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Alpha-Mannosidosis

Synonym: Lysosomal Alpha-D-Mannosidase Deficiency

, MD, PhD and , PhD.

Author Information
, MD, PhD
Senior Consultant, Tromsø Center of Internal Medicine
Tromsø, Norway
, PhD
Professor, Department of Clinical Medicine - Medical Genetics
University of Tromsø
Senior Scientist, Division of Child and Adolescent Health
Department of Medical Genetics
University Hospital of North Norway
Tromsø, Norway

Initial Posting: ; Last Update: May 3, 2012.

Summary

Disease characteristics. Alpha-mannosidosis encompasses a continuum of clinical findings from mild to severe. Three clinical subtypes include:

  • A mild form recognized after age ten years with absence of skeletal abnormalities, myopathy, and slow progression (type 1);
  • A moderate form recognized before age ten years with presence of skeletal abnormalities, myopathy, and slow progression (type 2); and
  • A severe form manifested as prenatal loss or early death from progressive central nervous system involvement (type 3).

Individuals with a milder phenotype have mild-to-moderate intellectual disability, impaired hearing, characteristic coarse features, clinical or radiographic skeletal abnormalities, immunodeficiency, and primary central nervous system disease, mainly cerebellar involvement causing ataxia. Periods of psychiatric symptoms are common. Associated medical problems can include corneal opacities, hepatosplenomegaly, aseptic destructive arthritis, and metabolic myopathy. Alpha-mannosidosis is insidiously progressive; some individuals may live into the sixth decade.

Diagnosis/testing. The diagnosis of alpha-mannosidosis relies on demonstration of deficient acid alpha-mannosidase enzyme activity in peripheral blood leukocytes or other nucleated cells such as fibroblasts. Carrier testing by this method is unreliable because of overlap of enzyme activity between carriers and non-carriers. MAN2B1 is the only gene known to be associated with alpha-mannosidosis.

Management. Treatment of manifestations: Aimed at preventing complications and optimizing quality of life; may include early use of antibiotics for bacterial infections, hearing aids for hearing loss, insertion of pressure-equalizing tubes if fluid accumulates in the middle ear, glasses to correct refractive error, physiotherapy, use of a wheelchair, orthopedic intervention, and shunting as needed for hydrocephalus. Educational considerations include use of sign language for individuals with hearing loss, early educational intervention for development of social skills, speech therapy, and special education to maximize learning.

Prevention of secondary complications: Prophylactic vaccinations because of immunodeficiency.

Surveillance: Medical history and physical examination every year and specific otolaryngology, audiometry, ophthalmologic, neuropsychological, and skeletal examinations, along with blood tests and CT scans of the brain.

Evaluation of relatives at risk: Test at-risk newborn sibs to permit early intervention for affected children.

Therapies under investigation: Bone marrow or peripheral blood stem cell transplantation has been proven effective; the efficiency of enzyme replacement therapy is currently under investigation.

Genetic counseling. Alpha-mannosidosis is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if the disease-causing mutations in the family are known. Prenatal testing for pregnancies at increased risk is possible by assay of acid alpha-mannosidase enzymatic activity or molecular genetic testing once the disease-causing mutations have been identified in the family.

Diagnosis

Clinical Diagnosis

Alpha-mannosidosis should be suspected in individuals with intellectual disability, hearing loss, ataxia, skeletal abnormalities, and coarse facial features.

Testing

Alpha-mannosidosis is caused by deficiency of lysosomal alpha-mannosidase (MAN2B1) (E.C. 3.2.1.24) [Chester et al 1982]. During normal turnover and catabolism, glycoproteins are digested by proteinases and glycosidases within the lysosomes. These enzymes degrade glycoproteins into fragments small enough to be excreted or transported to the cytosol for reuse. Lack or deficiency of a hydrolase, such as lysosomal alpha-mannosidase, results in the multisystemic accumulation of undigested oligosaccharides in the lysosomes. However, the pathophysiology of lysosomal storage disorders is complex, and accumulation of storage material alone cannot fully explain disease mechanisms.

Note: MAN2B1 is occasionally referred to as LAMAN (lysosomal alpha-mannosidase).

Acid alpha-mannosidase enzyme activity. The most efficient and reliable method of establishing the diagnosis of alpha-mannosidosis is the assay of acid alpha-mannosidase enzyme activity in leukocytes or other nucleated cells. This fluorometric assay is performed at low pH (usually at pH 4) and uses the substrate 4-methylumbelliferyl-α-D-mannopyranoside.

