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Background: a-mannosidosis (MAN) is a rare genetic condition that segregates in an autosomal recessive manner. Lack of lysosomal alpha-mannosidase is the underlying cause of the disease. Symptoms of the disease gradually worsen with the age. Newborns are usually asymptomatic, however, some cases are reported with either congenital ankle equinus or hydrocephalus during the first year. Primary symptoms are characterized by immune deficiency, hearing loss, skeletal abnormalities, progressive mental, motor and speech functions' impairment followed by facial asymmetry. Methods: We studied two Saudi families (A and B) with bilateral moderate hearing loss (family A) and clubfoot with glaucoma (family B). Clinical diagnosis was not reached based on phenotype of patients. Therefore, hypothesis-free whole exome sequencing (WES) was performed on DNA samples from affected individuals of both the families, followed by Sanger sequencing and segregation analysis to validate the segregation of the identified variant. Furthermore, 3D protein modelling was performed to determine the in silico effects of the identified variant on the protein structure and function. Results: Re-examination of clinical features revealed that the patients in family A have speech delay and hearing impairment along with craniostenosis, whereas the patients from family B have only clubfoot and glaucoma. WES identified a well known pathogenic homozygous frameshift variant (NM_000528.4: c.2402dupG; p.S802fs*129) in MAN2B1 in both the families. Sanger sequencing confirmed the segregation of the variant with the disease phenotype in both the families. 3D structural modeling of the MAN2B1 protein revealed significant changes in the tertiary structure of the mutant protein, which would affect enzyme function. This report presents a new case where partial and novel a-mannosidosis phenotypes are associated with a MAN2B1 gene pathogenic variant. Conclusion: Patients in both the families have manifested peculiar set of clinical symptoms associated with a-mannosidosis. Family A manifested partial clinical symptoms missing several characteristic features like intellectual disability, dysmorphic features, neurological and abdominal manifestations, whereas family B has no reported clinical symptoms related to a-mannosidosis except the novel symptoms including club foot and glaucoma which has never been reported earlier The current findings support the evidence that biallelic variants of MAN2B1 are associated with new clinical variants of a-mannosidosis. [ABSTRACT FROM AUTHOR]

Alpha‐mannosidosis is a rare autosomal recessive lysosomal storage disorder caused by biallelic mutations in the MAN2B1 gene and characterized by a wide clinical heterogeneity. Diagnosis for this multisystemic disorder is confirmed by the presence of either a deficiency in the lysosomal enzyme acid alpha‐mannosidase or biallelic mutations in the MAN2B1 gene. This diagnosis confirmation is crucial for both clinical management and genetic counseling purposes. Here we describe a late diagnosis of alpha‐mannosidosis in a patient presenting with syndromic intellectual disability, and a rare retinopathy, where reverse phenotyping played a pivotal role in interpreting the exome sequencing result. While a first missense variant was classified as a variant of uncertain significance, the phenotype‐guided analysis helped us detect and interpret an in‐trans apparent alu‐element insertion, which appeared to be a copy number variant (CNV) not identified by the CNV caller. A biochemical analysis showing abnormal excretion of urinary mannosyloligosaccharide and an enzyme assay permitted the re‐classification of the missense variant to likely pathogenic, establishing the diagnosis of alpha‐mannosidosis. This work emphasizes the importance of reverse phenotyping in the context of exome sequencing. [ABSTRACT FROM AUTHOR]

