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Molecular Genetics and Metabolism Apr 2019Alpha-mannosidosis is an ultra-rare progressive lysosomal storage disorder caused by deficiency of alpha-mannosidase. Timely diagnosis of the disease has the potential...
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.
Topics: Adolescent; Adult; Age Factors; Algorithms; Child; Child, Preschool; Consensus; Disease Progression; Humans; Internationality; Middle Aged; Young Adult; alpha-Mannosidosis
PubMed: 30792122
DOI: 10.1016/j.ymgme.2019.01.024 -
Orphanet Journal of Rare Diseases Jun 2018α-mannosidosis is a rare, autosomal-recessive, lysosomal storage disease caused by a deficient activity of α-mannosidase. Typical symptoms include intellectual, motor...
BACKGROUND
α-mannosidosis is a rare, autosomal-recessive, lysosomal storage disease caused by a deficient activity of α-mannosidase. Typical symptoms include intellectual, motor and hearing impairment, facial coarsening, and musculoskeletal abnormalities. Ocular pathologies reported previously were mainly opacities of the cornea and lens, strabismus, and ocular motility disorders. However, retinal and optic nerve degeneration have been rarely described.
METHODS
We report ocular findings of 32 patients with α-mannosidosis. We particularly concentrated on retinal abnormalities which we supported by posterior segment examination, fundus photography, and Spectral-Domain optical coherence tomography (SD-OCT) imaging.
RESULTS
Tapeto-retinal degeneration with bone spicule formations in the peripheral retina or macular changes were seen in three patients (9.4%) on funduscopy; of these, two with optic nerve atrophy. Eight retinal images could be obtained by OCT or fundus photography; of these, six showed thinning of the outer retinal layers on OCT. Overall, optic nerve atrophy was seen in six patients (18.8%); of these, four with partial atrophy. Two patients had partial optic nerve atrophy with no retinal abnormalities on funduscopy. Cataract was seen in two (6.3%), corneal haze also in two patients (6.3%). Six patients (18.8%) had manifest strabismus, four (12.5%) nystagmus, and in five patients (15.6%) impaired smooth pursuit eye movements were seen.
CONCLUSION
Ocular pathologies are not exclusively confined to opacities of the cornea and lens or strabismus and ocular motility disorders but tapeto-retinal degeneration and optic nerve atrophy may be a common feature in α-mannosidosis. OCT technology helps detecting early outer retinal thinning which can progress with age and potentially leads to vision loss over time.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Male; Middle Aged; Nerve Degeneration; Optic Atrophy; Retina; Retinal Degeneration; Tomography, Optical Coherence; Young Adult; alpha-Mannosidosis
PubMed: 29859105
DOI: 10.1186/s13023-018-0829-z -
Journal of Inherited Metabolic Disease Nov 2018This phase III, double-blind, randomised, placebo-controlled trial (and extension phase) was designed to assess the efficacy and safety of velmanase alfa (VA) in... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial.
INTRODUCTION
This phase III, double-blind, randomised, placebo-controlled trial (and extension phase) was designed to assess the efficacy and safety of velmanase alfa (VA) in alpha-mannosidosis (AM) patients.
METHODS
Twenty-five patients were randomised to weekly 1 mg/kg VA or placebo for 52 weeks. At study conclusion, placebo patients switched to VA; 23 patients continued receiving VA in compassionate-use/follow-on studies and were evaluated in the extension phase [last observation (LO)]. Co-primary endpoints were changes in serum oligosaccharide (S-oligo) and in the 3-min stair-climb test (3MSCT).
RESULTS
Mean relative change in S-oligo in the VA arm was -77.6% [95% confidence interval (CI) -81.6 to -72.8] at week 52 and -62.9% (95% CI -85.8 to -40.0) at LO; mean relative change in the placebo arm was -24.1% (95% CI -40.3 to -3.6) at week 52 and -55.7% (95% CI -76.4 to -34.9) at LO after switch to active treatment. Mean relative change in 3MSCT at week 52 was -1.1% (95% CI -9.0 to 7.6) and - % (95% CI -13.4 to 6.5) for VA and placebo, respectively. At LO, the mean relative change was 3.9% (95% CI -5.5 to 13.2) in the VA arm and 9.0% (95% CI -10.3 to 28.3) in placebo patients after switch to active treatment. Similar improvement pattern was observed in secondary parameters. A post hoc analysis investigated whether some factors at baseline could account for treatment outcome; none of those factors were predictive of the response to VA, besides age.
CONCLUSIONS
These findings support the utility of VA for the treatment of AM, with more evident benefit over time and when treatment is started in the paediatric age.
