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International Journal of Molecular... May 2018Alpha-mannosidosis (α-mannosidosis) is a rare lysosomal storage disorder with an autosomal recessive inheritance caused by mutations in the gene encoding for the... (Review)
Review
Alpha-mannosidosis (α-mannosidosis) is a rare lysosomal storage disorder with an autosomal recessive inheritance caused by mutations in the gene encoding for the lysosomal α-d-mannosidase. So far, 155 variants from 191 patients have been identified and in part characterized at the biochemical level. Similarly to other lysosomal storage diseases, there is no relationship between genotype and phenotype in alpha-mannosidosis. Enzyme replacement therapy is at the moment the most effective therapy for lysosomal storage disease, including alpha-mannosidosis. In this review, the genetic of alpha-mannosidosis has been described together with the results so far obtained by two different therapeutic strategies: bone marrow transplantation and enzyme replacement therapy. The primary indication to offer hematopoietic stem cell transplantation in patients affected by alpha-mannosidosis is preservation of neurocognitive function and prevention of early death. The results obtained from a Phase I⁻II study and a Phase III study provide evidence of the positive clinical effect of the recombinant enzyme on patients with alpha-mannosidosis.
Topics: Animals; Bone Marrow Transplantation; Combined Modality Therapy; Enzyme Activation; Enzyme Replacement Therapy; Genetic Association Studies; Humans; Mutation; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 29772816
DOI: 10.3390/ijms19051500 -
Frontiers in Bioscience (Landmark... Jan 2017Lysosomal 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... (Review)
Review
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.
Topics: Animals; Disease Models, Animal; Enzyme Replacement Therapy; Humans; Lysosomes; Mutation; Recombinant Proteins; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 27814608
DOI: 10.2741/4478 -
Orphanet Journal of Rare Diseases Jul 2022Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder (LSD) caused by reduced activity of alpha-mannosidase. Clinical manifestations include... (Review)
Review
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.
Topics: Adult; Child, Preschool; Female; Humans; Male; Middle Aged; alpha-Mannosidase; alpha-Mannosidosis; Hearing Loss; Intellectual Disability
PubMed: 35871018
DOI: 10.1186/s13023-022-02422-6 -
JIMD Reports Nov 2019Alpha-mannosidosis is a rare inherited metabolic disorder (OMIM #248500) caused by mutations in the enzyme α-mannosidase encoded by the gene . Patients have distinct...
Alpha-mannosidosis is a rare inherited metabolic disorder (OMIM #248500) caused by mutations in the enzyme α-mannosidase encoded by the gene . 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.
PubMed: 31741826
DOI: 10.1002/jmd2.12073 -
Cells Jun 2020The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis,... (Review)
Review
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
Topics: Animals; Enzyme Replacement Therapy; Glycoproteins; Hematopoietic Stem Cell Transplantation; Humans; Lysosomal Storage Diseases
PubMed: 32517081
DOI: 10.3390/cells9061411 -
Frontiers in Genetics 2023Alpha-mannosidosis caused by mutations in the gene is a rare genetic disorder characterized by physical abnormalities and intellectual disabilities. The objective of...
Alpha-mannosidosis caused by mutations in the gene is a rare genetic disorder characterized by physical abnormalities and intellectual disabilities. The objective of this study was to analyze the carrier frequency and estimated incidence of alpha-mannosidosis in East Asian populations, as limited data exists on its incidence in this group. In this study, a total of 125,748 exomes from the gnomAD database was analyzed. Additionally, 5,305 data from the KOVA and 1,722 data from the KRGDB, both representing Korean populations, were included. The global carrier frequency of alpha-mannosidosis in gnomAD was 0.23%; the highest carrier frequency was observed in the Finnish at 0.49%, and East Asians had the second highest carrier frequency at 0.30%. Globally, the approximate incidence of alpha-mannosidosis was calculated at 1 in 784,535, l in 166,801 Europeans (Finnish), and l in 431,689 East Asians. By integrating the data from the 8,936 Koreans in gnomAD Korean, KOVA and KRGDB, the carrier frequency of alpha-mannosidosis in the Korean population was 0.04% and estimated incidence was 1 in 19,963,024. This study is the first to investigate the carrier frequencies of alpha-mannosidosis in East Asians and Koreans, including specific subpopulations, utilizing gnomAD and the Korean genomic database. The variant spectrum of genes in East Asians showed significant differences compared to other ethnic groups. Our data provide valuable reference information for future investigations into alpha-mannosidosis, aiding in understanding the genetic diversity and specific variants associated with the condition in East Asian populations.
PubMed: 38107468
DOI: 10.3389/fgene.2023.1297543 -
Anais Da Academia Brasileira de Ciencias 2021It 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... (Review)
Review
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. fistulosa, 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.
Topics: Animals; Argentina; Guinea Pigs; Plant Poisoning; Plants, Toxic; Ruminants; alpha-Mannosidosis
PubMed: 34787167
DOI: 10.1590/0001-3765202120191496 -
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 -
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