In affected individuals, acid alpha-mannosidase enzyme activity in peripheral blood leukocytes is 5%-10% of normal activity.

Note: (1) This "residual" enzyme activity seems to represent mannosidase from other organelles or compartments (e.g., Golgi apparatus or cytosol) since they show some activity also at low pH. (2) Following immunoprecipitation with anti-acid alpha-mannosidase polyclonal antibodies, acid alpha-mannosidase enzyme activity ranges from 0.1% to 1.3% of normal [Berg et al 1999]. Such testing is not performed routinely.

In carriers, acid alpha-mannosidase enzyme activity is usually 40%-60% of normal, and thus is unreliable for carrier detection given the overlap in carriers and non-carriers.

Note: When molecular genetic testing is unavailable or has been uninformative, some laboratories may offer carrier testing by enzyme analysis.

Urine. Elevated urinary excretion of mannose-rich oligosaccharides can be demonstrated by thin-layer chromatography [Michalski & Klein 1999]. This finding is suggestive of alpha-mannosidosis, but not diagnostic.

Peripheral blood. Light microscopy demonstrates vacuoles in lymphocytes from peripheral blood in 90% of affected individuals [Chester et al 1982]. Although detection of vacuoles is a useful screening test, supplementary investigations are necessary when alpha-mannosidosis is suspected.

Molecular Genetic Testing

Gene. MAN2B1 is the only gene in which mutations are known to cause alpha-mannosidosis.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Alpha-Mannosidosis

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 1
MAN2B1Sequence analysis 4Sequence variants 598.5%
Deletion/duplication analysis 6, 7Partial- or whole-gene deletions<2%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. A total of 125 different disease-causing mutations have been reported in the literature [Nilssen et al 1997, Gotoda et al 1998, Berg et al 1999, Frostad Riise et al 1999, Beccari et al 2003, Olmez et al 2003, Urushihara et al 2004, Sbaragli et al 2005, Castelnovo et al 2007, Lyons et al 2007, Pittis et al 2007, Magner et al 2008, Broomfield et al 2010, Riise Stensland et al 2012]. Most mutations are private, occurring in one or a few families only. Three mutations (p.Arg750Trp, p.Leu809Pro, c.1830+1G>C) accounted for 35.4% of all disease alleles detected among 130 unrelated patients with alpha-mannosidosis [Riise Stensland et al 2012]. The missense mutation c.2248C>T (p.Arg750Trp) is common among individuals with alpha-mannosidosis (see Molecular Genetics, Pathogenic allelic variants). Splice site mutations resulting in exon skipping have been reported [Berg et al 1999, Riise Stensland et al 2012].

4. Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. A few affected individuals were found to have a deletion of one or more exons [Riise Stensland et al 2012].

Test characteristics. Information on test sensitivity and specificity as well as other test characteristics can be found at EuroGentest [Nilssen et al 2011 (full text)].

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Assay of acid alpha-mannosidase enzyme activity in leukocytes or other nucleated cells is the confirmatory diagnostic test.
  • Molecular genetic testing of MAN2B1 and the identification of two disease-causing alleles can confirm the diagnosis but should not be used in place of biochemical testing.
    • Targeted mutation analysis or sequence analysis of exon 18 should be performed first to screen for the most common mutation, c.2248C>T (p.Arg750Trp). Unless the patient is homozygous for this mutation, the remaining 23 exons of MAN2B1 should be sequenced.
    • When no mutations are detected by DNA sequencing analysis or when an affected individual is heterozygous for a disease-causing mutation, deletion/duplication analysis should be considered.
    • Notably, large deletions or duplications will generally remain undetected when using a PCR/DNA sequencing-based approach. Therefore, point mutations detected by DNA sequencing should always be verified in the parents of the affected individual, particularly if the affected individual is an apparent homozygote.

Carrier testing for at-risk relatives can be performed, preferably after the identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis for at-risk pregnancies requires either assay of acid alpha-mannosidase enzymatic activity or molecular genetic testing when the family-specific MAN2B1 mutations are known.

Clinical Description

Natural History

Development and onset of symptoms. Alpha-mannosidosis, previously described as having two discrete phenotypes [Autio et al 1982], is now recognized as encompassing a continuum of clinical findings from a perinatal-lethal form (manifest as prenatal loss) to an asymptomatic form or one that is diagnosed initially in adulthood [Berg et al 1999].