Topics: Adolescent; Adult; Child; Child, Preschool; Double-Blind Method; Enzyme Replacement Therapy; Europe; Female; Humans; Male; Quality of Life; Recombinant Proteins; Severity of Illness Index; Treatment Outcome; Young Adult; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 29846843
DOI: 10.1007/s10545-018-0185-0 -
International Journal of Molecular... May 2018Alpha-mannosidosis (α-mannosidosis) is a rare lysosomal storage disorder with an autosomal recessive inheritance caused by mutations in the gene encoding for the... (Review)
Review
Alpha-mannosidosis (α-mannosidosis) is a rare lysosomal storage disorder with an autosomal recessive inheritance caused by mutations in the gene encoding for the lysosomal α-d-mannosidase. So far, 155 variants from 191 patients have been identified and in part characterized at the biochemical level. Similarly to other lysosomal storage diseases, there is no relationship between genotype and phenotype in alpha-mannosidosis. Enzyme replacement therapy is at the moment the most effective therapy for lysosomal storage disease, including alpha-mannosidosis. In this review, the genetic of alpha-mannosidosis has been described together with the results so far obtained by two different therapeutic strategies: bone marrow transplantation and enzyme replacement therapy. The primary indication to offer hematopoietic stem cell transplantation in patients affected by alpha-mannosidosis is preservation of neurocognitive function and prevention of early death. The results obtained from a Phase I⁻II study and a Phase III study provide evidence of the positive clinical effect of the recombinant enzyme on patients with alpha-mannosidosis.
Topics: Animals; Bone Marrow Transplantation; Combined Modality Therapy; Enzyme Activation; Enzyme Replacement Therapy; Genetic Association Studies; Humans; Mutation; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 29772816
DOI: 10.3390/ijms19051500 -
Journal of Inherited Metabolic Disease Nov 2018Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Activities of Daily Living; Adolescent; Adult; Child; Enzyme Replacement Therapy; Europe; Female; Follow-Up Studies; Humans; Male; Quality of Life; Recombinant Proteins; Severity of Illness Index; Treatment Outcome; Young Adult; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 29725868
DOI: 10.1007/s10545-018-0175-2 -
Molecular Genetics and Metabolism Jun 2018Alpha-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...
Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis.
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.
Topics: Adolescent; Adult; Child; Child, Preschool; Enzyme Replacement Therapy; Female; Humans; Male; Prognosis; Quality of Life; Recombinant Proteins; Young Adult; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 29716835
DOI: 10.1016/j.ymgme.2018.04.003 -
Cell Structure and Function Mar 2018Inflammatory bowel disease (IBD) is a refractory disease of the gastrointestinal tract that is believed to develop in genetically susceptible individuals. Glycosylation,...
Inflammatory bowel disease (IBD) is a refractory disease of the gastrointestinal tract that is believed to develop in genetically susceptible individuals. Glycosylation, a type of post-translational modification, is involved in the development of a wide range of diseases, including IBD, by modulating the function of various glycoproteins. To identify novel genes contributing to the development of IBD, we analyzed single nucleotide polymorphisms (SNPs) of glycosylation-related genes in IBD patients and identified MAN2A1, encoding alpha-mannosidase II (α-MII), as a candidate gene. α-MII plays a crucial, but not exclusive, role in the maturation of N-glycans. We also observed that intestinal epithelial cells (IECs), which establish the first-line barrier and regulate gut immunity, selectively expressed α-MII with minimal expression of its isozyme, alpha-mannosidase IIx (α-MIIx). This led us to hypothesize that IEC-intrinsic α-MII is implicated in the pathogenesis of IBD. To test this hypothesis, we generated IEC-specific α-MII-deficient (α-MII) mice. Although α-MII deficiency has been shown to have a minimal effect on N-glycan maturation in most cell types due to the compensation by α-MIIx, ablation of α-MII impaired the maturation of N-glycans in IECs. α-MII mice were less susceptible to dextran sulfate sodium-induced colitis compared with control littermates. In accordance with this, neutrophil infiltration in the colonic mucosa was attenuated in α-MII mice. Furthermore, gene expression levels of neutrophil-attracting chemokines were downregulated in the colonic tissue. These results suggest that IEC-intrinsic α-MII promotes intestinal inflammation by facilitating chemokine expression. We propose SNPs in MAN2A1 as a novel genetic factor for IBD.Key words: inflammatory bowel disease, alpha-mannosidase II, intestinal epithelial cell, N-glycosylation.
Topics: Animals; Chemokines; Colitis; Colon; Dextran Sulfate; Down-Regulation; Epithelial Cells; Gastrointestinal Microbiome; Genome-Wide Association Study; Glycosylation; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Mannosidases; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Polymorphism, Single Nucleotide; alpha-Mannosidosis
PubMed: 29343654
DOI: 10.1247/csf.17022 -
Revista de Neurologia May 2017Individually, neurometabolic diseases are ultra rare, but for some of them there is an effective treatment. (Review)
Review
INTRODUCTION
Individually, neurometabolic diseases are ultra rare, but for some of them there is an effective treatment.
