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Cureus Apr 2024Alpha-mannosidosis is a rare lysosomal storage disorder with progressive impairments in motor functions, skeletal deformities, and immunodeficiency. Enzyme replacement...
Prenatal Diagnosis of c.437-1G>A Mutation in the MAN2B1 Gene in a Family With Alpha-Mannosidosis: Unraveling Clinical Presentation and Treatment Outcomes in a Novel Prenatal Case.
Alpha-mannosidosis is a rare lysosomal storage disorder with progressive impairments in motor functions, skeletal deformities, and immunodeficiency. Enzyme replacement therapy (ERT) should be initiated early to achieve optimal outcomes. This report describes how alpha-mannosidosis diagnosis in a seven-year-old girl led to a successful prenatal diagnosis in the subsequent pregnancy and pre-symptomatic treatment at the early disease stage. The index patient was a seven-year-old girl who was referred with a confirmed diagnosis of alpha-mannosidosis based on the presence of homozygous c.437-1G>A mutation in the MAN2B1 gene. A prenatal diagnosis was made in the subsequent pregnancy through molecular analysis, which revealed the same homozygous variant. The patient was treated at the fifth week of age and showed mild skeletal involvement and normal development at ERT initiation. At 11 months of age, the ERT level increased to 15.8 µmol/l/h. The motor assessment showed that the patient was developmentally normal and was able to maintain her sitting and walking for a few steps only. Prenatal molecular screening in affected families can allow for the early identification and implementation of appropriate management strategies for alpha-mannosidosis.
PubMed: 38800253
DOI: 10.7759/cureus.58922 -
Clinical Dysmorphology Jan 2024Alpha-mannosidosis (MIM #248500) is an ultra-rare autosomal recessive lysosomal storage disease with multi-system involvement and a wide phenotypic spectrum. Information...
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 first symptoms ranged from 0-1 to 10 years. The diagnostic delay ranged from 2 to 22 years (median= 11 years). Coarse face, hearing, heart valves, joints, gait, language, dysarthria, psychiatric symptoms, I.Q., MRI, walking disabilities, orthopedic disturbances and surgeries showed a slow worsening over the decades. Our patients showed a slowly worsening progressive outcome over the decades. Psychiatric symptoms were present in 100% of our population and improved with the appropriate pharmacological intervention. This aspect requires attention when following up on these patients. Our description of the long-term evolution of alpha-mannosidosis patients may provide basic knowledge for understanding the effects of specific treatments.
Topics: Male; Female; Humans; Infant, Newborn; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; alpha-Mannosidosis; Delayed Diagnosis; Mental Disorders; Inheritance Patterns; Italy
PubMed: 37791705
DOI: 10.1097/MCD.0000000000000474 -
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 -
Journal of Veterinary Internal Medicine 1988Three Domestic Long-haired cats from a litter of five afflicted with alpha-mannosidosis (alpha-mannosidosis) were studied clinically and pathologically. Many of these...
Three Domestic Long-haired cats from a litter of five afflicted with alpha-mannosidosis (alpha-mannosidosis) were studied clinically and pathologically. Many of these findings contrasted with those made previously in kittens with deficiency of alpha-mannosidase. In these cats, the clinical signs were generally milder, more slowly progressive, and did not include the prominent skeletal deformities, ocular abnormalities, or hepatomegaly that were reported in prior studies of Persian and Domestic Short-haired kittens. While the Domestic Long-haired cats were spared the central nervous system (CNS) myelin deficiency, which was severe in the Persian but mild in the Domestic Short-haired cats, the extensive loss of Purkinje cells in their cerebellar cortices was without precedent. Additionally, ultrastructural study of the neuronal cytosomes showed a diversity not recorded in the earlier cases. The observed phenotypic heterogeneity was sufficient enough to consider separating feline alpha-mannosidosis into severe, acute and milder, chronic forms in a manner analogous to the Type I and Type II distinctions made in infants and juveniles.
Topics: Animals; Brain; Brain Diseases; Cat Diseases; Cats; Female; Male; Mannosidases; Microscopy, Electron; Neurons; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 3230555
DOI: 10.1111/j.1939-1676.1988.tb00311.x -
Molecular Genetics and Metabolism May 2024Alpha-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... (Review)
Review
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.
Topics: Humans; alpha-Mannosidosis; Enzyme Replacement Therapy; alpha-Mannosidase; Delayed Diagnosis; Rare Diseases
PubMed: 38555683
DOI: 10.1016/j.ymgme.2024.108444 -
Journal of Medical Genetics Feb 1986Chromosome 19 is currently the most fully mapped of the smaller chromosomes, with about 40 loci assigned to it (HGM8). Major inherited disorders on this chromosome... (Review)
Review
Chromosome 19 is currently the most fully mapped of the smaller chromosomes, with about 40 loci assigned to it (HGM8). Major inherited disorders on this chromosome include myotonic dystrophy and familial hypercholesterolaemia. Other loci include five blood groups, a cluster of apolipoprotein genes, and the receptors for insulin and polio virus. A number of cloned genes and random DNA sequences identify polymorphisms which, together with blood group and other protein polymorphisms, have been used to establish a framework for ordering the loci and estimating genetic distances. Hybrid cell lines allow loci to be assigned to one of eight different regions and a detailed genetic map of the chromosome will be possible in the near future.