Backgroundα-mannosidosis (MAN) is a rare genetic condition that segregates in an autosomal recessive manner. Lack of lysosomal alpha-mannosidase is the underlying cause of the disease. Symptoms of the disease gradually worsen with the age. Newborns are usually asymptomatic, however, some cases are reported with either congenital ankle equinus or hydrocephalus during the first year. Primary symptoms are characterized by immune deficiency, hearing loss, skeletal abnormalities, progressive mental, motor and speech functions’ impairment followed by facial asymmetry.MethodsWe studied two Saudi families (A and B) with bilateral moderate hearing loss (family A) and clubfoot with glaucoma (family B). Clinical diagnosis was not reached based on phenotype of patients. Therefore, hypothesis-free whole exome sequencing (WES) was performed on DNA samples from affected individuals of both the families, followed by Sanger sequencing and segregation analysis to validate the segregation of the identified variant. Furthermore, 3D protein modelling was performed to determine the in silico effects of the identified variant on the protein structure and function.ResultsRe-examination of clinical features revealed that the patients in family A have speech delay and hearing impairment along with craniostenosis, whereas the patients from family B have only clubfoot and glaucoma. WES identified a well known pathogenic homozygous frameshift variant (NM_000528.4: c.2402dupG; p.S802fs*129) in MAN2B1 in both the families. Sanger sequencing confirmed the segregation of the variant with the disease phenotype in both the families. 3D structural modeling of the MAN2B1 protein revealed significant changes in the tertiary structure of the mutant protein, which would affect enzyme function. This report presents a new case where partial and novel α-mannosidosis phenotypes are associated with a MAN2B1 gene pathogenic variant.ConclusionPatients in both the families have manifested peculiar set of clinical symptoms associated with α-mannosidosis. Family A manifested partial clinical symptoms missing several characteristic features like intellectual disability, dysmorphic features, neurological and abdominal manifestations, whereas family B has no reported clinical symptoms related to α-mannosidosis except the novel symptoms including club foot and glaucoma which has never been reported earlier The current findings support the evidence that biallelic variants of MAN2B1 are associated with new clinical variants of α-mannosidosis.

Background: Alpha-mannosidosis caused by mutations in the MAN2B1 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. Methods: 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. Results: 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. Conclusion: This study is the first to investigate the carrier frequencies of alphamannosidosis in East Asians and Koreans, including specific subpopulations, utilizing gnomAD and the Korean genomic database. The variant spectrum of MAN2B1 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. [ABSTRACT FROM AUTHOR]

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. 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. 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. [ABSTRACT FROM AUTHOR]

An outbreak of α‐mannosidosis in a bovine herd from Buenos Aires province is reported. Postmortem examination, histology, lectin histochemistry and electron microscopy were performed on five calves born with nervous signs. Hair samples from dams and calves were genetically analysed. The α‐mannosidase gene including exon 7 was amplified and sequenced. At postmortem examination, no gross changes were evident. Histologically, cytoplasmic neuronal vacuolation in the brain and cerebellum of the five calves, staining moderately to intensively, with lectin histochemistry was evident. Ultrastructurally, vacuoles containing finely granulated material in the cytoplasm of neurons, myelin degeneration and axonal swelling were seen in the brain. Genetic analysis revealed a heterozygous carrier state for 961T→C transition in the exon 7 of α‐mannosidosis gene of four cows, and a recessive homozygous state for 961T→C transition in the same genes in the calves analysed. This highlights the importance of identifying and removing animals carrying the α‐mannosidosis mutated gene. [ABSTRACT FROM AUTHOR]

AbstractAlpha-mannosidosis is an inherited rare disorder of mannose-containing oligosaccharides metabolism that is currently treated by enzyme replacement therapy (ERT), bone marrow transplantation (BMT), or supportive therapy (ST). However, the relative cost-effectiveness of these treatment options is yet unknown. Our study aimed to compare the cost-effectiveness of the treatment options for mild to moderate alpha-mannosidosis. The study is based on a modeling approach using a Discrete-Event Simulation model to generate and simulate the course of the disease under the influence of each of the treatment options: ERT, BMT, and ST. The model had a lifetime horizon and was made from the perspective of the Serbian Health Insurance Fund. Currently, available causal therapy of mild to moderate alpha-mannosidosis with velmanase alpha enzyme replacement is not cost-effective compared with supportive therapy (ICER = 941,587,152 RSD) or bone marrow transplantation (ICER = −398,412,755 RSD). Bone marrow transplantation can be cost-effective compared to supportive therapy (ICER = 6,032,689 RSD), but only if the willingness-to-pay threshold is increased to 9 gross domestic products (GDP) per capita per QALY gained. According to the current threshold, velmanase-alfa is not cost-effective compared to BMT or ST. To make alfa-mannosidosis therapy widely accessible to patients, criteria for assessing the cost-effectiveness of orphan drugs must include not only the absolute value of ICER but other aspects like equity weightings of QALYs, risk-sharing, reimbursement of severe forms of a disease only, or availability of dedicated funding.

