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Alpha-Mannosidosis

Deficiency of Alpha-Mannosidase

Alpha-mannosidosis (AM) is a lysosomal storage disease, which may also be referred to as lysosomal acid hydrolase alpha-mannosidase or LAHAM. It is caused by mutations of the MAN2B1 gene, which lead to alpha-mannosidase deficiency. AM is associated with facial dysmorphism, skeletal abnormalities, motor and mental disabilities, hearing impairment, and immune deficiency. The disease follows a progressive course, but its severity varies largely. It may be fatal in infancy, but milder forms of AM may allow for prolonged survival.


Presentation

The clinical presentation of AM varies largely. Mental retardation, dysmorphic features, skeletal abnormalities, motor deficits, hearing impairment, and immune deficiency are the clinical hallmarks of AM, but the severity of the disease and the speed of progression differ between individual patients. Indeed, the distinction of severe and mild AM, also referred to as type 1 and type 2 disease, has been proposed, but intermediate phenotypes have repeatedly been reported [1]. In a large study comprising 130 cases, 13 cases have been classified as severe, 11 as mild, and 106 as intermediate [2], but even the distinction of three subtypes doesn't do justice to the continuum of symptoms and severity [3].

Coarse facial features and skeletal abnormalities such as scoliosis, kyphosis, pectus carinatum, genu valgum, and pes equinus may be noted at birth. Even though facial dysmorphism may be subtle and mild to moderate AM may not be immediately recognized, virtually all patients eventually develop Hurler-like facies with a prominent forehead, rounded eyebrows, a flattened nasal bridge, prognathism, widely spaced teeth, and macroglossia. Mental and motor development is delayed, but in this context, the progressive course of AM has to be considered: Affected children often appear clumsy, and milestones in speech and language development are achieved late. Overt mental retardation in infancy is not an exclusion criterion, however, and long-term studies rather suggest a gradual decline of intellectual and motor skills. It should be noted that those suffering from severe AM may not live to develop sensorineural hearing loss, learning difficulties and other cognitive deficits, psychiatric disorders, ataxia, and polyarthropathy, which are often diagnosed during childhood [4]. In particularly mild forms of the disease, these conditions may not be noted until the late first decade of life or teenage years [1].

Immune deficiency is a life-threatening feature of AM. The molecular mechanisms behind the impairment of the immune systems are poorly understood, but recurrent infections mainly occur in the first decade of life. In severe AM, repeated ear, respiratory, and gastrointestinal infections may be the presenting and dominating symptoms. Hepatomegaly is commonly diagnosed. Unfortunately, severely affected children usually succumb to infections during their first years of life [4].

