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Line Borgwardt - One of the best experts on this subject based on the ideXlab platform.

  • use of the bruininks oseretsky test of motor proficiency bot 2 to assess efficacy of velmanase alfa as enzyme therapy for alpha mannosidosis
    Molecular genetics and metabolism reports, 2020
    Co-Authors: Dawn Phillips, Line Borgwardt, Nathalie Guffon, Anna Tylkiszymanska, Mercedes Gilcampos, Julia B Hennermann, Yasmina Amraoui, Silvia Geraci, Diego Ardigo, Federica Cattaneo
    Abstract:

    Abstract Objectives Alpha-Mannosidosis is a rare autosomal recessive lysosomal storage disorder resulting from deficient lysosomal alpha-mannosidase activity. Clinical manifestations include progressive balance disorders, immune deficiency, skeletal abnormalities and cognitive deficits beginning in early childhood. Enzyme replacement therapy with recombinant human alpha-mannosidase (velmanase alfa) is scheduled for clinical development in the US beginning in 2020 and has been approved in the EU for treatment of non-neurological manifestations in cases of mild to moderate disease. This study assessed effects of velmanase alfa on fine and gross motor proficiency in children and adults. Methods Integrated Bruininks-Oseretsky (BOT-2) test of Motor Proficiency data from velmanase alfa clinical trials was stratified by age for 14 adults and 19 children treated for up to 4 years. Results Patients showed global developmental delays at baseline. For the combined adult and pediatric group there was a statistically significant increase (improvement) in BOT-2 total point score of 13% (p = .035, 95% CI 1.0, 25.0) from baseline to last observation. When stratified by pediatric versus adult patients, there was improvement in BOT-2 total point score in patients Conclusions There was limited ability to assess the BOT-2 change responses in adults. Pediatric patients showed stability or improvement in scaled scores relative to healthy peers, indicating continued skill acquisition, which may increase independence and contribute to improved patient quality of life.

  • recognition of alpha mannosidosis in paediatric and adult patients presentation of a diagnostic algorithm from an international working group
    Molecular Genetics and Metabolism, 2019
    Co-Authors: Nathalie Guffon, Line Borgwardt, Allan M. Lund, Anna Tylkiszymanska, Mercedes Gilcampos, Rossella Parini, Julia B Hennermann
    Abstract:

    Abstract Alpha-Mannosidosis is an ultra-rare progressive lysosomal storage disorder caused by deficiency of alpha-mannosidase. Timely diagnosis of the disease has the potential to influence patient outcomes as preventive therapies can be initiated at an early stage. However, no internationally-recognised algorithm is currently available for the diagnosis of the disease. With the aim of developing a diagnostic algorithm for Alpha-Mannosidosis an international panel of experts met to reach a consensus by applying the nominal group technique. Two proposals were developed for diagnostic algorithms of Alpha-Mannosidosis, one for patients ≤10 years of age and one for those >10 years of age. In younger patients, hearing impairment and/or speech delay are the cardinal symptoms that should prompt the clinician to look for additional symptoms that may provide further diagnostic clues. Older patients have different clinical presentations, and the presence of mental retardation and motor impairment progression and/or psychiatric manifestations should prompt the clinician to assess for other symptoms. In both younger and older patients, either additional metabolic monitoring or referral for testing is warranted upon suspicion of disease. Oligosaccharides in urine (historically performed) or serum were considered as an initial screening procedure, while enzymatic activity may also be considered as first choice in some centres. Molecular testing should be performed as a final confirmatory step. The developed algorithms can easily be applied in a variety of settings, and may help to favour early diagnosis of alpha mannosidosis and treatment.