It has been suggested that at least two major forms of alpha-mannosidosis exist: one serious form with hepatomegaly and severe infections leading to early death, and a milder form characterized by intellectual disability, hearing loss, and survival into adulthood [Desnick et al 1976, Bach et al 1978]. However, the clinical expression of alpha-mannosidosis deficiency varies considerably with a wide spectrum of clinical findings and broad variability in individual presentation; thus, designating clinical types can be useful in prognosis and management. At least three clinical types (mild, moderate, and severe) have been suggested [Chester et al 1982, Malm & Nilssen 2008]. Most individuals described fit into the moderate type.

  • Type 1. Mild form clinically recognized after age ten years, with myopathy, slow progression, and absence of skeletal abnormalities
  • Type 2. Moderate form clinically recognized before age ten years, with myopathy, slow progression, and presence of skeletal abnormalities
  • Type 3. Severe form with obvious progression, leading to early death from primary central nervous system involvement or infection

Motor function. Affected children learn to walk somewhat later than normal. They are generally clumsy; ataxia is the most characteristic and specific motor disturbance. In addition to joint abnormalities and a metabolic myopathy [Alroy et al 1984], the disease particularly affects those areas of the brain responsible for fine motor function and muscular coordination. Muscular hypotonia is common. Spastic paraplegia has also been described [Kawai et al 1985], but in general, spasticity, rigidity, and dyskinesia are not observed. Follow-up observations have also suggested progressive impairment of motor function with age [Autio et al 1982]. A longitudinal clinical study on a brother and sister indicated no progression over a period of 25 years [Ara et al 1999]. However, as their basic neuropsychological impairment was described as severe, progression would be difficult to detect.

Intellectual disability. Early psychomotor development may appear normal, but intellectual disability occurs in all individuals. Individuals with adult-onset disease are usually mildly or moderately intellectually disabled with an IQ of 60-80 [Aylsworth et al 1976, Bach et al 1978]. The measurement of total mental performance is very complex, and individuals tend to score better in nonverbal tests. Individuals are late in initiating speech (sometimes as late as the second decade of life), their vocabularies are restricted, and their pronunciation is difficult to understand – possibly the results of congenital and/or later-onset hearing loss.

Most affected individuals described have been children; therefore, information on the natural course of alpha-mannosidosis is based on a limited number of observations. Some investigators suggest that intellectual disability progresses slowly [Autio et al 1982], others suggest that disease progression ceases after puberty [Yunis et al 1976]. In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [Noll et al 1989]. In a longitudinal study of a brother and sister over a period of 25 years, decreased speech capacity was seen in one, but not the other, sibling [Ara et al 1999].

Psychiatric symptoms. Psychiatric symptoms distinct from the intellectual disability may affect 25% or more of persons with alpha-mannosidosis. Onset is typically from late puberty to early adolescence. Episodes may be recurrent and of limited duration; medication may be necessary to alleviate symptoms.

In nine individuals with alpha-mannosidosis and psychiatric symptoms, a physical or psychological stressor preceded the rapid development of confusion, delusions, hallucinations, anxiety, and often depression, leading to severe loss of function usually lasting three to 12 weeks, and followed by a period of somnolence, asthenia, and prolonged sleep [Malm et al 2005]. In four of the nine individuals, evaluation of the psychiatric syndrome did not reveal an underlying organic cause.

Neuroimaging. Brain MRI including sagittal T1 and axial T2 sections reveals a partially empty sella turcica, cerebellar atrophy, and white matter signal modifications. Progressive cortico-subcortical atrophy, especially in the cerebellar vermis, has been described [Ara et al 1999]. High signal abnormalities involving the parieto-occipital white matter are identified on axial T2-weighted scans in some individuals and are probably related to demyelination and associated gliosis as described by Dietemann et al [1990].

Hearing loss. Most individuals appear to have early-childhood-onset, non-progressive hearing loss. In many, if not most, individuals, the hearing loss is partly conductive and partly sensorineural [Autio et al 1982]. Individuals typically experience early ear infections with fluid in the middle ear, probably the result of immunodeficiency and bony abnormalities of the skull leading to closure of the eustachian tubes. If untreated in early childhood, reduced hearing contributes to disturbances in speech and mental function.

Facial features. Independent of family and race, individuals have typical Hurler-like facies (see Mucopolysaccharidosis Type 1) or coarse facial features, characterized by a large head with a prominent forehead, depressed nasal bridge, rounded eyebrows, prognathism, widely spaced teeth, and macroglossia. The features can also be so subtle that they may be overlooked by an inexperienced observer.