Recurrent Infection
  • The older brother, the index case, was diagnosed at the age of 3 years and underwent transplantation at 13 years for the treatment of increasing somatic problems and recurrent infections.[ncbi.nlm.nih.gov]
  • Major symptoms include mental retardation, skeletal changes and recurrent infections. Recently, a successful bone marrow transplantation (BMT) in an alpha-mannosidosis patient was reported.[ncbi.nlm.nih.gov]
  • In humans, alpha-mannosidosis results in progressive facial- and skeletal abnormalities, motor impairment, hearing impairment, intellectual disability, recurrent infections and immune deficiency.[ncbi.nlm.nih.gov]
  • The disease characterized by mental retardation, skeletal changes, hearing impairment, and recurrent infections. Stem cell transplantation has been shown to be an effective treatment.[ncbi.nlm.nih.gov]
  • Patients with the autosomal recessive lysosomal storage disease alpha-mannosidosis suffer from recurrent infections.[ncbi.nlm.nih.gov]
Developmental Delay
  • These disorders, although rare, should be considered in the approach to a child with dysmorphism, developmental delay, skeletal deformities, and visceromegaly.[ncbi.nlm.nih.gov]
  • The extent of the patients' developmental delay before HSCT varied over a wide range. After HSCT, patients made developmental progress, although normal development was not achieved. Hearing ability improved in some, but not in all patients.[ncbi.nlm.nih.gov]
  • Despite being homozygous for the same mutation, the older brother had more severe developmental delay, hearing loss, and growth retardation.[ncbi.nlm.nih.gov]
  • delay and skeletal involvement (dysostosis multiplex).[ncbi.nlm.nih.gov]
  • Home Alpha-Mannosidosis Alpha-Mannosidosis Alpha-mannosidosis is an inherited disease characterized by developmental delays, facial and skeletal abnormalities, hearing loss, and immune deficiency.[integratedgenetics.com]
Splenomegaly
  • The earlier system delineated a more severe 'type I,' which shows infantile onset, rapid mental deterioration, hypotonia, splenomegaly, severe dysostosis multiplex, and severe recurrent infections, often resulting in death by age 8 years.[diseaseinfosearch.org]
  • The onset of the most severe form, type III, begins within the first months of life and includes a quick progression of intellectual disability , liver and spleen enlargement ( splenomegaly ), hearing loss, respiratory infections and skeletal abnormalities[ipfs.io]
Hepatomegaly
  • The disorder has been described as two distinct phenotypes: a severe form with hepatomegaly and early death following severe infections (type 1) and a mild form with hearing loss and mental retardation (type 2).[genome.jp]
  • Hepatomegaly is commonly diagnosed. Unfortunately, severely affected children usually succumb to infections during their first years of life. Clinical findings may raise suspicion as to a lysosomal storage disease but are hardly diagnostic of AM.[symptoma.com]
  • The cells that make up your liver just become engorged with sugar they cannot process and therefore become swollen with it, leading to hepatomegaly.[study.com]
  • Individuals with the most severe form of the condition experience hepatomegaly and early childhood death due to recurrent severe infections.[oncofertility.northwestern.edu]
  • Alpha-mannosidosis has been described as two distinct phenotypes: one severe form with hepatomegaly and early death following severe infections (Type I), and a mild form with hearing loss, mental retardation, and survival into adulthood (Type II) [ 4,[ojrd.com]
Widely Spaced Teeth
  • The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common.[ncbi.nlm.nih.gov]
  • Clinical findings Macrocephaly, thickened calvaria, coarse face, macroglossia, wide-spaced teeth, prognathism, deafness, mental retardation, hepatosplenomegaly.[medical-dictionary.thefreedictionary.com]
  • The facial dysmorphism is marked by a large head with a prominent forehead, rounded eyebrows, a flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common.[orpha.net]
  • spaced teeth, overgrown gums, large tongue, cataracts, vertebral anomalies, long bone and joint abnormalities, ataxia, and myopathy.[secure.ssa.gov]
  • Facial features may include a large head, prominent forehead, low hairline, rounded eyebrows, big ears, flattened bridge of the nose, protruding jaw, widely spaced teeth, gums too large and large tongue.[ivami.com]
Macroglossia
  • The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common.[ncbi.nlm.nih.gov]
  • Clinical findings Macrocephaly, thickened calvaria, coarse face, macroglossia, wide-spaced teeth, prognathism, deafness, mental retardation, hepatosplenomegaly.[medical-dictionary.thefreedictionary.com]
  • Dental anomalies (diastema), large ears, macroglossia, joint stiffness,, hepatosplenomegaly, enlarged head circumference, hearing loss (sensorineural), increased susceptibility to infections, dysarthria, and spondylolysis may be present.[disorders.eyes.arizona.edu]
  • The facial dysmorphism is marked by a large head with a prominent forehead, rounded eyebrows, a flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common.[orpha.net]
Prognathism
  • The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common.[ncbi.nlm.nih.gov]
  • Clinical findings Macrocephaly, thickened calvaria, coarse face, macroglossia, wide-spaced teeth, prognathism, deafness, mental retardation, hepatosplenomegaly.[medical-dictionary.thefreedictionary.com]
  • The facial dysmorphism is marked by a large head with a prominent forehead, rounded eyebrows, a flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common.[orpha.net]
  • Even though facial dysmorphism may be subtle and mild to moderate AM may not be immediately recognized, virtually all patients eventually develop Hurler-like facies with a prominent forehead, rounded eyebrows, a flattened nasal bridge, prognathism, widely[symptoma.com]
  • […] specifically motor skill delay Late initiation of speech Restricted Vocabulary Distinctive facial features Coarse, Hurler syndrome-like features Classically large head Prominent forehead Rounded eyebrows Flattened nasal bridge Macroglossia Widely spaced teeth Prognathism[oncofertility.northwestern.edu]