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 nonneurologic 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. [ABSTRACT FROM AUTHOR]

Abstract Alpha‐mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 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 MAN2B1 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 MAN2B1 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 (n = 2; G1: 1012 U/ml and G2: 440 U/ml) experienced mild/moderate IRRs that were well‐managed; patients with lower titers (n = 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 MAN2B1 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.

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. [ABSTRACT FROM AUTHOR]

Alpha-mannosidosis is a devastating metabolic disorder characterized by intellectual disability, facial dysmorphism, musculoskeletal and immune abnormalities. This study identifies a genetic mutation in a complex consanguineous Pakistani family of Punjabi language group. The family presented with rare complex neurological symptoms including mental retardation, facial dysmorphism, skeletal and muscle abnormalities. Five affected family members were recruited along with unaffected members, and whole blood was collected for genomic DNA extraction. A genome-wide scan was carried out on four affected members to establish homozygosity linkage. The analysis for genotype assessment was carried out, and three homozygous regions were identified. Whole exome sequencing was carried out to identify the mutation in putative gene/s. The data was arranged, and MAN2B1 was selected for the DNA sequencing. Protein homology was analyzed by the pymol tool to predict the effect on the mutant protein. A novel missense mutation c. 2710A>T; p.904Tyr>Ser was detected, and co-segregation analysis was established in the complex neurological family. The pymol analysis detected the loss of hydrogen bonding between Thr at 904 with Arg at 916 in mutant MAN2B1. It is concluded that a novel mutation is identified in MAN2B1 associated with a complex neurological disease. The results indicate huge heterogeneity in the Pakistani population due to consanguinity. The combination of next-generation sequencing has facilitated the identification of genes in complex disorders like alpha-mannosidosis. [ABSTRACT FROM AUTHOR]

Abstract 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.

IntroductionLong-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM).MethodsPatient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and the 3-minute stair climb test (3MSCT).ResultsMean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the overall population at 12 months (mean change: -72.7%, P

Alpha-mannosidosis is an inherited rare disorder of mannose-containing oligosaccharides metabolism that is currently treated by enzyme replacement therapy (ERT), bone marrow transplantation (BMT), or supportive therapy (ST). However, the relative cost-effectiveness of these treatment options is yet unknown. Our study aimed to compare the cost-effectiveness of the treatment options for mild to moderate alpha-mannosidosis. The study is based on a modeling approach using a Discrete-Event Simulation model to generate and simulate the course of the disease under the influence of each of the treatment options: ERT, BMT, and ST. The model had a lifetime horizon and was made from the perspective of the Serbian Health Insurance Fund. Currently, available causal therapy of mild to moderate alpha-mannosidosis with velmanase alpha enzyme replacement is not cost-effective compared with supportive therapy (ICER = 941,587,152 RSD) or bone marrow transplantation (ICER = −398,412,755 RSD). Bone marrow transplantation can be cost-effective compared to supportive therapy (ICER = 6,032,689 RSD), but only if the willingness-to-pay threshold is increased to 9 gross domestic products (GDP) per capita per QALY gained. According to the current threshold, velmanase-alfa is not cost-effective compared to BMT or ST. To make alfa-mannosidosis therapy widely accessible to patients, criteria for assessing the cost-effectiveness of orphan drugs must include not only the absolute value of ICER but other aspects like equity weightings of QALYs, risk-sharing, reimbursement of severe forms of a disease only, or availability of dedicated funding. [ABSTRACT FROM AUTHOR]

