Alpha-Mannosidosis

Clinical characteristics.

Alpha-mannosidosis encompasses a continuum of clinical findings from mild to severe. Three major clinical subtypes have been suggested:

• 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)
• A severe form manifested as prenatal loss or early death from progressive central nervous system involvement or infection (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 is established in a proband by identification of deficient acid alpha-mannosidase enzyme activity in peripheral blood leukocytes or other nucleated cells such as fibroblasts. Identification of biallelic pathogenic variants in MAN2B1 by molecular genetic testing can confirm the diagnosis and allow for family studies.

Management.

Treatment of manifestations: The enzyme replacement therapy velmanase alfa has been approved in some European countries for treatment of alpha-mannosidosis. Treatments aimed at preventing complications and optimizing quality of life also 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: Annual or semiannual medical history and physical examination 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.

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 pathogenic variants 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 pathogenic variants have been identified in the family.

Suggestive Findings

Alpha-mannosidosis should be suspected in individuals with the following clinical, laboratory, and pathology findings.

Clinical features

• Facial features (e.g., coarse facial features, macrocephaly, prominent forehead, highly arched brows, depressed nasal bridge, widely spaced teeth, macroglossia, prognathism)
• Skeletal abnormalities (e.g., dysostosis multiplex, focal lytic or sclerotic lesions, osteonecrosis, osteopenia)
• Hearing loss, mixed
• Frequent infections
• Developmental delay
• Intellectual disability
• Ataxia

Laboratory features. Elevated urinary excretion of mannose-rich oligosaccharides can be demonstrated by thin-layer chromatography [Humble & Collart 1975] or capillary high-performance anion exchange chromatography [Bruggink et al 2012].

Histopathology. Light microscopy demonstrates vacuoles in lymphocytes from peripheral blood in 90% of affected individuals.

Establishing the Diagnosis

The diagnosis of alpha-mannosidosis can be established in a proband by identification of deficiency of lysosomal enzyme acid alpha-mannosidase (MAN2B1) in leukocytes or other nucleated cells. In affected individuals, alpha-mannosidase enzyme activity in peripheral blood leukocytes is 5%-10% of normal activity. Note: This "residual" enzyme activity appears to represent mannosidase from other organelles or compartments (e.g., Golgi apparatus or cytosol) since they show some activity also at low pH.

Molecular genetic testing. Identification of biallelic pathogenic variants in MAN2B1 by molecular genetic testing can establish the diagnosis (see Table 1). Approaches can include single-gene testing*, use of a multigene panel, and comprehensive genomic testing.

* Before single-gene testing, the activity of lysosomal alpha-mannosidase should be determined.

• Single-gene testing. Sequence analysis of MAN2B1 is then performed, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes MAN2B1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. (4) In individuals with only MAN2B1 variants of uncertain significance identified, DNA sequencing should be followed by testing alpha-mannosidase activity in peripheral blood leukocytes.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing. When the diagnosis of alpha-mannosidosis is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

The clinical phenotype of alpha-mannosidosis varies considerably with a wide spectrum of clinical findings and broad variability in individual presentation. Designating clinical types can be useful in prognosis and management. At least three clinical types (mild, moderate, and severe) have been suggested [Malm & Nilssen 2008]. Most individuals described fit into the moderate type.

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

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) and have restricted vocabulary and difficult-to-understand pronunciation – 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 sib but not the other [Ara et al 1999].

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 ethnicity, individuals have typical Hurler-like facies (see Mucopolysaccharidosis Type 1) or coarse facial features, macrocephaly with a prominent forehead, highly arched eyebrows, depressed nasal bridge, widely spaced teeth, macroglossia, and prognathism. The features can also be so subtle that they may be overlooked by an inexperienced observer.

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 appear 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.

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.

Ocular features. 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).

Other

• Communicating hydrocephalus can occur at any age [Halperin et al 1984].
• Cardiac and renal complications are rarely observed; however, aortic regurgitation may be more common in individuals with alpha-mannosidosis.
• Systemic lupus erythematosus has been frequently observed in individuals with alpha-mannosidosis.

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].

Pathophysiology. 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.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Nomenclature

Alpha-mannosidosis may also be referred to as "lysosomal alpha-d-mannosidase deficiency."

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 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].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with alpha-mannosidosis, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Medical history including evidence of hearing loss, irritability, depression; change in social, domestic, school- or work-related activities or in ability to walk distances; diarrhea or incontinence, 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. Clinical examination and immunologic tests (e.g., antinuclear antibodies, anti-ds-DNA antibodies) to exclude systemic lupus erythematosus (SLE)
• 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 in older individuals
• 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)
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Enzyme replacement therapy (ERT). Velmanase alfa has been developed as a treatment for alpha-mannosidosis. Improvement in both biochemical and functional parameters have been reported [Borgwardt et al 2018, Lund et al 2018]. ERT with velmanase alfa was approved by the European Medical Agency in July 2018. Velmanase alfa has been very well tolerated and is now regarded as a standard treatment for alpha-mannosidosis.

Note: ERT has been studied extensively as a treatment for alpha-mannosidosis. The effects of ERT in knockout mice could be seen in both thin layer chromatography and histology. At lower doses, the clearing of oligosaccharides in spleen and kidney tissue was obvious, but not in brain. However, with increased enzyme doses there was also an effect both in the peripheral and central nervous system. In addition to reduced brain pathology, the mice showed reduced ataxia on treadmill testing. Although only a stabilization of findings was expected, a significant improvement both on pathologic and clinical parameters was observed in the animals [Damme et al 2015, Stroobants et al 2017].

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 (annually) including number and type of infections, hearing, weight, development, irritability, depression, change in social, domestic, school- or work-related activities, ability to walk distances, diarrhea, muscle pain, joint aches or reduced range of movement, and bone pain
• Physical examination (annually) including otoscopy, ophthalmoscopy, 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 in case of inflammation, serum concentrations of alanine aminotransferase 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

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).

Evaluations can include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Assay of acid alpha-mannosidase enzyme activity in leukocytes or other nucleated cells if the pathogenic variants in the family are not known.

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

Therapies Under Investigation

Bone marrow transplantation (BMT) has been tried as a treatment for alpha-mannosidosis. Early diagnosis and prompt treatment with BMT increases the chances of preventing cognitive decline and improving symptoms. However, more research is necessary to determine the long-term safety and efficacy of this potential therapy. BMT is not without drawbacks. The procedure carries the risk of serious complications including graft-versus-host disease (GVHD) and other long-term and late effects as described by Mynarek et al [2012]. Two of 17 individuals died of procedure-related causes, two developed severe GVHD, and six developed chronic GVHD. After BMT, affected individuals made developmental progress, although normal development was not achieved. The perfect donor is familial HLA-identical, but often this type of donor cannot be identified, in which case enzyme replacement therapy (ERT) will be the best option.

Gene therapy is also being studied as a possible therapy for some lysosomal storage disorders. Given the permanent transfer of the normal gene, which can produce active enzyme, this form of therapy is theoretically most likely to lead to a cure. However, at this time, there are many technical difficulties to resolve before gene therapy can succeed.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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].