Muscle Weakness
  • Symptoms of the moderate form of alpha-mannosidosis include: coarse facial features hypotonia skeletal abnormalities mental retardation progressive muscle weakness hearing loss ataxia arthritis corneal clouding and slow disease progression Individuals[egl-eurofins.com]
  • For children with Type I, symptoms appear after age 10 and progress slowly; affected children have muscle weakness but not skeletal abnormalities, and they may live well into adulthood.[secure.ssa.gov]
  • Common Features of the Disorder Intellectual disability Coarse facial features (e.g. prominent forehead, flat nasal bridge) Skeletal issues (e.g. reduced bone density, bowed knees) Difficulty with coordinated movements Muscle Weakness Hearing loss Cataracts[evolvegene.com]
  • Affected individuals may also experience difficulty in coordinating movements (ataxia); muscle weakness (myopathy); delay in developing motor skills such as sitting and walking; speech impairments; increased risk of infections; enlargement of the liver[ismrd.org]
Osteopenia
  • Meanwhile, skeletal abnormalities characteristic of the disease may include osteopenia, bone thickening calvarial, deformation of the vertebrae, bowlegged or knock knees, and deterioration of the bones and joints.[ivami.com]
  • Often the appearance of an affected individual includes the following: Intellectual disability; distinctive facial features; and skeletal abnormalities such as reduced bone density (osteopenia), thickening of the bones at the top of the skull (calvaria[ismrd.org]
  • Symptoms may include distinctive facial features, skeletal abnormalities such as osteopenia, calvaria, vertebrae, bowed legs or knock knees, and deterioration of the bones and joints, hearing loss, intellectual disability, and dysfunction of the immune[cags.org.ae]
  • The skeletal abnormalities that can occur in this disorder include reduced bone density (osteopenia), thickening of the bones at the top of the skull (calvaria), deformations of the bones in the spine ( vertebrae ), bowed legs or knock knees, and deterioration[ghr.nlm.nih.gov]
  • Restricted Vocabulary Distinctive facial features Coarse, Hurler syndrome-like features Classically large head Prominent forehead Rounded eyebrows Flattened nasal bridge Macroglossia Widely spaced teeth Prognathism Unusually short neck Skeletal abnormalities Osteopenia[oncofertility.northwestern.edu]
Genu Valgum
  • Coarse facial features and skeletal abnormalities such as scoliosis, kyphosis, pectus carinatum, genu valgum, and pes equinus may be noted at birth.[symptoma.com]
  • PubMed Google Scholar Odunusi E, Peters C, Krivit W, Ogilvie J: Genu valgum deformity in Hurler syndrome after hematopoietic stem cell transplantation: correction by surgical intervention.[ojrd.com]
Osteoporosis
  • He is also at risk for osteoporosis, which we will need to monitor. Muscles: Luke’s muscles are weaker and have lower muscle tone, meaning he is not as athletic as his peers.[lukechaplin.wordpress.com]
Hearing Impairment
  • 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.[ncbi.nlm.nih.gov]
  • In humans, alpha-mannosidosis results in progressive facial- and skeletal abnormalities, motor impairment, hearing impairment, intellectual disability, recurrent infections and immune deficiency.[ncbi.nlm.nih.gov]
  • The disease characterized by mental retardation, skeletal changes, hearing impairment, and recurrent infections. Stem cell transplantation has been shown to be an effective treatment.[ncbi.nlm.nih.gov]
  • The resulting intracellular accumulation of mannose-containing oligosaccharides leads to mental retardation, hearing impairment, skeletal changes, and immunodeficiency.[ncbi.nlm.nih.gov]
  • The questionnaire allowed us to assess the following features: Facial dysmorphism, columnar disease, arthritis, myopathy, hearing impairment, mental impairment, psychosis, bone disease and motor function as well as general health.[ncbi.nlm.nih.gov]
Strabismus
  • Slight strabismus is common. The clinical variability is significant, representing a continuum in severity. The disorder is caused by lysosomal alpha-mannosidase deficiency.[ncbi.nlm.nih.gov]
  • Nystagmus and strabismus have been described. Pigmentary changes of a mottled nature can be present in the posterior pole and may be associated with retinal vessel attenuation and diminished ERG responses. Retinal thinning can be demonstrated.[disorders.eyes.arizona.edu]
  • Slight strabismus is common. The clinical variability is significant, representing a continuum in severity. Etiology The disorder is caused by lysosomal alpha-mannosidase deficiency.[orpha.net]
Delusion
  • The clinical picture has several similarities: a physical or psychological stressor precedes a rapid development of a state of confusion, delusions, hallucinations, anxiety and often depression leading to a severe loss of function.[ncbi.nlm.nih.gov]
Coarse Face
  • She had a coarse face with flat and wide nasal bridge, hepatosplenomegaly, umbilical hernia, lumbar gibbus, motor and mental retardation and deafness.[ncbi.nlm.nih.gov]
  • This disease shows a wide range of clinical phenotypes, from a severe, infantile form (type I), which is fatal at 3-8 years of age, to a less severe, late-onset form (type II), which ultimately may involve hearing loss, coarse face, mental retardation[ncbi.nlm.nih.gov]
  • Clinical findings Macrocephaly, thickened calvaria, coarse face, macroglossia, wide-spaced teeth, prognathism, deafness, mental retardation, hepatosplenomegaly.[medical-dictionary.thefreedictionary.com]
  • Table 1 Clinical types of alpha-mannosidosis Type II: Less severe, late onset form involving hearing loss, coarse face, mental retardation, and hepatosplenomegaly.[ojrd.com]
Clumsiness
  • Mental and motor development is delayed, but in this context, the progressive course of AM has to be considered: Affected children often appear clumsy, and milestones in speech and language development are achieved late.[symptoma.com]
  • Associated motor function disturbances The development of motor functions in affected patients is generally slow, and the children appear clumsy.[ojrd.com]