Bone disease. Bone disease ranges from asymptomatic osteopenia to focal lytic or sclerotic lesions and osteonecrosis. Clinical or radiographic evidence of mild-to-moderate dysostosis multiplex occurs in 90% of individuals diagnosed with alpha-mannosidosis [Chester et al 1982]; intrafamilial variation is considerable. Conventional radiographs (x-rays) may reveal thickened calvaria; ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; hypoplasia of the inferior portions of the ilia; and mild expansion of the short tubular bones of the hands.

Knock-knee is common and contributes to the gait disturbance.

The skeletal abnormalities may decrease with age [Spranger et al 1976].

Cranial MRI, including sagittal T1 and axial T2 sections, demonstrates several skeletal abnormalities including brachycephaly, thick calvarium, and poor pneumatization of the sphenoid body [Dietemann et al 1990].

Immunodeficiency. Individuals with alpha-mannosidosis have frequent infections. Malm et al [2000] compared humoral and cellular immunocompetence in six affected individuals to that of six healthy controls. They determined that individuals with alpha-mannosidosis seem to have decreased ability to produce specific antibodies in response to antigen presentation. Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies. In addition, leukocytes have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections.

Ocular changes. Hyperopia, myopia, or slight strabismus is common. Lenticular changes, superficial corneal opacities [Bach et al 1978], and blurred discs [Kjellman et al 1969] have been reported. Most of these ophthalmologic findings can be remedied (see Management).

Hepatosplenomegaly. The liver and spleen are often enlarged, especially in more severely affected individuals; however, this has no clinical significance. Liver function is normal. Liver biopsy reveals the same vacuoles in hepatocytes as described in several hematologic cell lines.

Other

  • Communicating hydrocephalus can occur at any age [Halperin et al 1984].
  • Cardiac and renal complications are rarely encountered.

Natural course of the disease. The first decade of life is characterized by a high incidence of recurrent infections, including the common cold, pneumonia, gastroenteritis, and more rarely, infections of the urinary tract. Serous otitis media is common and is usually not bacterial.

The infections diminish in the second and third decade, when ataxia and muscular weakness are more prominent. However, many individuals are able to ski, ride a bike, or play soccer up to the third decade. At any time, individuals risk setbacks in the form of acute necrotizing arthritis or acute hydrocephalus, both requiring surgery. Worsening of the myopathy has also been described [Kawai et al 1985, unpublished personal data].

Genotype-Phenotype Correlations

The variability in the clinical course of the disease may in part be the result of external factors not relevant to the primary genetic defect, e.g., factors such as background genetics, educational opportunities, or quality of health services [Malm, personal observation].

The first suggestion of lack of genotype-phenotype correlation came with the observation that affected sibs (with identical mutations) could present with strikingly different phenotypes [Mitchell et al 1981, Michelakakis et al 1992]. This finding was further sustained by the observation that in all affected individuals, the level of cross-reacting alpha-mannosidase enzyme activity was less than 1.3% of that in controls, with no consistent variation among affected individuals [Berg et al 1999]. Thus, the amount of residual acid alpha-mannosidase enzyme activity as measured in vitro from extracts of nucleated cells correlated with neither the nature of the mutation nor the disease type or severity.

Nomenclature

In the past alpha-mannosidosis has been described as having two distinct phenotypes:

  • A severe form with hepatomegaly and early death following severe infections (Type I)
  • A mild form with hearing loss, intellectual disability, and survival into adulthood (Type II)

However, findings in published cases form a continuum; thus, classification based on two distinct types is not sufficient to cover the wide clinical spectrum. Three clinical types have been suggested [Chester et al 1982, Malm & Nilssen 2008]:

  • Type 1. Mild form clinically recognized after age ten years, without skeletal abnormalities and very slow progression
  • Type 2. Moderate form, clinically recognized before age ten years, with skeletal abnormalities and slow progression with development of ataxia at age 20-30 years
  • Type 3. Severe form, immediately recognized, with skeletal abnormalities and obvious progression leading to an early death from primary CNS involvement or myopathy

Prevalence

Little is known about the prevalence of alpha-mannosidosis. A study from Australia reported a prevalence of one in 500,000 [Meikle et al 1999]. A study from Norway reported six individuals in a population of 4.5 million [Malm et al 1995], and recently a prevalence of one in 300,000 was reported in the Czech Republic [Poupetová et al 2010].