  • the sparkle study shedding light on alpha mannosidosis
    Molecular Genetics and Metabolism, 2019
    Co-Authors: Julia B Hennermann, Line Borgwardt, Allan M. Lund, Nathalie Guffon, Anna Tylkiszymanska, Mercedes Gilcampos, Federica Cattaneo, Stefania Pirondi, Nicole Muschol
    Abstract:

    Alpha-Mannosidosis (AM) is a lysosomal storage disorder caused by reduced activity of the enzyme alpha-mannosidase, leading to intracellular accumulation of mannose-rich oligosaccharides in various organs. Velmanase alfa (VA) is a human recombinant alpha-mannosidase approved in Europe in 2018 as enzyme replacement therapy for the treatment of non-neurological manifestations in mild to moderate AM patients. A post-authorization safety and efficacy registry called SPARKLE was designed as a multi-centre, multi-national, non-interventional, prospective cohort study. SPARKLE has two objectives. The first is to assess post-marketing safety and effectiveness of VA (product registry) the second is to gain new understanding of the natural course of AM (disease registry). In terms of effectiveness, the primary focus is to estimate the treatment response rate based on a multi-parametric response model. The effectiveness assessment includes the measurement of serum oligosaccharides, serum immunoglobulin G levels, endurance, pulmonary function, hearing tests, incidence of infections, use of antibiotics, psychotic events, questionnaires on quality of life and burden of disease for caregivers, among others. All patients affected by AM can participate into the registry, regardless of their treatment. Based on the current protocol, the study will be opened for participation for an indefinite time and each patient will be followed up for 15 years. The protocol does not foresee a pre-specified sample size and aims at including most of the patients treated with VA in clinical practice. The SPARKLE study will start in Europe in the second half of 2019.

  • Health Related Quality of Life, Disability, and Pain in Alpha Mannosidosis: Long-Term Data of Enzyme Replacement Therapy With Velmanase Alfa (Human Recombinant Alpha Mannosidase)
    Journal of Inborn Errors of Metabolism and Screening, 2018
    Co-Authors: Line Borgwardt, Allan M. Lund, Nathalie Guffon, Mercedes Gil-campos, Anna Tylki-szymanska, Yasmina Amraoui, Simon A. Jones, Linda De Meirleir, Johanna M. P. Van Den Hout, Silvia Geraci
    Abstract:

    Alpha-Mannosidosis, a rare lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha-mannosidase, results in accumulation of mannose-rich glycoproteins in the tissues and sequel...

  • enzyme replacement therapy with velmanase alfa human recombinant alpha mannosidase novel global treatment response model and outcomes in patients with alpha mannosidosis
    Molecular Genetics and Metabolism, 2018
    Co-Authors: Paul Harmatz, Allan M. Lund, Nathalie Guffon, Christian J Hendriksz, Julia B Hennermann, Silvia Geraci, Federica Cattaneo, Diego Ardigo, Line Borgwardt
    Abstract:

    Abstract Alpha-Mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate Alpha-Mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for Alpha-Mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to ≥2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n = 15) compared with 30% of patients receiving placebo (n = 10). Longer-term data from all patients in the clinical program (n = 33) showed 88% of patients were global responders, including all (100%) pediatric patients (n = 19) and the majority (71%) of adult patients (n = 14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with Alpha-Mannosidosis with this ERT.

Oivind Nilssen - One of the best experts on this subject based on the ideXlab platform.

  • The Turkish Journal of Pediatrics 2003; 45: 46-50 Case Alpha-Mannosidosis and mutational analysis in a Turkish patient
    2015
    Co-Authors: Akgün Ölmez, Oivind Nilssen, Helle Klenow, Turgay Coþkun
    Abstract:

