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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 -
Advances in Therapy Jan 2021Alpha-mannosidosis is a rare lysosomal storage disorder that generally presents in early childhood. It is a progressive, highly heterogeneous disease that is difficult...
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.
Topics: Adult; Caregivers; Child; Child, Preschool; Female; Humans; Italy; Male; Physicians; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 33231860
DOI: 10.1007/s12325-020-01574-w -
Pediatric Pulmonology Sep 2020α Mannosidosis is an extremely rare, progressive, and complex lysosomal storage disease, characterized by mental retardation, hearing impairment, coarse facial...
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.
Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Disease Progression; Exercise Test; Female; Humans; Male; Respiratory Function Tests; Tomography, X-Ray Computed; Young Adult; alpha-Mannosidosis
PubMed: 32445542
DOI: 10.1002/ppul.24864 -
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 -
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 -
International Journal of Pediatric... Jun 2023Alpha-mannosidase catalyze lysosomal cleaving of mannose residues from glycoproteins. The enzyme is encoded by the MAN2B1 gene. Biallelic pathogenic variants cause...
Alpha-mannosidase catalyze lysosomal cleaving of mannose residues from glycoproteins. The enzyme is encoded by the MAN2B1 gene. Biallelic pathogenic variants cause enzymatic deficiency, which clinically results in alpha-mannosidosis (AM), an autosomal recessively inherited condition. Typical features observed in AM patients include intellectual disability, loss of speech, dysmorphic features, progressive motor problems, ataxia, hearing impairment and recurrent otitis. The cause of the latter is mainly attributed to immunodeficiency. The aim of our study was to demonstrate the otolaryngologic and hearing outcomes in patients with AM. The study group consisted of 8 AM patients: 6 males and 2 females, aged 2.5-37 yrs. The clinical course, dysmorphic ENT features, hearing status and the HRCT scans of the temporal bones were analyzed. MS Excel for Windows and Statistica software package were used for the comparison of interaural audiometric loss, mean hearing loss and mean hearing threshold for each patient's audiometric frequency tested. We identified ENT dysmorphic features in all of our AM patients, while the hearing loss was detected in 6 out of our 8 patients. For those cases, the onset of deafness was noted in the first decade of life, this impairment was sensorineural, of cochlear origin, bilateral, of a moderate degree (mean loss 62.76 dB; median 60 dB, standard deviation 12.5 dB), symmetrical and stable. The shape of the audiometric curves of our patients can be described as slightly sloping towards the higher tested frequencies, with a marked improvement at 4 kHz. The radiological examination revealed normal structures of the ears, with the exception of one case where a persistent otitis generated a cochlear gap. We therefore concluded that the hearing loss in our AM patients derived from cochlear impairment unrelated with recurrent otitis.
Topics: Male; Female; Humans; alpha-Mannosidosis; Poland; Hearing Loss; alpha-Mannosidase; Audiometry; Hearing Loss, Sensorineural
PubMed: 37099947
DOI: 10.1016/j.ijporl.2023.111556 -
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 -
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