DEVELOPMENT
Several recent therapeutic advances are reviewed. Today, the possibilities of treatment for lysosomal diseases have improved. In recent years the use of enzyme replacement therapy has become more widely extended to treat mucopolysaccharidosis type IVA (Morquio A), mucopolysaccharidosis type VII (Sly syndrome), lysosomal acid lipase deficiency and alpha-mannosidosis. It has been proven that very early treatment of mucopolysaccharidoses can change their natural course. Intrathecal enzyme replacement therapy is being tried in some mucopolysaccharidoses with cognitive involvement, in an attempt to halt neurodegeneration. Very positive results have been obtained with genetically modified autotransplants in late-onset infantile metachromatic leukodystrophy and research is being conducted on other pathologies (mucopolysaccharidosis type III, X-linked adrenoleukodystrophy). Novel outcomes are also being achieved in the treatment of some encephalopathies that are sensitive to vitamins or cofactors: triple therapy in pyridoxine dependency, treatment with thiamine for some subacute encephalopathies with involvement of the basal ganglia, treatment with folinic acid for children with cerebral folate deficiency, or treatment with cyclic pyranopterin monophosphate in molybdenum cofactor deficiency type A.
CONCLUSIONS
As neuropaediatricians we must update our knowledge, especially in the case of treatable neurometabolic pathologies, since early treatment can change their prognosis significantly.
Topics: Avitaminosis; Brain Diseases, Metabolic, Inborn; Carrier Proteins; Child; Clinical Trials as Topic; Coenzymes; Early Diagnosis; Early Medical Intervention; Enzyme Replacement Therapy; Epilepsy; Genetic Therapy; Humans; Infant, Newborn; Lysosomal Storage Diseases, Nervous System; Nervous System Diseases; Therapies, Investigational
PubMed: 28524215
DOI: No ID Found -
PeerJ 2017Deficiencies in lysosomal a-mannosidase (LAM) activity in animals, caused either by mutations or by consuming toxic alkaloids, lead to severe phenotypic and behavioural...
BACKGROUND
Deficiencies in lysosomal a-mannosidase (LAM) activity in animals, caused either by mutations or by consuming toxic alkaloids, lead to severe phenotypic and behavioural consequences. Yet, epialleles adversely affecting LAM expression exist in the honey bee population suggesting that they might be beneficial in certain contexts and cannot be eliminated by natural selection.
METHODS
We have used a combination of enzymology, molecular biology and metabolomics to characterise the catalytic properties of honey bee LAM (AmLAM) and then used an indolizidine alkaloid swainsonine to inhibit its activity and .
RESULTS
We show that AmLAM is inhibited by swainsonine albeit at slightly higher concentrations than in other animals. Dietary exposure of growing larvae to swainsonine leads to pronounced metabolic changes affecting not only saccharides, but also amino acids, polyols and polyamines. Interestingly, the abundance of two fatty acids implicated in epigenetic regulation is significantly reduced in treated individuals. Additionally, swainsonie causes loco-like symptoms, increased mortality and a subtle decrease in the rate of larval growth resulting in a subsequent developmental delay in pupal metamorphosis.
DISCUSSION
We consider our findings in the context of cellular LAM function, larval development, environmental toxicity and colony-level impacts. The observed developmental heterochrony in swainsonine-treated larvae with lower LAM activity offer a plausible explanation for the existence of epialleles with impaired LAM expression. Individuals carrying such epialleles provide an additional level of epigenetic diversity that could be beneficial for the functioning of a colony whereby more flexibility in timing of adult emergence might be useful for task allocation.
PubMed: 28321369
DOI: 10.7717/peerj.3109 -
Frontiers in Bioscience (Landmark... Jan 2017Lysosomal alpha-mannosidase with acidic pH optimum is ubiquitous in human tissues where is expressed in two major forms, A and B that are the product of a single gene... (Review)
Review
Lysosomal alpha-mannosidase with acidic pH optimum is ubiquitous in human tissues where is expressed in two major forms, A and B that are the product of a single gene located on chromosome 19. Mutations in the gene encoding for alpha-mannosidase cause alpha- mannosidosis, an autosomal recessive disease, resulting in the accumulation of unprocessed mannose containing oligosaccharide material. This rare disease has an estimated incidence of 1/500.0.00 live births and clinically is divided into three subgroups. Today the most promising therapy for this disease is the enzyme replacement therapy. To develop this strategy a mouse model for alpha-mannosidosis has been generated and a recombinant human alpha-mannosidase has been produced from Chinese-hamster ovary cells. Interestingly it has been shown that the recombinant enzyme, used in high dose, can cross the blood brain barrier. This recombinant enzyme has been tested in the first randomized study investigating the efficacy of enzyme replacement therapy in patients with alpha-mannosidosis. This review contains the scientific progresses on lysosomal alpha-mannosidase from the cloning to the beginning of the therapy.
Topics: Animals; Disease Models, Animal; Enzyme Replacement Therapy; Humans; Lysosomes; Mutation; Recombinant Proteins; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 27814608
DOI: 10.2741/4478