    We present a case of Alpha-Mannosidosis with its mutational analysis. She was referred to our hospital with the provisional diagnosis of mucolipidosis. She was the first child of second-degree relative parents. She had a coarse face with flat and wide nasal bridge, hepatosplenomegaly, umbilical hernia, lumbar gibbus, motor and mental retardation and deafness. On peripheral blood smear, lymphocytes revealed vacuoles and neutrophils contained some granules resembling Reilly bodies seen in mucopolysaccharidosis (MPS). Based on these findings, the diagnosis of Alpha-Mannosidosis was suspected. Her urine oligosaccharide chromatography showed an abnormal pattern with a heavy trisaccharide band. Enzyme studies on white cells confirmed a deficiency of alpha-mannosidase activity, which was 2.6 umol/g/hr. Her DNA analysis showed a S453Y mutation. Key words: Alpha-Mannosidosis, mutation, neutrophilic granules. Alpha-mannodisosis is an autosomal recessive lysosomal storage disease caused by deficiency of the enzyme acid mannosidase. Patients affected by Alpha-Mannosidosis excrete increased amounts of mannose-rich oligosaccharides in the urine, and mannose-rich compounds accumulate in the various tissues of Alpha-Mannosidosis patients1. The severe infantile phenotype is referred to as ‘type 1 ’ and a milder juvenile adult type is referred to as ‘type 2’. All patients have psychomotor retardation, facial coarsening and some degree of dysostosis multiplex. Common findings include recurrent bacterial infections, deafness, hepatomegaly, hernias, and lenticular or corneal opacities2. The clinical features vary in patients and several Alpha-Mannosidosis causing mutations have been found, but no correlation between the types of mutations and the clinical manifestations could be shown3. In this report we present a case with Alpha-Mannosidosis homozygous for a S453 mutation

  • alpha mannosidosis correlation between phenotype genotype and mutant man2b1 subcellular localisation
    Orphanet Journal of Rare Diseases, 2015
    Co-Authors: Line Borgwardt, K. J. Olsen, Jens Fogh, Helle Klenow, Yasmina Amraoui, Michael Beck, Hilde Monica Frostad Riise Stensland, Flemming Wibrand, Laila Arash, Oivind Nilssen
    Abstract:

    Alpha-Mannosidosis is caused by mutations in MAN2B1, leading to loss of lysosomal alpha-mannosidase activity. Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities. To study the genotype-phenotype relationship for Alpha-Mannosidosis 66 patients were included. Based on the predicted effect of the mutations and the subcellular localisation of mutant MAN2B1 in cultured cells, the patients were divided into three subgroups. Clinical and biochemical data were collected. Correlation analyses between each of the three subgroups of genotype/subcellular localisation and the clinical and biochemical data were done to investigate the potential relationship between genotype and phenotype in Alpha-Mannosidosis. Statistical analyses were performed using the SPSS software. Analyses of covariance were performed to describe the genotype-phenotype correlations. The phenotype parameters were modelled by the mutation group and age as a covariate. P values of <0.05 were considered as statistically significant. Complete MAN2B1 genotypes were established for all patients. We found significantly higher scores in the Leiter-R test, lower concentrations of CSF-oligosaccharides, higher point scores in the Bruininks-Oseretsky Test of Motor Proficiency subtests (BOT-2); Upper limb coordination and Balance, and a higher FVC% in patients in subgroup 3, harbouring at least one variant that allows localisation of the mutant MAN2B1 protein to the lysosomes compared to subgrou 2 and/or subgroup 1 with no lysosomal localization of the mutant MAN2B1 protein. Our results indicate a correlation between the MAN2B1 genotypes and the cognitive function, upper limb coordination, balance, FVC% and the storage of oligosaccharides in CSF. This correlation depends on the subcellular localisation of the mutant MAN2B1 protein.

  • identification of 83 novel alpha mannosidosis associated sequence variants functional analysis of man2b1 missense mutations
    Human Mutation, 2012
    Co-Authors: Hilde Monica Frostad Riise Stensland, Oivind Nilssen, Gaute Martin Hansen, Dag Malm, Helle Klenow, Lam Van Nguyen
    Abstract:

    The lysosomal storage disorder Alpha-Mannosidosis is caused by deficiency of the enzyme lysosomal alpha-mannosidase (MAN2B1). In this study, 96 disease-associated sequence variants were identified in 130 unrelated Alpha-Mannosidosis patients from 30 countries. Eighty-three novel variants were detected, extending the mutation spectrum from 42 to 125. In total, 256 of the 260 mutant alleles (98.5%) were identified. Most of the variants were unique to each family, however, c.2248C>T (p.Arg750Trp) was detected in 50 patients from 16 countries, and accounted for 27.3% of the disease alleles. Haplotype analysis revealed that the c.2248T variant was present on four MAN2B1 haplotype backgrounds, where one major haplotype accounted for 95% of the alleles. The distribution of the c.2248T-associated haplotypes differed remarkably from those of the control populations, suggesting that c.2248C>T has occurred on a few ancestral haplotypes where the major haplotype subsequently has spread by founder effects. The disease-associated missense mutations were introduced into the human MAN2B1 cDNA, expressed in cell culture and assayed for MAN2B1 activity. The majority of the variants were inactive, however, ten showed MAN2B1 activity above background, and more detailed studies are necessary to further evaluate the pathogenicity of these variants.