Topics: ABO Blood-Group System; Apolipoproteins C; Apolipoproteins E; Chromosome Mapping; Chromosomes, Human, 6-12 and X; DNA Repair; Enzymes; Genes; Humans; Hypercholesterolemia; Myotonic Dystrophy; Neurofibromatosis 1; Polymorphism, Genetic; Proteins; alpha-Mannosidosis
PubMed: 3081724
DOI: 10.1136/jmg.23.1.2 -
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 -
The British Journal of Radiology Jan 2014Lysosomal storage diseases (LSDs) are a large group of genetic metabolic disorders that result in the accumulation of abnormal material, such as mucopolysaccharides,... (Review)
Review
Lysosomal storage diseases (LSDs) are a large group of genetic metabolic disorders that result in the accumulation of abnormal material, such as mucopolysaccharides, glycoproteins, amino acids and lipids, within cells. Since many LSDs manifest during infancy or early childhood, with potentially devastating consequences if left untreated, timely identification is imperative to prevent irreversible damage and early death. In this review, the key imaging features of the non-lipid or extralipid LSDs are examined and correlated with salient clinical manifestations and genetic information. Disorders are stratified based on the type of excess material causing tissue or organ dysfunction, with descriptions of the mucopolysaccharidoses, mucolipidoses, alpha-mannosidosis, glycogen storage disorder II and cystinosis. In addition, similarities and differences in radiological findings between each of these LSDs are highlighted to facilitate further recognition. Given the rare and extensive nature of the LSDs, mastery of their multiple clinical and radiological traits may seem challenging. However, an understanding of the distinguishing imaging characteristics of LSDs and their clinical correlates may allow radiologists to play a key role in the early diagnosis of these progressive and potentially fatal disorders.
Topics: Diagnosis, Differential; Glucuronidase; Humans; Lyases; Lysosomal Storage Diseases; Metabolism, Inborn Errors; Mucopolysaccharidosis I; Mucopolysaccharidosis II; Mucopolysaccharidosis III; Mucopolysaccharidosis IV; Mucopolysaccharidosis VI; Mucopolysaccharidosis VII
PubMed: 24234586
DOI: 10.1259/bjr.20130467 -
The Journal of Biological Chemistry Sep 1991Lysosomal alpha-mannosidases were partially purified from bovine and feline liver and employed to digest a large number of oligosaccharides with structures corresponding... (Comparative Study)
Comparative Study
Lysosomal alpha-mannosidases were partially purified from bovine and feline liver and employed to digest a large number of oligosaccharides with structures corresponding to the oligomannosyl parts of complex, hybrid, and high-mannose glycans. The incubation products were identified by high pressure liquid chromatography with reference compounds of defined structure and by acetolysis. For all classes of substrates, the lysosomal alpha-mannosidases displayed a high degree of in vitro specificity with regard to the hydrolysis of mannose residues. Thus, in each case, 1 or at most 2 residues were always preferentially cleaved so that the degradative process proceeded down a well defined pathway. A comparison of the relative efficiency with which lysosomal alpha-mannosidases catalyzed the hydrolysis of particular oligosaccharides and of the structures of the resulting intermediates with those of the compounds accumulated in alpha-mannosidosis allows conclusions to be drawn regarding the nature of the enzymatic defect. In bovine alpha-mannosidosis, the oligosaccharides are those expected for a partial deficiency of normal lysosomal alpha-mannosidase, so that they correspond to intermediates in the normal catabolic pathway. In feline alpha-mannosidosis, in which the alpha-mannosidase deficiency is more severe than in cattle, the accumulated oligosaccharides primarily represent intact oligomannosyl moieties of N-linked glycans rather than the products of residual alpha-mannosidase activity.
Topics: Animals; Carbohydrate Sequence; Cats; Cattle; Chromatography, High Pressure Liquid; Liver; Lysosomes; Mannose; Mannosidases; Molecular Sequence Data; Oligosaccharides; Polysaccharides; Substrate Specificity; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 1885586
DOI: No ID Found -
Journal of Neuropathology and... Jan 2011α-Mannosidosis is a rare lysosomal storage disease with accumulation of undegraded mannosyl-linked oligosaccharides in cells throughout the body, most notably in the... (Comparative Study)
Comparative Study
α-Mannosidosis is a rare lysosomal storage disease with accumulation of undegraded mannosyl-linked oligosaccharides in cells throughout the body, most notably in the CNS. This leads to a broad spectrum of neurological manifestations, including progressive intellectual impairment, disturbed motor functions, and cerebellar atrophy. To develop therapeutic outcome measures for enzyme replacement therapy that could be used for human patients, a gene knockout model of α-mannosidosis in mice was analyzed for CNS pathology and motor deficits. In the cerebellar molecular layer, α-mannosidosis mice display clusters of activated Bergman glia, infiltration of phagocytic macrophages, and accumulation of free cholesterol and gangliosides (GM1), notably in regions lacking Purkinje cells. α-Mannosidosis brain lysates also displayed increased expression of Lamp1 and hyperglycosylation of the cholesterol binding protein NPC2. Detailed assessment of motor function revealed age-dependent gait defects in the mice that resemble the disturbed motor function in human patients. Short-term enzyme replacement therapy partially reversed the observed cerebellar pathology with fewer activated macrophages and astrocytes but unchanged levels of hyperglycosylated NPC2, gangliosides, and cholesterol. The present study demonstrates cerebellar alterations in α-mannosidosis mice that relate to the motor deficits and pathological changes seen in human patients and can be used as therapeutic outcome measures.
Topics: Animals; CHO Cells; Cerebellum; Cricetinae; Cricetulus; Disease Models, Animal; Enzyme Replacement Therapy; Gene Targeting; Humans; Lameness, Animal; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Neurologic Mutants; Treatment Outcome; alpha-Mannosidase; alpha-Mannosidosis
PubMed: 21157375
DOI: 10.1097/NEN.0b013e31820428fa