Workup

Clinical findings may raise suspicion as to a lysosomal storage disease but are hardly diagnostic of AM. Laboratory analyses of blood and urine samples may yield further hints at a specific disorder. In detail, AM is characterized by an increased excretion of mannose-containing oligosaccharides, and peripheral blood smears often reveal the presence of vacuoles in lymphocytes [4]. In order to confirm a tentative diagnosis of AM, the activity of alpha-mannosidase should be assessed in leukocytes or fibroblasts. The identification of the underlying MAN2B1 mutation isn't mandatory if the results of enzyme activity measurements are in agreement with a diagnosis of AM, but knowledge regarding the genotype of a determined patient may largely facilitate the workup of related cases, including, but not limited to, prenatal diagnosis.

Treatment

To date, there is no curative treatment. Decades ago, the supplementation of zinc had been postulated to augment the residual activity of alpha-mannosidase. This hypothesis was based on observations made in vitro but couldn't be reproduced in vivo [5]. Because enzyme replacement therapy and hematopoietic stem cell transplantation have successfully been used to treat other lysosomal storage disorders, they have also been considered in AM patients. In animal models, both have yielded promising results [6] [7], and although few patients have been treated with these methods, important advances have been made in men:

  • In 2004, Grewal and colleagues reported four AM patients who successfully underwent hematopoietic stem cell transplantation. Three patients experienced a stabilization of cognitive functions as well as an improvement of adaptive skills and hearing. The progression of skeletal abnormalities could be halted [8]. Similar results were obtained in a later study comprising 17 patients [3].
  • In 2018, velmanase alfa, human recombinant alpha-mannosidase, has been approved for the treatment of non-neurological symptoms of mild to moderate AM. Velmanase alfa has been shown to permanently decrease serum oligosaccharide concentrations, to increase immunoglobulin levels, and to improve physical performance, motor proficiency, and lung function. The drug has been found to be effective in pediatric and adult patients and has been well tolerated throughout the study [9].

Beyond that, affected individuals should be provided symptomatic treatment and supportive care [4]:

  • Many patients benefit from physical and occupational therapy, but surgical interventions may be necessary to correct skeletal abnormalities. Epiphyseal arthrodesis, for instance, is generally recommended to reduce the consequences of genu valgum. Orthopedic shoes may provide additional support to the ankles and feet.
  • Although hearing impairment is mainly sensorineural, the accumulation of liquids in the middle ear contributes to disability and may be prevented by the implantation of pressure equalization tubes. Hearing aids should be provided according to the necessities of the individual patient. Early improvement of hearing may help to prevent delays in language and speech acquisition.
  • Notwithstanding the above, educational support should be offered according to the individual needs of the patient.
  • Antimicrobials should be used early in cases of apparent bacterial, viral, or fungal infection.