The disease is not specific to any ethnic group; individuals from all parts of the world have been described [Riise Stensland et al 2012].

Differential Diagnosis

The main clinical features in alpha-mannosidosis — intellectual disability, ataxia, coarse face, and Hurler-like skeletal changes — may show overlap with other lysosomal storage diseases (e.g., mucopolysaccharidosis type 1). However, the distinctive clinical features associated with these other lysosomal storage diseases, the availability of biochemical testing in clinical laboratories, and an understanding of their natural history should help in distinguishing between them.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with alpha-mannosidosis, the following evaluations are recommended:

  • Medical history including evidence of hearing loss, weight loss, headache, fatigue, irritability, depression; change in social, domestic, school- or work-related activities or in ability to walk distances; diarrhea or incontinence, abdominal pain, muscle pain, joint aches, reduced range of movement, and bone pain
  • Physical examination including otoscopy, ophthalmoscopy, assessment of liver and spleen size, auscultation of heart and lungs, neurologic status including gait, and orthopedic evaluation including joint range of motion. In children, attention to growth (plot height, weight, and especially head circumference using standardized growth charts)
  • Examination by an otolaryngologist to detect impaired hearing and middle-ear infections
  • Audiometry. If intellectual disability or young age makes cooperation difficult, brain stem evoked response testing
  • Ophthalmologic examination to evaluate for corneal opacities, myopia, hyperopia, and strabismus
  • Neuropsychological testing to establish functional level and learning capacity
  • Blood tests. PLOT and C-reactive protein for evidence of inflammation, serum concentrations of alanine aminotransferase (ALT) for evaluation of concomitant liver disease and creatinine for assessment of renal function. Clinical examination and immunologic tests (e.g., antinuclear antibodies, anti-ds-DNA antibodies) to exclude systemic lupus erythematosus (SLE) are recommended.
  • Skeletal assessment. Plain radiographs of the head, knees (anterior-posterior view), spine (lateral view) and any symptomatic sites
  • Bone densitometry to detect osteopenia or osteoporosis
  • CT scan of the brain to evaluate the size of the ventricles and shape and size of the cerebellum, particularly if signs and symptoms of hydrocephalus are present (e.g., headache, increasing gait ataxia, nausea, papilledema)
  • Genetics consultation

Treatment of Manifestations

Some affected individuals, including those who have had bone marrow transplantation (BMT), may require symptomatic treatment. The overall aim is to prevent complications and to optimize quality of life.

Medical measures

  • Early use of antibiotics for bacterial infections. A clinical consequence of the immunodeficiency is that bacterial and viral infections must be treated with vigilance.
  • Hearing aids as early as possible for individuals with sensorineural hearing loss to improve hearing and enhance speech development and social functioning
  • Insertion of PE (pressure-equalizing) tubes to reduce the conductive/mechanical component of hearing loss from fluid in the middle ear
  • Glasses (spectacles) to correct refractive error to improve vision. Although lens replacement for cataract is a standard procedure in alpha-mannosidosis, corneal transplantation can be difficult; postoperative complications include astigmatism (which may be correctable with repeat surgery, laser treatment, or optical devices).
  • Physiotherapy including hydrotherapy to avoid strain on the joints
  • Use of a wheelchair if necessary
  • Treatment of osteoporosis or osteopenia identified on bone densitometry with palmidronate (Aredia®) monthly or zoledronic acid (Aclasta®) once a year
  • Orthopedic intervention if necessary. Special shoes may help with ankle and foot support.
  • Ventriculocaval shunt for communicating hydrocephalus

    Note: Ventriculoperitoneal shunts may cause ascites because of the reduced absorptive capacity of the peritoneal cavity [Malm, personal communication]. Therefore, ventriculocaval shunts are preferred.

Educational opportunities/social considerations

  • Use of sign language in individuals with significant hearing loss
  • Early educational intervention for development of social skills
  • Speech therapy to improve speech
  • Special education to maximize learning
  • Planning housing for possible future wheelchair use

Prevention of Primary Manifestations

Most affected individuals are clinically normal at birth. Since alpha-mannosidosis can be treated with BMT, and possibly also by ERT in the future, there is a pressing need for newborn screening to identify affected individuals early, before the onset of severe, irreversible, pathology [Meikle et al 2006].

Prevention of Secondary Complications

Because of immunodeficiency, affected individuals should be included in prophylactic vaccination programs.

