Long-term outcome of a cohort of Italian patients affected with alpha-Mannosidosis.
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ABSTRACT:
SUBMITTER: Bertolini A
PROVIDER: S-EPMC10702697 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Long-term outcome of a cohort of Italian patients affected with alpha-Mannosidosis.
Bertolini Anna A Rigoldi Miriam M Cianflone Annalia A Mariani Raffaella R Piperno Alberto A Canonico Francesco F Cefalo Graziella G Carubbi Francesca F Simonati Alessandro A Urban Maria Letizia ML Beccari Tommaso T Parini Rossella R
Clinical dysmorphology 20231123 1
Alpha-mannosidosis (MIM #248500) is an ultra-rare autosomal recessive lysosomal storage disease with multi-system involvement and a wide phenotypic spectrum. Information on long-term outcomes remains poor. We present the long-term outcomes (median, 19 years) of nine patients with alpha-mannosidosis, three females and six males, followed at a single center. The findings of the nine patients were collected from medical records and reported as mean ± SD or median, and range. The age of onset of the ...[more]
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Project description:INTRODUCTION:Long-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). METHODS:Patient 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). RESULTS:Mean (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 < 0.001) and remained statistically significant at last observation (-62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric subgroup. No treatment-emergent adverse events were reported leading to permanent treatment discontinuation. CONCLUSIONS:Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were maintained for up to 4 years. Long term follow-up is important and further supports the use of velmanase alfa as an effective and well-tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints.
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Project description: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.
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Project description:α-Mannosidosis, OMIM #248500, is an autosomal recessive lysosomal storage disease caused by acidic α-mannosidase deficiency. Treatment options include bone marrow transplantation (BMT) and, possibly in the future, enzyme replacement therapy. Brain magnetic resonance spectroscopy (MRS) enables non-invasive monitoring of cerebral treatment effect. Accumulated cerebral mannose-containing oligosaccharides were demonstrated by MRS in a patient who at age 2 years and 11 months received a BMT from a haploidentical non-carrier sibling. The cerebral mannose-containing oligosaccharides had disappeared as early as 9½ months after BMT. MRS furthermore demonstrated the persistent treatment effect at regular intervals up to 5½ years after BMT. MRS is a non-invasive tool that can demonstrate the effect of BMT treatment. Likewise, MRS may be used to demonstrate the cerebral effect of other potential treatments such as enzyme replacement therapy.
| S-EPMC3755547 | biostudies-literature
Project description:Alpha-mannosidosis is an inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual disability. It occurs in approximately 1 of 500,000 live births. The children are often born apparently normal, and their condition worsens progressively. Some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life), skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum), hearing impairment (moderate-to-severe sensorineural hearing loss), gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia. The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common. The clinical variability is significant, representing a continuum in severity. The disorder is caused by lysosomal alpha-mannosidase deficiency. Alpha-mannosidosis is inherited in an autosomal recessive fashion and is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12). Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic. Differential diagnoses are mainly the other lysosomal storage diseases like the mucopolysaccharidoses. Genetic counseling should be given to explain the nature of the disease and to detect carriers. Antenatal diagnosis is possible, based on both biochemical and genetic methods. The management should be pro-active, preventing complications and treating manifestations. Infections must be treated frequently. Otolaryngological treatment of fluid in the middle ear is often required and use of hearing aids is invariably required. Early educational intervention for development of social skills is needed and physiotherapy is important to improve bodily function. Orthopedic surgery may be necessary. The long-term prognosis is poor. There is an insidiously slow progression of neuromuscular and skeletal deterioration over several decades, making most patients wheel-chair dependent. No patients manage to be completely socially independent. Many patients are over 50 years of age.
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Project description:BackgroundAlpha-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.ResultsThe 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.ConclusionThis 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.
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Project description: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.
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Project description: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.
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Project description: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.
| S-EPMC6850974 | biostudies-literature
Project description:Backgroundα-mannosidosis is an inborn error of metabolism caused by the deficiency of the lysosomal enzyme α-mannosidase, which is encoded by the MAN2B1 gene and inherited in an autosomal recessive manner. The impairment of affected individuals is multisystemic and very similar to the observed in some mucopolysaccharidosis (MPS) patients. The aim of this study was to search for α-mannosidosis cases in individuals with clinical suspicion of MPS without a confirmed diagnosis. Biochemical and molecular analysis were standardized by our group for this study. Two hundred and fifty samples from patients with clinical suspicion of MPS, but with inconclusive MPS biochemical and/or molecular analysis, were screened for α-mannosidase activity. Subsequently the MAN2B1 gene was sequenced in samples from 53 patients by the Sanger method.ResultsThe measurement of enzymatic activity detected fifty-three samples with abnormal results, suggesting α-mannosidosis. Molecular analysis confirmed three affected families, which presented the nonsense variant p.Ser899Ter. This variant generates a premature stop codon in exon 22, resulting in a truncated protein with no residual enzymatic activity.ConclusionIn conclusion, this work brings data for the beginning of a genetic characterization of α-mannosidosis in the Brazilian population. It also shows that α-mannosidosis cases may be underdiagnosed due to the clinical similarity to MPS and the lack of information about this ultra-rare disease. Based on our data, we strongly recommend to all screening centers to consider α-mannosidosis testing together with screening for MPS as a tool for diagnosis to MPS-like phenotype individuals, since the phenotype similarity between these diseases poses a significant challenge for clinicians worldwide and often leads to the failure of the correct clinical diagnosis and treatment.
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Project description:BACKGROUND: Classical organic acidurias including methylmalonic aciduria (MMA), propionic aciduria (PA) and isovaleric aciduria (IVA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids, presenting with severe complications. METHODS: This study investigated the long-term outcome of 80 patients with classical organic aciduria (38 with MMA, 24 with PA and 18 with IVA) by integrating clinical, radiological, biochemical and genetic data. RESULTS: Patients were followed-up for a mean of 14 years [age 3.3-46.3 years]. PA included a greater number of patients with abnormal neurological examination (37% in PA, 24% in MMA and 0% in IVA), lower psychometric scores (abnormal evaluation at age 3 years in 61% of patients with PA versus 26% in MMA and 18% in IVA) and more frequent basal ganglia lesions (56% of patients versus 36% in MMA and 17% in IVA). All patients with IVA presented a normal neurological examination and only 1/3 presented cognitive troubles. Prognosis for MMA was intermediate. Biochemical metabolite analysis excluding acute decompensations revealed significant progressive increases of glycine, alanine and glutamine particularly in PA and possibly in MMA but no correlation with neurological outcome. A significant increase of plasma methylmalonic acid was found in MMA patients with intellectual deficiency (mean level of 199 ?mol/L versus 70 ?mol/L, p < 0.05), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 167 ?mol/L. Urinary 3-hydroxypropionate (3-HP) levels were significantly higher in PA patients with intellectual deficiency (mean level of 68.9 ?mol/mmol of creatinine versus 34.6 ?mol/mmol of creatinine, p < 0.01), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 55 ?mol/mmol. As for molecular analysis, prognosis of MMA patients with mutations involving the MMAA gene was better compared to patients with mutations involving the MUT gene. CONCLUSION: Propionic aciduria had the most severe neurological prognosis. Our radiological and biochemical data are consistent with a mitochondrial toxicity mechanism. Follow-up plasma MMA and urinary 3-HP levels may have prognostic significance calling for greater efforts to optimize long-term management in these patients.
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