Current literature lacks consensus on initial assessments and routine follow-up care of patients with alpha-mannosidosis (AM). A Delphi panel was conducted to generate and validate recommendations on best practices for initial assessment, routine follow-up care, and integrated care coordination of patients with AM. A modified Delphi method involving 3 rounds of online surveys was used. An independent administrator and 2 nonvoting physician co-chairs managed survey development, anonymous data collection, and analysis. A multidisciplinary panel comprising 20 physicians from 12 countries responded to 57 open-ended questions in the first survey. Round 2 consisted of 11 ranking questions and 44 voting statements. In round 3, panelists voted to validate 60 consensus statements. The panel response rate was ≥95% in all 3 rounds. Panelists used 5-point Likert scales to indicate importance (score of ≥3) or agreement (score of ≥4). Consensus was defined a priori as ≥75% agreement with ≥75% of panelists voting. Consensus was reached on 60 statements, encompassing 3 key areas: initial assessments, routine follow-up care, and treatment-related follow-up. The panel agreed on the type and frequency of assessments related to genetic testing, baseline evaluations, quality of life, biochemical measures, affected body systems, treatment received, and integrated care coordination in patients with AM. Forty-nine statements reached 90% to 100% consensus, 8 statements reached 80% to 85% consensus, and 1 statement reached 75% consensus. Two statements each reached consensus on 15 baseline assessments to be conducted at the initial follow-up visit after diagnosis in pediatric and adult patients. This is the first Delphi study providing internationally applicable, best-practice recommendations for monitoring patients with AM that may improve their care and well-being. • This Delphi consensus study aimed to address the gap in standardized clinical monitoring guidelines for patients with alpha-mannosidosis (AM). • A global multidisciplinary team of physician-experts in AM formed a Delphi panel. • Sixty consensus statements on best practices related to monitoring were generated. • The recommendations from this study may improve patient care and well-being in AM. [ABSTRACT FROM AUTHOR]

Background: Alpha-mannosidosis [Online Mendelian Inheritance in Man (OMIM): 248500] is an autosomal recessive disorder due to a deficiency of the lysosomal enzyme alpha-mannosidase. It is an ultra-orphan disease. In this paper, we report a case of alpha-mannosidosis in a Saudi boy of consanguineous parents, who was referred to our hospital to be worked up for possible mucopolysaccharidosis. Case Presentation: The patient was presented with dysmorphic features, global developmental delay, hearing defect, and recurrent respiratory tract infections. On examination, he had short stature, a short neck, cataracts, hearing impairment, chest deformity, hepatomegaly, umbilical hernia, right inguinal hernia, and two Mongolian spots in the back. He had normal peripheral blood smear: urinary oligosaccharide and dry blood spot for mucopolysaccharide enzyme assay founded to be negative. Definitive diagnosis was performed by directly sequencing the MAN2B1 gene of the peripheral blood leukocytes. It showed a homozygous variant c.1065delC; p.Ala356fs*7 (NM_001173498.1) as likely pathogenic. Conclusion: We report a novel variant mutation in MAN2B1 gene mutation. Also, to the best of authors' knowledge, this is the first reported case of alpha-mannosidosis in a Saudi patient. [JBCGenetics 2021; 4(2.000): 118-121]

Enzyme replacement therapy (ERT) using velmanase alfa previously showed promising efficacy and safety outcomes for up to 4 years of therapy in patients with alpha-mannosidosis. This pooled analysis from two multicenter, open-label phase IIIb extension trials rhLAMAN-07 (N = 13; NCT01908712) and rhLAMAN-09 (N = 8; NCT01908725) evaluated the long-term effects of velmanase alfa. Sixteen patients who previously completed phase I-III rhLAMAN-02/-03/-04/-05/-08 trials and five ERT-naïve patients were enrolled. Patients received 1 mg/kg velmanase alfa once weekly. Endpoints included changes from treatment baseline (before initial dose of velmanase alfa in any trial) in serum oligosaccharides, 6-minute walk test (6MWT), 3-minute stair climb test (3MSCT), pulmonary function (forced vital capacity [FVC], % predicted), serum immunoglobulin G (IgG) levels, and adverse events. The overall cohort comprised 21 patients, divided by age at treatment baseline into pediatric (n = 14) and adult subgroups (n = 7). Distance walked according to 6MWT increased or stabilized in pediatric patients, while in adults either stabilization or slight decline was observed. Similarly, pediatric patients performed better in the 3MSCT. Changes in FVC, % predicted, were comparable in both subgroups up to ~6 years of observation, diverging thereafter. Overall, sustained serum oligosaccharide clearance and serum IgG level increase was observed upon treatment initiation and persisted until last common observation. Velmanase alfa treatment was generally well tolerated, with the majority of reported adverse events being of mild-to-moderate intensity. With follow-up of up to 12 years, long-term efficacy and safety outcomes indicate continued benefits of velmanase alfa in patients with alpha-mannosidosis., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