  • Alpha-Mannosidosis
    Orphanet Journal of Rare Diseases, 2008
    Co-Authors: Dag Malm, Oivind Nilssen
    Abstract:

    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.

  • Sisters with α-mannosidosis and systemic lupus erythematosus
    European Journal of Pediatrics, 2004
    Co-Authors: Maki Urushihara, Oivind Nilssen, Dag Malm, Shoji Kagami, Koji Yasutomo, Shuji Kondo, Akiko Kitamura, Helle Klenow, Yasuhiro Kuroda
    Abstract:

    Alpha-Mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal α-mannosidase (LAMAN). Here, we report two sisters with α-mannosidosis who developed systemic lupus erythematosus (SLE). The sisters were both homozygous for a one bp deletion within the LAMAN gene resulting in a truncated gene product. The coincidence of α-mannosidosis and SLE are discussed with regard to both clinical and molecular findings. Conclusion: α-mannnosidosis may contribute to the onset of systemic lupus erythematosus in predisposed patients.

Allan M. Lund - One of the best experts on this subject based on the ideXlab platform.

  • recognition of alpha mannosidosis in paediatric and adult patients presentation of a diagnostic algorithm from an international working group
    Molecular Genetics and Metabolism, 2019
    Co-Authors: Nathalie Guffon, Line Borgwardt, Allan M. Lund, Anna Tylkiszymanska, Mercedes Gilcampos, Rossella Parini, Julia B Hennermann
    Abstract:

    Abstract Alpha-Mannosidosis is an ultra-rare progressive lysosomal storage disorder caused by deficiency of alpha-mannosidase. Timely diagnosis of the disease has the potential to influence patient outcomes as preventive therapies can be initiated at an early stage. However, no internationally-recognised algorithm is currently available for the diagnosis of the disease. With the aim of developing a diagnostic algorithm for Alpha-Mannosidosis an international panel of experts met to reach a consensus by applying the nominal group technique. Two proposals were developed for diagnostic algorithms of Alpha-Mannosidosis, one for patients ≤10 years of age and one for those >10 years of age. In younger patients, hearing impairment and/or speech delay are the cardinal symptoms that should prompt the clinician to look for additional symptoms that may provide further diagnostic clues. Older patients have different clinical presentations, and the presence of mental retardation and motor impairment progression and/or psychiatric manifestations should prompt the clinician to assess for other symptoms. In both younger and older patients, either additional metabolic monitoring or referral for testing is warranted upon suspicion of disease. Oligosaccharides in urine (historically performed) or serum were considered as an initial screening procedure, while enzymatic activity may also be considered as first choice in some centres. Molecular testing should be performed as a final confirmatory step. The developed algorithms can easily be applied in a variety of settings, and may help to favour early diagnosis of alpha mannosidosis and treatment.

  • the sparkle study shedding light on alpha mannosidosis
    Molecular Genetics and Metabolism, 2019
    Co-Authors: Julia B Hennermann, Line Borgwardt, Allan M. Lund, Nathalie Guffon, Anna Tylkiszymanska, Mercedes Gilcampos, Federica Cattaneo, Stefania Pirondi, Nicole Muschol
    Abstract:

    Alpha-Mannosidosis (AM) is a lysosomal storage disorder caused by reduced activity of the enzyme alpha-mannosidase, leading to intracellular accumulation of mannose-rich oligosaccharides in various organs. Velmanase alfa (VA) is a human recombinant alpha-mannosidase approved in Europe in 2018 as enzyme replacement therapy for the treatment of non-neurological manifestations in mild to moderate AM patients. A post-authorization safety and efficacy registry called SPARKLE was designed as a multi-centre, multi-national, non-interventional, prospective cohort study. SPARKLE has two objectives. The first is to assess post-marketing safety and effectiveness of VA (product registry) the second is to gain new understanding of the natural course of AM (disease registry). In terms of effectiveness, the primary focus is to estimate the treatment response rate based on a multi-parametric response model. The effectiveness assessment includes the measurement of serum oligosaccharides, serum immunoglobulin G levels, endurance, pulmonary function, hearing tests, incidence of infections, use of antibiotics, psychotic events, questionnaires on quality of life and burden of disease for caregivers, among others. All patients affected by AM can participate into the registry, regardless of their treatment. Based on the current protocol, the study will be opened for participation for an indefinite time and each patient will be followed up for 15 years. The protocol does not foresee a pre-specified sample size and aims at including most of the patients treated with VA in clinical practice. The SPARKLE study will start in Europe in the second half of 2019.

  • Health Related Quality of Life, Disability, and Pain in Alpha Mannosidosis: Long-Term Data of Enzyme Replacement Therapy With Velmanase Alfa (Human Recombinant Alpha Mannosidase)
    Journal of Inborn Errors of Metabolism and Screening, 2018
    Co-Authors: Line Borgwardt, Allan M. Lund, Nathalie Guffon, Mercedes Gil-campos, Anna Tylki-szymanska, Yasmina Amraoui, Simon A. Jones, Linda De Meirleir, Johanna M. P. Van Den Hout, Silvia Geraci
    Abstract:

    Alpha-Mannosidosis, a rare lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha-mannosidase, results in accumulation of mannose-rich glycoproteins in the tissues and sequel...

  • enzyme replacement therapy with velmanase alfa human recombinant alpha mannosidase novel global treatment response model and outcomes in patients with alpha mannosidosis
    Molecular Genetics and Metabolism, 2018
    Co-Authors: Paul Harmatz, Allan M. Lund, Nathalie Guffon, Christian J Hendriksz, Julia B Hennermann, Silvia Geraci, Federica Cattaneo, Diego Ardigo, Line Borgwardt
    Abstract:

    Abstract Alpha-Mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate Alpha-Mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for Alpha-Mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to ≥2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n = 15) compared with 30% of patients receiving placebo (n = 10). Longer-term data from all patients in the clinical program (n = 33) showed 88% of patients were global responders, including all (100%) pediatric patients (n = 19) and the majority (71%) of adult patients (n = 14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with Alpha-Mannosidosis with this ERT.

  • comprehensive long term efficacy and safety of recombinant human alpha mannosidase velmanase alfa treatment in patients with alpha mannosidosis
    Journal of Inherited Metabolic Disease, 2018
    Co-Authors: Allan M. Lund, Line Borgwardt, Mercedes Gilcampos, Linda De Meirleir, Silvia Geraci, Federica Cattaneo, Diego Ardigo, Cecile Laroche, Philippe Dolhem, Duncan Cole
    Abstract:

    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.

Nathalie Guffon - One of the best experts on this subject based on the ideXlab platform.

  • use of the bruininks oseretsky test of motor proficiency bot 2 to assess efficacy of velmanase alfa as enzyme therapy for alpha mannosidosis
    Molecular genetics and metabolism reports, 2020
    Co-Authors: Dawn Phillips, Line Borgwardt, Nathalie Guffon, Anna Tylkiszymanska, Mercedes Gilcampos, Julia B Hennermann, Yasmina Amraoui, Silvia Geraci, Diego Ardigo, Federica Cattaneo
    Abstract:

    Abstract Objectives Alpha-Mannosidosis is a rare autosomal recessive lysosomal storage disorder resulting from deficient lysosomal alpha-mannosidase activity. Clinical manifestations include progressive balance disorders, immune deficiency, skeletal abnormalities and cognitive deficits beginning in early childhood. Enzyme replacement therapy with recombinant human alpha-mannosidase (velmanase alfa) is scheduled for clinical development in the US beginning in 2020 and has been approved in the EU for treatment of non-neurological manifestations in cases of mild to moderate disease. This study assessed effects of velmanase alfa on fine and gross motor proficiency in children and adults. Methods Integrated Bruininks-Oseretsky (BOT-2) test of Motor Proficiency data from velmanase alfa clinical trials was stratified by age for 14 adults and 19 children treated for up to 4 years. Results Patients showed global developmental delays at baseline. For the combined adult and pediatric group there was a statistically significant increase (improvement) in BOT-2 total point score of 13% (p = .035, 95% CI 1.0, 25.0) from baseline to last observation. When stratified by pediatric versus adult patients, there was improvement in BOT-2 total point score in patients Conclusions There was limited ability to assess the BOT-2 change responses in adults. Pediatric patients showed stability or improvement in scaled scores relative to healthy peers, indicating continued skill acquisition, which may increase independence and contribute to improved patient quality of life.

  • recognition of alpha mannosidosis in paediatric and adult patients presentation of a diagnostic algorithm from an international working group
    Molecular Genetics and Metabolism, 2019
    Co-Authors: Nathalie Guffon, Line Borgwardt, Allan M. Lund, Anna Tylkiszymanska, Mercedes Gilcampos, Rossella Parini, Julia B Hennermann
    Abstract:

    Abstract Alpha-Mannosidosis is an ultra-rare progressive lysosomal storage disorder caused by deficiency of alpha-mannosidase. Timely diagnosis of the disease has the potential to influence patient outcomes as preventive therapies can be initiated at an early stage. However, no internationally-recognised algorithm is currently available for the diagnosis of the disease. With the aim of developing a diagnostic algorithm for Alpha-Mannosidosis an international panel of experts met to reach a consensus by applying the nominal group technique. Two proposals were developed for diagnostic algorithms of Alpha-Mannosidosis, one for patients ≤10 years of age and one for those >10 years of age. In younger patients, hearing impairment and/or speech delay are the cardinal symptoms that should prompt the clinician to look for additional symptoms that may provide further diagnostic clues. Older patients have different clinical presentations, and the presence of mental retardation and motor impairment progression and/or psychiatric manifestations should prompt the clinician to assess for other symptoms. In both younger and older patients, either additional metabolic monitoring or referral for testing is warranted upon suspicion of disease. Oligosaccharides in urine (historically performed) or serum were considered as an initial screening procedure, while enzymatic activity may also be considered as first choice in some centres. Molecular testing should be performed as a final confirmatory step. The developed algorithms can easily be applied in a variety of settings, and may help to favour early diagnosis of alpha mannosidosis and treatment.

  • the sparkle study shedding light on alpha mannosidosis
    Molecular Genetics and Metabolism, 2019
    Co-Authors: Julia B Hennermann, Line Borgwardt, Allan M. Lund, Nathalie Guffon, Anna Tylkiszymanska, Mercedes Gilcampos, Federica Cattaneo, Stefania Pirondi, Nicole Muschol
    Abstract:

    Alpha-Mannosidosis (AM) is a lysosomal storage disorder caused by reduced activity of the enzyme alpha-mannosidase, leading to intracellular accumulation of mannose-rich oligosaccharides in various organs. Velmanase alfa (VA) is a human recombinant alpha-mannosidase approved in Europe in 2018 as enzyme replacement therapy for the treatment of non-neurological manifestations in mild to moderate AM patients. A post-authorization safety and efficacy registry called SPARKLE was designed as a multi-centre, multi-national, non-interventional, prospective cohort study. SPARKLE has two objectives. The first is to assess post-marketing safety and effectiveness of VA (product registry) the second is to gain new understanding of the natural course of AM (disease registry). In terms of effectiveness, the primary focus is to estimate the treatment response rate based on a multi-parametric response model. The effectiveness assessment includes the measurement of serum oligosaccharides, serum immunoglobulin G levels, endurance, pulmonary function, hearing tests, incidence of infections, use of antibiotics, psychotic events, questionnaires on quality of life and burden of disease for caregivers, among others. All patients affected by AM can participate into the registry, regardless of their treatment. Based on the current protocol, the study will be opened for participation for an indefinite time and each patient will be followed up for 15 years. The protocol does not foresee a pre-specified sample size and aims at including most of the patients treated with VA in clinical practice. The SPARKLE study will start in Europe in the second half of 2019.