The tendency to develop caries as a result of poor tooth quality can be reversed or delayed by good tooth hygiene or dental support [Malm, personal observation].

Regular physiotherapy to increase muscle strength may help compensate for the slowly progressive ataxia [Malm, personal observation].

Surveillance

Suggested serial monitoring to evaluate severity and rate of disease progression

  • Medical history (every 6-12 months) including number and type of infections, hearing, weight loss, headache, fatigue, irritability, depression, change in social, domestic, school- or work-related activities, ability to walk distances; diarrhea, abdominal pain, muscle pain, joint aches or reduced range of movement, and bone pain
  • Physical examination (every 6-12 months) including otoscopy, ophthalmoscopy, assessment of liver and spleen size, heart and lungs, joint range of motion, gait, neurologic status, and orthopedic evaluation. In children, attention to growth (height, weight, and especially head circumference using standardized growth charts)
  • Examination by an otolaryngologist to detect impaired hearing and middle-ear infections
  • Audiometry. If intellectual disability makes cooperation difficult, brain stem evoked response testing
  • Ophthalmologic examination to detect corneal opacities, myopia, hyperopia, and strabismus
  • Neuropsychological testing to establish functional level and learning capacities
  • Blood tests. PLOT and C-reactive protein for evidence of inflammation, serum concentrations of ALT for evaluation of concomitant liver disease and creatinine for assessment of renal function. Immunologic status, focusing on SLE, is recommended.
  • Skeletal assessment. Plain radiographs of the head, knees (anterior-posterior view), spine (lateral view) and any symptomatic sites
  • Bone densitometry every two to five years to assess osteopenia
  • CT scan of the brain to evaluate the size of the ventricles and shape and size of the cerebellum if signs and symptoms of hydrocephalus are present (e.g., headache, increasing gait ataxia, nausea, papilledema)

Evaluation of Relatives at Risk

At-risk sibs should be tested either prenatally or in the newborn period as they will benefit from early intervention (see Treatment of Manifestations). Molecular genetic testing is possible if both mutations have been identified in the family.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Bone marrow transplantation (BMT), which transfers enzyme from the engrafted stem cells to the incompetent host cells via cell-to-cell contact or via the blood stream, has been attempted in alpha-mannosidosis.

Early BMT attempts were unsuccessful in one child [Will et al 1987] and successful in another [Wall et al 1998]. In four untreated children with the expected slowing of neurocognitive development and sensorineural hearing loss, Grewal et al [2004] demonstrated improvement in adaptive skills and verbal memory following hematopoietic stem cell transplantation (HSCT) in three of four individuals studied. They emphasize the importance of early diagnosis and treatment with HSCT.

In a retrospective multi-institutional analysis, Mynarek et al [2012] summarize the experience of allogeneic HSCT in 17 individuals with alpha-mannosidosis. In summary, after HSCT, affected individuals made developmental progress, although normal development was not achieved. Hearing ability improved in some, but not in all. They conclude that HSCT may promote mental development in alpha-mannosidosis.

Avenarius et al [2011] reported a proton nuclear magnetic resonance spectroscopic (MRS) detection method for the accumulation of abnormal metabolites in multiple parts of the brain (basal ganglia, periventricular white matter, and occipital grey matter) of individuals with alpha-mannosidosis. The spectroscopy also showed that the abnormal deposits resolved in an affected individual treated with BMT six years earlier. Thus, MRS could be a useful noninvasive method to monitor the effect of treatments such as BMT or ERT in individuals with alpha-mannosidosis.

However, BMT remains a risky procedure: a retrospective study of 17 patients who had undergone BMT reported high rates of sepsis, graft-vs-host disease (GvHD), and multiple virus infections; two patients died of multi-organ failure [Mynarek et al 2012].

Chronic immune-mediated axonal polyneuropathy that followed BMT improved following plasma exchange in one individual [Mulrooney et al 2003].

Peripheral blood stem cell transplantation (PBSCT). A 24-month-old boy underwent uncomplicated PBSCT with his HLA-identical mother as the donor. T-cell depletion was used to reduce the risk of GvHD. Studies showed 50%-60% donor cells in blood; enzyme activity was slightly below normal. The urinary excretion of mannose-rich oligosaccharides resolved gradually and was almost absent 13 months after PBSCT. Skeletal dysplasia as judged by radiographs of the hands normalized after ten months; delayed myelination as demonstrated by MRI normalized after 12 months [Albert et al 2003].