Prognosis

AM follows a progressive course. Available data - which have been gathered before the approval of velmanase alfa for AM therapy - show that mortality is high for severe AM, where children die from infections or central nervous system disorders. Hydrocephalus, cerebral atrophy, and demyelination have all been related to the disease. Mild to moderate AM is associated with significant morbidity, with the progressive loss of cognitive and motor functions. The majority of patients becomes wheelchair-dependent and requires assistance in their everyday life. Little is known about the life expectancy of these individuals, but several patients have been reported that lived beyond the age of 50 [4].

Whether velmanase alfa treatment is associated with long-term improvements, increased quality of life and prolonged survival times could not yet be proven, but experts are confident that enzyme replacement therapy may change the outcome for the better [9].

Etiology

AM is inherited in an autosomal recessive manner. The disease is caused by mutations of the MAN2B1 gene, which is located at 19p13.13 and encodes for alpha-mannosidase. Alpha-mannosidase is a lysosomal enzyme catalyzing the hydrolysis of alpha-linked mannose residues from N-linked oligosaccharides. To this day, >100 pathogenic mutations of MAN2B1 have been described. Insertions, deletions, duplications, missense, nonsense, and splicing mutations have been reported, with most of them being private [10]. However, missense mutation c.2248C>T (p.R750W) has been identified in several kindreds from different countries. In agreement with the haplotype background of carriers of this mutation, it has been speculated to originate from two founder events. It accounts for about a quarter of all cases known to date [2].

The establishment of genotype-phenotype correlations has initially been hindered by the 4spectrum of mutations. Still, Kuokkanen and colleagues have made valuable contributions to this field and have identified a number of mutations that prevent the enzyme's transport to the lysosome, thereby inducing a complete deficiency of alpha-mannosidase. These mutations affect arginine, proline, and cysteine residues, and they include the aforementioned mutation c.2248C>T [10]. However, most individuals who are homozygous for c.2248C>T show an intermediate phenotype, which is suggestive of the influence of additional genetic or environmental factors [2]. Additional research is required to identify these factors, to evaluate how they may modulate the phenotype associated with a given genotype.

Epidemiology

AM is a rare, but pan-ethnic disease. The incidence of AM has been estimated to be 1 in 500,000 life births [4].

Sex distribution
Age distribution

Pathophysiology

MAN2B1 mutations may result in a dysfunctional active site of alpha-mannosidase or may interfere with the post-translational processing of the enzyme, either causing it to be retained in the endoplasmatic reticulum or remain dysfunctional despite locating to the lysosomes. Mutations leading to retention in the endoplasmatic reticulum are associated with a complete lack of enzyme activity and have thus been postulated to induce severe AM [10]. This hypothesis, however, is not unequivocally supported by clinical findings: Retention in the endoplasmatic reticulum is observed in individuals carrying mutation c.2248C>T, but most of these patients develop moderate AM only [2] [11]. On the other hand, residual enzyme activities between 5 and 15% are measured in AM patients with mild, moderate, or severe disease, so there is no apparent correlation between test results and disease severity. Possibly, these results don't reflect true alpha-mannosidase activity but rather the activity of related enzymes able to cleave the substrate [4].

In any case, deficiency of alpha-mannosidase results in the progressive accumulation of partially degraded mannose-containing oligosaccharides in the lysosomes [10]. Subsequent lysosomal swelling interferes with a myriad of cellular functions but doesn't seem to be the only trigger of clinical disease [4]. Further research is required to shed more light on the pathogenetic mechanisms underlying AM.

Prevention

Affected families may benefit from genetic counseling. Prenatal diagnosis is largely facilitated if the genotypes of the parents-to-be are known, but a more general approach is also feasible. Newborn screenings for lysosomal storage diseases have been proposed in distinct countries and may be based on urinary oligosaccharide profiles [12].

Summary

AM is a rare lysosomal storage disease. Due to alpha-mannosidase deficiency, mannose-containing oligosaccharides cannot be adequately degraded and accumulate within the lysosomes of cells in all tissues. Notwithstanding differences in the enzymes' substrates, the pathophysiological events causing clinical disease in AM patients largely resemble those observed in other lysosomal storage diseases. Thus, there are considerable overlaps between the clinical presentations of AM, mucopolysaccharidosis, mucolipidosis, and other entities belonging to this group of disorders. They are characterized by Hurler-like facial features, skeletal abnormalities, and intellectual disability, and should therefore be included in the differential diagnosis. Analyses of blood and urine samples, enzyme activity measurements, and molecular biological studies should be carried out to distinguish these conditions and to confirm a tentative diagnosis of AM. While the disease remains incurable, enzyme replacement therapy has recently been approved for the treatment of determined forms of the disease.