  • Health Related Quality of Life, Disability, and Pain in Alpha Mannosidosis: Long-Term Data of Enzyme Replacement Therapy With Velmanase Alfa (Human Recombinant Alpha Mannosidase)
    Journal of Inborn Errors of Metabolism and Screening, 2018
    Co-Authors: Line Borgwardt, Allan M. Lund, Nathalie Guffon, Mercedes Gil-campos, Anna Tylki-szymanska, Yasmina Amraoui, Simon A. Jones, Linda De Meirleir, Johanna M. P. Van Den Hout, Silvia Geraci
    Abstract:

    Alpha-Mannosidosis, a rare lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha-mannosidase, results in accumulation of mannose-rich glycoproteins in the tissues and sequel...

  • enzyme replacement therapy with velmanase alfa human recombinant alpha mannosidase novel global treatment response model and outcomes in patients with alpha mannosidosis
    Molecular Genetics and Metabolism, 2018
    Co-Authors: Paul Harmatz, Allan M. Lund, Nathalie Guffon, Christian J Hendriksz, Julia B Hennermann, Silvia Geraci, Federica Cattaneo, Diego Ardigo, Line Borgwardt
    Abstract:

    Abstract Alpha-Mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate Alpha-Mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for Alpha-Mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to ≥2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n = 15) compared with 30% of patients receiving placebo (n = 10). Longer-term data from all patients in the clinical program (n = 33) showed 88% of patients were global responders, including all (100%) pediatric patients (n = 19) and the majority (71%) of adult patients (n = 14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with Alpha-Mannosidosis with this ERT.

Tommaso Beccari - One of the best experts on this subject based on the ideXlab platform.

  • Lysosomal alpha-mannosidase and Alpha-Mannosidosis.
    Frontiers in Bioscience, 2017
    Co-Authors: Silvia Paciotti, Michela Codini, Anna Tasegian, Maria Rachele Ceccarini, Samuela Cataldi, Cataldo Arcuri, Bernard Fioretti, Elisabetta Albi, Tommaso Beccari
    Abstract:

    : 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.

  • funtional characterization of four novel man2b1 mutations causing juvenile onset alpha mannosidosis
    Clinica Chimica Acta, 2007
    Co-Authors: Maria Gabriela Pittis, Anna Lisa E Montalvo, Pirkko Heikinheimo, Michele Sbaragli, Chiara Balducci, Emanuele Persichetti, L Van Maldergem, Mirella Filocamo, Bruno Bembi, Tommaso Beccari
    Abstract:

    Alpha-Mannosidosis is a recessively inherited disorder due to the deficiency of the lysosomal alpha-mannosidase. We report the molecular analysis performed in two patients with the late onset form of Alpha-Mannosidosis. Four new alleles were identified: three missense mutations involving highly conserved residues, c.597 C>A (p.H200N), c.1553 T>C (p.L518P) and c.2746 C>A (p.R916S) and a single nucleotide deletion, c.2660delC. In vitro expression studies in COS-1 cells demonstrated that pH200N, p.L518P and p.R916S proteins are expressed but retained no residual enzyme activity. These data are supported by structural 3D analysis which predicted that both p.L518P and p.R916S could affect the interaction of the small E-domain with the active site domain or the main body of the structure while the pH200N might alter substrate binding or other catalytic properties. Finally, the c.2660delC causes a frameshift introducing a premature stop codon (p.T887SfsX45), presuming to be a severe mutation.