Enzyme replacement therapy (ERT)

  • Fibroblasts. In many in vitro studies with the purified active enzyme added to the media of mannosidase-deficient fibroblasts, the accumulation of lysosomal substrate was corrected [Abraham et al 1985].
  • Mouse. ERT studies in alpha-mannosidosis mouse models have found a decrease in mannose-containing oligosaccharides in tissues, including brain [Roces et al 2004]. Therefore, ERT could be an efficient treatment in humans in the future. However, in a guinea pig model, no histologic changes were seen in the brain, whereas lysosomal vacuolation decreased markedly in liver, kidney, spleen, pancreas, and trigeminal ganglion neurons [Crawley et al 2006]. Later studies in mice using higher doses (500 U/kg) of enzyme showed a distinct reduction in pathologic brain storage material [Blanz et al 2008] and even short-term ERT partially reversed the observed cerebellar pathology [Damme et al 2011].
  • Human. Mannosidase substitution (ERT) in humans is under investigation in the Seventh Framework EU project ALPHA-MAN. According to a press release of 10-17-2011, a Phase 2 study involving nine affected individuals found a significant improvement in the six-minute walk test, the three-minute stair case climb test, and spirometry but not intellectual ability (as measured with the Leiter test).

Gene therapy for alpha-mannosidosis is a theoretical possibility that has not been investigated

Search ClinicalTrials.gov for access to information on clinical studies related to alpha-mannosidosis.

Other

Because of the limited number of affected individuals with psychiatric symptoms, no conclusion about the benefit of various psychotropic drugs can be made at this time. However, to date, olanzapine 5-15 mg at bedtime, has been used in several affected individuals with some success [Malm, unpublished observations].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Alpha-mannosidosis is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of a proband are obligate heterozygotes, and therefore carry one benign and one pathogenic MAN2B1 allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of a proband are obligate heterozygotes for the disease-causing mutation in MAN2B1.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing

  • Carrier testing is possible once the disease-causing mutations have been identified in the family.
  • It is appropriate to offer molecular genetic testing of MAN2B1 to the reproductive partner of a person with alpha-mannosidosis.

Biochemical testing. Acid alpha-mannosidase enzyme activity is usually 40%-60% of normal in carriers, but is unreliable for carrier detection given the overlap in carriers and non-carriers.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible either by analysis of acid alpha-mannosidase enzymatic activity in fetal cells obtained by chorionic villus sampling (usually performed at ~10-12 weeks’ gestation) or by molecular genetic testing of DNA from the same source or from cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation). Mutation analysis must be carried out in the parents in advance of pregnancy. Given the wide variability in phenotype and lack of genotype-phenotype correlation, mutation analysis does not allow prediction of severity of disease.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Advocate for Glycoprotein Storage Diseases (ISMRD)
    3921 Country Club Drive
    Lakewood CA 90712
    Email: info@ismrd.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • National MPS Society
    PO Box 14686
    Durham NC 27709-4686
    Phone: 877-677-1001 (toll-free); 919-806-0101
    Fax: 919-806-2055
    Email: info@mpssociety.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Alpha-Mannosidosis: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
MAN2B119p13​.2Lysosomal alpha-mannosidaseMAN2B1 databaseMAN2B1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Alpha-Mannosidosis (View All in OMIM)

248500MANNOSIDOSIS, ALPHA B, LYSOSOMAL; MANSA
609458MANNOSIDASE, ALPHA, CLASS 2B, MEMBER 1; MAN2B1

Gene structure. MAN2B1 spans 21.5 kb and contains 24 exons [Riise et al 1997]; the cDNA is approximately 3.5 kb [Nilssen et al 1997]. There are two potential upstream ATG start codons [Nilssen et al 1997]. The first ATG is equivalent to the first ATG found in the bovine gene [Tollersrud et al 1997] and the feline gene [Berg et al 1997]. A second putative ATG start codon is located in the same reading frame, 24 codons downstream. Both start codons may be functional. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The abnormal alleles include exonic missense and nonsense mutations, splice junction mutations, and deletions and insertions of one or more nucleotides. A few disease alleles result from larger gene rearrangements (e.g., large gene deletions that include several exons; see Table 1) [Riise Stensland et al 2012]. A total of 125 different disease-causing mutations have been reported in patients from about 30 countries over the last fifteen years [Nilssen et al 1997, Gotoda et al 1998, Berg et al 1999, Frostad Riise et al 1999, Beccari et al 2003, Olmez et al 2003, Urushihara et al 2004, Sbaragli et al 2005, Lyons et al 2007, Castelnovo et al 2007, Pittis et al 2007, Magner et al 2008, Broomfield et al 2010, Riise Stensland et al 2012.]. Most patients studied originate from Europe. The genetic aberrations reported are distributed throughout MAN2B1. Most mutations are private, occurring in one or a few families only. However, missense mutation c.2248C>T (p.Arg750Trp) appears to be frequent among individuals with alpha-mannosidosis: it has been reported in most European populations studied and accounts for more than 27% of all disease alleles detected by Riise Stensland et al [2012].