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. [ABSTRACT FROM AUTHOR]

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. • Alpha-mannosidosis (MAN2B1 variants) is an ultra-rare lysosomal disease. • Symptoms include neurological deterioration, hearing loss, and skeletal dysmorphia. • Successful treatment with enzyme replacement therapy relies on early diagnosis. • Disease registries, screening tools, and improved clinician education are required. • Patient advocacy groups may raise disease awareness and facilitate early diagnosis. [ABSTRACT FROM AUTHOR]

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 t-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.

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 MAN2B1 gene was c.2245C > T, p.(Arg749Trp). The mean time of follow-up in our study was approximately 14years (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.

Abstract 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.

Abstract Alpha‐mannosidosis is a rare inherited metabolic disorder (OMIM #248500) caused by mutations in the enzyme α‐mannosidase encoded by the gene MAN2B1. 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.

Alpha mannosidosis is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in the MAN2B1 gene. It manifests with clinical features, including intellectual disability, hearing impairment, coarse facial appearance, skeletal anomalies, immunodeficiency, central nervous system involvement, psychiatric comorbidities, corneal opacity, and hepatosplenomegaly. This multicenter study assesses the long-term outcomes of individuals diagnosed with alpha-mannosidosis, examining demographic, clinical, laboratory, and molecular characteristics. Sixteen patients diagnosed with alpha-mannosidosis who presented to four pediatric metabolic units were included in the study. The patients' medical records were analyzed and data on demographics, clinical presentation and laboratory findings were recorded. Of the 16 patients (6 females, 10 males) with alpha mannosidosis included in the study, the mean age at the time of diagnosis was 79.4 ± 56.1 (16–208) months, and the mean diagnosis delay time was 57.9 ± 51.9 (4–181) months. Hearing loss was the primary manifestation found in seven out of 16 patients (43.8%), followed by speech delay in 37.8%. On clinical follow-up, 87.5% of patients experienced recurrent infections, mainly in the upper respiratory tract, with 12 requiring the use of a hearing aid. Hepatomegaly was found in six out of 13 patients who received abdominal ultrasonography; two out of 12 patients who underwent echocardiography were found to have mitral valve prolapse (16.6%). Upon neurological evaluation, five patients displayed no neurological manifestation. Delayed language development was observed in nine (56.3%) patients, intellectual disability in eight (50%) patients, and hypertonicity was identified in one (6.3%) patient with the severe form of the disease. Homozygous c.2477C>A (p.Ser826Ter) and homozygous c.967G>A (p.Glu323Lys) novel variants were detected in four patients and one patient, respectively. The most common variant observed in the study was c.2477C>A (p.Ser826Ter). The present study identified two novel MAN2B1 variants. An evaluation of the long-term outcome of alpha-mannosidosis, in which the early initiation of enzyme replacement therapy (ERT) may lead to a better clinical outcome, can permit a better analysis of the effect of ERT on the natural progression of the disease. [ABSTRACT FROM AUTHOR]

Abstract Background Procedural sedation is increasingly needed in pediatrics. Although different drugs or drugs association are available, which is the safest and most efficient has yet to be defined, especially in syndromic children with increased sedation-related risk factors. Case report we report the case of a five-year-old child affected by alpha-mannosidosis who required procedural sedation for an MRI scan and a lumbar puncture. We administered intranasal dexmedetomidine (4 μg/kg) 45 min before intravenous cannulation, followed by one bolus of ketamine (1 mg/kg) for each procedure. The patient maintained spontaneous breathing and no desaturation or any complication occurred. Conclusion intranasal dexmedetomidine and intravenous ketamine could be a feasible option for MRI and lumbar puncture in children with alpha-mannosidosis needing sedation.

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. [ABSTRACT FROM AUTHOR]