  • efficacy of enzyme replacement therapy in α mannosidosis mice a preclinical animal study
    Human Molecular Genetics, 2004
    Co-Authors: Diego Prieto Roces, Aldo Orlacchio, Tommaso Beccari, Jens Fogh, Renate Lullmannrauch, Claes Andersson, Chiara Balducci, Jianhe Peng, Ole K Tollersrud, Paul Saftig
    Abstract:

    Alpha-Mannosidosis is a lysosomal storage disorder which manifests itself in the excessive storage of mannose-containing oligosaccharides in the lysosomes of multiple peripheral tissues and in the brain. Here we report on the correction of storage in a mouse model of Alpha-Mannosidosis after intravenous administration of lysosomal acid alpha-mannosidase (LAMAN) from bovine kidney, and human and mouse recombinant LAMAN. The bovine and the human enzyme were barely phosphorylated, whereas the bulk of the mouse LAMAN contained mannose 6-phosphate recognition markers. The clearance decreased from bovine to human to mouse LAMAN with plasma half-times of 4, 8 and 12 min, respectively. The apparent half-life of the internalized enzyme was dependent on the enzyme source as well as tissue type and varied between 3 and 16 h. The corrective effect on the storage of neutral oligosaccharides was time-, tissue- and dose-dependent, and the effects were observed to be transient. After a single dose of LAMAN the maximum corrective effect was observed between 2 and 6 days after injection. In general the corrective effect of the human LAMAN was higher than that of the mouse LAMAN and lowest for the bovine LAMAN. Injection of 250 mU human LAMAN/g body weight followed by a subsequent injection 3.5 days later was sufficient to clear liver, kidney and heart from neutral oligosaccharides. Surprisingly a decrease in mannose containing oligosaccharides was also observed in the brain, with storage levels reported at <30% than that found in controls. These data clearly underline the efficacy of enzyme replacement therapy for the correction of storage in Alpha-Mannosidosis and suggest that this treatment can substantially decrease storage in the brain.

  • two novel mutations in the gene for human α mannosidase that cause α mannosidosis
    Journal of Inherited Metabolic Disease, 2003
    Co-Authors: Tommaso Beccari, Lucia Bibi, R Ricci, D Antuzzi, A Burgalossi, Egidia Costanzi, Aldo Orlacchio
    Abstract:

    Mutation analysis performed on two Italian patients with Alpha-Mannosidosis allowed the identification of two new mutations, IVS20-2A>G and 322-323insA. The patients were both homozygous for these mutations. The first mutation causes skipping of exon 21, whereas the second causes a frameshift introducing a stop codon at position 160 of the amino acid sequence.

  • targeted disruption of the lysosomal α mannosidase gene results in mice resembling a mild form of human α mannosidosis
    Human Molecular Genetics, 1999
    Co-Authors: Sofia Stinchi, Aldo Orlacchio, Tommaso Beccari, Renate Lullmannrauch, Dieter Hartmann, R Coenen, Kurt Von Figura, Paul Saftig
    Abstract:

    Alpha-Mannosidosis is a lysosomal storage disease with autosomal recessive inheritance caused by a deficiency of the lysosomal alpha-mannosidase, which is involved in the degradation of asparagine-linked carbohydrate cores of glycoproteins. An Alpha-Mannosidosis mouse model was generated by targeted disruption of the gene for lysosomal alpha-mannosidase. Homozygous mutant animals exhibit alpha-mannosidase enzyme deficiency and elevated urinary secretion of mannose-containing oligosaccharides. Thin-layer chromatography revealed an accumulation of oligosaccharides in liver, kidney, spleen, testis and brain. The cellular alterations were characterized by multiple membrane-limited cytoplasmic vacuoles as seen for instance in liver, exocrine pancreas, kidney, thyroid gland, smooth muscle cells, osteocytes and in various neurons of the central and peripheral nervous systems. The morphological lesions and their topographical distribution, as well as the biochemical alterations, closely resemble those reported for human Alpha-Mannosidosis. This mouse model will be a valuable tool for studying the pathogenesis of inherited Alpha-Mannosidosis and may help to evaluate therapeutic approaches for lysosomal storage diseases.