Patient Information

Alpha-mannosidosis (AM) is a hereditary lysosomal storage disease. Affected individuals harbor mutations of the MAN2B1 gene, which lead to alpha-mannosidase deficiency. Alpha-mannosidase is an enzyme required for the breakdown of determined macromolecules in the lysosomes of cells in all tissues, and in the absence of functional alpha-mannosidase, these macromolecules accumulate and interfere with a myriad of cell functions. Accordingly, AM is a multisystem disorder. Patients show coarse facial features and skeletal abnormalities comprising, but not limited to, abnormal curvature of the spine and knock-knees. Most are mentally retarded. Delays in the acquisition of language and speech may be due to intellectual disability, but are often associated with hearing impairment. Furthermore, AM patients suffer from immunodeficiency and are prone to infections. In sum, the clinical spectrum is broad and ranges from severe disease, often fatal in infancy, to intermediate phenotypes and mild AM, which is associated with prolonged survival.

The diagnosis of AM is based on laboratory analyses of blood and urine samples, measurements of the activity of alpha-mannosidase, and genetic studies. Curative treatment is not available, and, to date, affected individuals have mainly been provided with symptomatic therapy and supportive care. In this context, physical and occupational therapy, surgical interventions, hearing aids, and educational support, among others, have been offered according to the needs of the individual patient. Beyond that, in 2018, human recombinant alpha-mannosidase has been approved to treat non-neurological symptoms of mild to moderate AM. This drug, whose name is velmanase alfa, essentially compensates for the deficiency of alpha-mannosidase and aids by degrading the abovementioned macromolecules. Experts are confident that velmanasa alfa may improve the prognosis of patients suffering from this progressive disease.

References

Article

  1. Beck M, Olsen KJ, Wraith JE, et al. Natural history of alpha mannosidosis a longitudinal study. Orphanet J Rare Dis. 2013; 8:88.
  2. Riise Stensland HM, Klenow HB, Van Nguyen L, Hansen GM, Malm D, Nilssen Ø. Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense mutations. Hum Mutat. 2012; 33(3):511-520.
  3. Mynarek M, Tolar J, Albert MH, et al. Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients. Bone Marrow Transplant. 2012; 47(3):352-359.
  4. Malm D, Nilssen Ø. Alpha-mannosidosis. Orphanet J Rare Dis. 2008; 3:21.
  5. Wong LT, Vallance H, Savage A, Davidson AG, Applegarth D. Oral zinc therapy in the treatment of alpha-mannosidosis. Am J Med Genet. 1993; 46(4):410-414.
  6. Damme M, Stroobants S, Lüdemann M, et al. Chronic enzyme replacement therapy ameliorates neuropathology in alpha-mannosidosis mice. Ann Clin Transl Neurol. 2015; 2(11):987-1001.
  7. Stroobants S, Damme M, Van der Jeugd A, et al. Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice. Neurobiol Dis. 2017; 106:255-268.
  8. Grewal SS, Shapiro EG, Krivit W, et al. Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation. J Pediatr. 2004; 144(5):569-573.
  9. Lund AM, Borgwardt L, Cattaneo F, et al. Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis. J Inherit Metab Dis. 2018.
  10. Kuokkanen E, Riise Stensland HM, Smith W, et al. Molecular and cellular characterization of novel {alpha}-mannosidosis mutations. Hum Mol Genet. 2011; 20(13):2651-2661.
  11. Hansen G, Berg T, Riise Stensland HM, et al. Intracellular transport of human lysosomal alpha-mannosidase and alpha-mannosidosis-related mutants. Biochem J. 2004; 381(Pt 2):537-546.
  12. Ramsay SL, Meikle PJ, Hopwood JJ, Clements PR. Profiling oligosaccharidurias by electrospray tandem mass spectrometry: quantifying reducing oligosaccharides. Anal Biochem. 2005; 345(1):30-46.

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Last updated: 2019-07-11 21:27