Table 2. MAN2B1 Pathogenic Variants Occurring in >5 Families

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequence
c.1830+1G>C p.Val549_Glu610del 1NM_000528​.2
NP_000519​.2
c.2248C>Tp.Arg750Trp
c.2426T>Cp.Leu809Pro

Berg et al [1999]

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Effect on protein based on Berg et al [1999]

Normal gene product. Lysosomal alpha-mannosidase is an exoglycosidase that cleaves alpha-linked mannose residues from the non-reducing end during the ordered degradation of N-linked glycoproteins. The enzyme is synthesized as a single-chain precursor that is processed into three glycopeptides of 70, 42, and 15 kd. The 70-kd peptide is further partially proteolyzed into three more peptides that are joined by disulfide bridges. The MAN2B1 precursor contains 1011 amino acids, of which the 49 N-terminal residues constitute the signal peptide. Without the signal peptide, the predicted molecular mass is 108.6 kd [Nilssen et al 1997]. The active enzyme exists as a dimer [Heikinheimo et al 2003].

MAN2B1 has a broad substrate specificity, hydrolyzing α(1-2), α(1-3), and α(1-6) mannosyl linkages found in high-mannose and hybrid type glycans. Multiple forms of alpha-mannosidases with different subcellular locations have been described [Daniel et al 1994]. The enzyme is distinguished from other cellular alpha-mannosidase activities by a combination of low pH optimum (pH 4.5), Zn2+ dependence, a broad natural substrate specificity, activity toward the artificial substrate p-nitrophenyl-α-mannoside, and inhibition by swainsonine [Michalski et al 1990].

The three-dimensional structure of bovine lysosomal alpha-mannosidase has been determined at 2.7A resolution [Heikinheimo et al 2003]. Based on homology to the bovine MAN2B1 a three-dimensional structure was made for the human MAN2B1 [Kuokkanen et al 2011]. Studies of the effect of missense mutations on intracellular processing and transport and modeling of missense mutations into the MAN2B1 structure have greatly improved understanding of alpha-mannosidosis at the cellular and atomic level [Kuokkanen et al 2011].

Abnormal gene product. MAN2B1 mutations are predicted to result in mRNA instability, and/or severe protein truncation, or an enzyme with altered activity and/or conformation.

References

Published Guidelines/Consensus Statements

The University Hospital of Tromsø has been authorized by the Norwegian Board of Health to perform genetic testing according to the Act Relating to Application of Biotechnology in Medicine, No. 56 August 5th. 1994. This certification relates to genetic testing for diagnosing a disease or for research purposes. Diagnostic information obtained directly from research will be made available for use in genetic counseling if requested by the person/family to whom the result applies. Under such circumstances, results will be forwarded to the patient/family by a certified genetic counselor after a second, independent testing of new patient material.

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Suggested Reading

  1. Thomas GH. Disorders of glycoprotein degradation: alpha-mannosidosis, beta-mannosidosis, fucosidosis, and sialidosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 140. New York, NY: McGraw-Hill. Available online. 2013. Accessed 4-30-14.

Chapter Notes

Author Notes

Dr. Malm was the initiator of the "Tromsø Mannosidosis Group" in 1991. He is a member of the professional advisory board of ISMRD and the father of two children with alpha-mannosidosis.

Acknowledgments

The authors would like to thank the president of ISMRD, John Forman, Hutt City, New Zealand, for valuable comments to the manuscript.

Revision History

  • 3 May 2012 (me) Comprehensive update posted live
  • 26 August 2008 (cg) Comprehensive update posted to live Web site
  • 25 January 2006 (me) Comprehensive update posted to live Web site
  • 3 December 2003 (me) Comprehensive update posted to live Web site
  • 11 October 2001 (me) Review posted to live Web site
  • April 2001 (dm) Original submission
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