonymized normal hearing controls from Roma populations revealed a carrier/heterozygote frequency of 3.77%. This is about 925 times higher than the frequency of this variant in the gnomAD public database and classifies the c.2158-2A>G variant as a prevalent, ethnic-specific variant causing hearing loss and mental retardation in a homozygous state. The frequency of heterozygotes/carriers is similar to another pathogenic variant c.71G>A (p.W24*) in GJB2, regarded as the most frequent variant causing deafness in Roma populations.
CONLCUSION
Beta-mannosidosis, due to a homozygous c.2158-2A>G MANBA variant, is an important and previously unknown cause of hearing loss and mental retardation among Central European Roma.
Topics: Czech Republic; Deafness; Ethnicity; Hearing Loss; Humans; Minority Groups; Roma; Slovakia; beta-Mannosidosis
PubMed: 32847582
DOI: 10.1186/s13023-020-01508-3 -
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 -
Orphanet Journal of Rare Diseases Sep 2020Alpha-mannosidosis is a lysosomal storage disorder caused by reduced enzymatic activity of alpha-mannosidase. SPARKLE is an alpha-mannosidosis registry intended to...
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.
Topics: Enzyme Replacement Therapy; Humans; Multicenter Studies as Topic; Prospective Studies; Registries; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 32993743
DOI: 10.1186/s13023-020-01549-8 -
Molecular Genetics and Metabolism 2019Hereditary β-mannosidosis causing progressive lysosomal neuropathy and other clinical signs, has been previously described in humans, Nubian goats, and Salers cattle....
Hereditary β-mannosidosis causing progressive lysosomal neuropathy and other clinical signs, has been previously described in humans, Nubian goats, and Salers cattle. Here we report the clinicopathological, metabolic, and molecular genetic features of canine beta-mannosidase (MANBA, EC 3.2.1.25) deficiency. A 1-year-old male mix-breed dog from St. Kitts was presented with progressive stumbling, weakness, and regurgitation. Vacuolated lymphocytes were observed on the blood film. Postmortem findings included marked enlargement of nerves, megaesophagus, and internal hydrocephalus. Vacuolated macrophages, neurons, and secretory epithelial cells suggested an oligosaccharide storage disease. Plasma concentration of the β-mannosidosis specific oligosaccharide was approximately 75 fold that of controls. The plasma beta-mannosidase activity was severely reduced to ~5% of controls; five other lysosomal acid hydrolase activities were increased or within their normal reference interval. Genomic sequencing of this dog's MANBA gene identified a homozygous exonic five bp tandem duplication in the penultimate exon of the MANBA gene (c.2377_2381dupTATCA) which results in a reading frame shift, altering the subsequent amino acid sequence and creating a premature stop codon. The truncated beta-mannosidase enzyme is expected to be dysfunctional. This enzyme deficiency causes the accumulation of un-degraded oligosaccharides in cells, which affect the myelination of the peripheral and central nervous systems. This insertion was not encountered in 121 and 80-screened samples from dogs on St. Kitts (all were homozygous for wild-type) and Philadelphia region (wild-type), respectively. In conclusion, canine β-mannosidosis has similar clinicopathological features with some human patients, but milder signs than in ruminants and more severe than in knockout mice. Hence, dogs with β-mannosidosis could become a valuable disease model for the human disease.
Topics: Animals; Codon, Nonsense; DNA Mutational Analysis; Dog Diseases; Dogs; Exons; Male; Mutation; beta-Mannosidase; beta-Mannosidosis
PubMed: 31439511
DOI: 10.1016/j.ymgme.2019.08.002 -
The Journal of Veterinary Medical... Feb 2023Locoweeds, a type of poisonous weedare, are widely distributed throughout the world and have a significant impact on the development of herbivore animal husbandry....
Locoweeds, a type of poisonous weedare, are widely distributed throughout the world and have a significant impact on the development of herbivore animal husbandry. Swainsonine (SW), the main toxin in locoweeds, can competitively inhibit lysosomes α-mannosidase (LAM) in animal cells, resulting in α-mannosidosis. However, the specifics of the interaction between SW and LAM are still unclear. Here, we used molecular docking to predicte the interaction points between SW and LAM, built mutated lysosomes α-mannosidase (LAM), and analyzed its biochemical properties changes in presumption points. The Trp at the 28th position and the Tyr at the 599th position of the LAM were interaction point candidates, and the above two amino acids in Capra hircus LAM (chLAM), were successfully mutated to glycine by constructing recombinant yeast GS115/PIC9K- LAM. The results showed that the sensitivity of Capra hircus LAM (chLAM), to SW decreased significantly compared with wild-type LAM, the enzyme activity of LAM decreased approximately threefold, the optimum temperature of LAM decreased from 55°C to 50°C, the optimum pH value increased from 4.5 to 5.0, and the effects of Mn, Fe, Al, Co, Cr, and ethylenediaminetetraacetic acid (EDTA) on LAM enzyme activity before and after point mutation changed significantly. These findings help us better understanding the molecular mechanism of the interaction mechanism between SW and chLAM, and provide new reference for solving locoweeds poisoning.
Topics: Animals; alpha-Mannosidase; Molecular Docking Simulation; Lysosomes; Swainsonine; Goats; Mannosidases
PubMed: 36596563
DOI: 10.1292/jvms.22-0222 -
Journal of Pediatric Neurosciences 2021β-Mannosidosis is a rare lysosomal storage disorder that is caused by a deficiency of β-mannosidase activity, which is due to mutations of the gene. Two Indian...
β-Mannosidosis is a rare lysosomal storage disorder that is caused by a deficiency of β-mannosidase activity, which is due to mutations of the gene. Two Indian siblings born out of a third-degree consanguineous marriage presented during late infancy with global developmental delay. On examination, both the siblings had hypotonia; hepatosplenomegaly was present in the first sibling whereas it was absent in the second sibling. Fundus evaluation, hearing assessment, and skeletal survey were normal in both siblings. Enzyme assay showed the absence of the β-mannosidase enzyme. Next-generation sequencing showed a homozygous variation of c.1317 + 1G>A in intron 10 of the MANBA (-) gene in the elder sibling. Sanger sequencing confirmed the same mutation in the homozygous state in both siblings and in the heterozygous state in both parents.
PubMed: 35018184
DOI: 10.4103/jpn.JPN_65_20 -
SAGE Open Medical Case Reports 2021β-mannosidosis is a rare autosomal recessive lysosomal storage disease of glycoprotein catabolism caused by a deficiency of β-mannosidase. Clinical presentation...
β-mannosidosis is a rare autosomal recessive lysosomal storage disease of glycoprotein catabolism caused by a deficiency of β-mannosidase. Clinical presentation includes intellectual deficits, hearing loss, and recurrent respiratory infections. This report describes the dental treatment and follow-up dental care of a child with β-mannosidosis. The patient presented to the dental clinic at the age of 6 years with a localized swelling of his lower posterior teeth. Sickle cell disease and physical and mental developmental delays were noted. Clinical examination revealed a flattened nasal bridge, large head, short neck, open bite, gingival overgrowth, macroglossia, enlarged pulp chambers, and poor oral hygiene. Surgical treatment under general anesthesia included extractions, pulp therapy, and restorations. Four years later, the child returned with generalized gingival inflammation and new carious lesions. Periodontal and restorative treatment was provided, and a preventive dental regimen was established. Mannosidosis cases require complex dental procedures, consultations, and prompt follow-up.
PubMed: 34925842
DOI: 10.1177/2050313X211065796