Cataract associated with a metabolic disease
-Rare eye disease
-Rare genetic disease
Developmental anomaly of metabolic origin
-Rare developmental defect during embryogenesis
-Rare genetic disease
Lysosomal disease with hypertrophic cardiomyopathy
-Rare cardiac disease
-Rare genetic disease
Lysosomal storage disease with skeletal involvement
-Rare bone disease
-Rare genetic disease
Metabolic disease with cataract
-Rare eye disease
-Rare genetic disease
Metabolic disease with corneal opacity
-Rare eye disease
-Rare genetic disease
Neurometabolic disease
-Rare genetic disease
-Rare neurologic disease
Oligosaccharidosis
-Rare developmental defect during embryogenesis
-Rare genetic disease
Comment:
Three clinical subtypes of alpha-mannosidosis have been suggested: severe, moderate and mild forms. The severe form manifests early and produces skeletal abnormalities; the moderate form manifests before 10 years with milder or slower progression of clinical features; the mild form has an onset later in life with slower progression, that typically lacks skeletal abnormalities. In some case descriptions, a murmur of the heart is mentioned, but so far, reports on manifest heart disease have not been reported (PMID:24234586).
Alpha-mannosidosis is an autosomal recessive lysosomal storage disease characterized by mental retardation, coarse facial features, skeletal abnormalities, hearing impairment, neurologic motor problems, and immune deficiency. Expression of the disease varies considerably, and there is a wide spectrum of ... Alpha-mannosidosis is an autosomal recessive lysosomal storage disease characterized by mental retardation, coarse facial features, skeletal abnormalities, hearing impairment, neurologic motor problems, and immune deficiency. Expression of the disease varies considerably, and there is a wide spectrum of clinical findings and severity. Affected children are often normal at birth and during early development. They present in early childhood with delayed psychomotor development, delayed speech, and hearing loss. Additional features include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, dysostosis multiplex, and motor impairment (summary by Malm and Nilssen, 2008). - Classification Systems Two classification systems have been used to describe the clinical presentation of alpha-mannosidosis. 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. Individuals with the less severe 'type II' show normal early development with later childhood development of mental retardation, hearing loss, coarse facies, neurologic deterioration, and survival well into adulthood (summary by Desnick et al., 1976 and Gotoda et al., 1998). A later classification system delineated 3 clinical types. Type 1 is the mildest form, with onset after age 10 years, without skeletal abnormalities and very slow progression. Type 2 is a moderate form, with onset before age 10 years, presence of skeletal abnormalities, and slow progression with development of ataxia by age 20 to 30 years. Type 3 is the severe form, with onset in early infancy, skeletal abnormalities, and obvious progression leading to early death from primary central nervous system involvement or myopathy. Most patients belong to clinical type 2 (summary by Malm and Nilssen, 2008). Despite the clinical heterogeneity of the disorder, there are no apparent genotype/phenotype correlations (Berg et al., 1999; Riise Stensland et al., 2012).
Poenaru et al. (1979) reported successful prenatal diagnosis of mannosidosis in 2 at-risk families by analyzing enzyme activity of amniotic cells from the fetus.
Ockerman (1967, 1969) reported a boy with a generalized lysosomal storage disorder resembling Hurler syndrome (607014), but the storage material was not acid mucopolysaccharide. The patient had coarse features, macroglossia, flat nose, large clumsy ears, widely spaced teeth, ... Ockerman (1967, 1969) reported a boy with a generalized lysosomal storage disorder resembling Hurler syndrome (607014), but the storage material was not acid mucopolysaccharide. The patient had coarse features, macroglossia, flat nose, large clumsy ears, widely spaced teeth, large head, big hands and feet, tall stature, lenticular opacities, muscular hypotonia, lumbar gibbus, and radiographic skeletal abnormalities. He also had mild hepatosplenomegaly, dilated cerebral ventricles, hypogammaglobulinemia, and susceptibility to infection. Vacuolated lymphocytes were present in the bone marrow and blood. The patient died at age 4.5 years during an episode of increased intracranial pressure. Histologic study showed storage material in the cerebral cortex, brainstem, spinal medulla, neurohypophysis, retina, and myenteric plexus. Total mannose in the liver was strikingly increased. Alpha-mannosidase activity in all tissues studied was abnormally low, whereas other acid hydrolases had higher than normal activities. The term 'mannosidosis' was suggested as the name of the disorder. Ockerman et al. (1973) referred to the identification of mannosidosis in 2 Hungarian sisters and 3 Finnish boys, including 2 brothers. A procedure for the study of low molecular weight urinary compounds containing mannose was useful in the study of these cases. Bach et al. (1978) reported 2 sibs, born of consanguineous Palestinian parents, with mild mental retardation, delayed speech, coarse facies, and limited mobility of the large joints. Cultured fibroblasts showed partial alpha-mannosidase deficiency (20% of normal), and the sibs were considered to be mildly affected. However, both patients had vacuolated leukocytes and fibroblasts consistent with the disease phenotype. In cultured cell from patients with mannosidosis, Desnick et al. (1976) found defects of neutrophil function, including depressed chemotactic responsiveness and impaired phagocytosis of bacteria. They suggested that recurrent respiratory tract infections resulted from immunoglobulin deficiencies. Montgomery et al. (1982) found reports of about 50 cases of mannosidosis. Clinical expression varied from few symptoms to death in childhood. Most patients were in their first or second decade of life. Montgomery et al. (1982) described a 32-year-old man who had been diagnosed as having a 'lipochondrodystrophy possibly Hurler syndrome' at the age of 18 months on the basis of hepatosplenomegaly, dysostosis multiplex, and coarse facies. He had a relatively mild and nonprogressive course with deafness, mental retardation, pectus carinatum, thoracolumbar gibbus, thick calvaria, and lens opacities. Press et al. (1983) reported a man with mannosidosis who was 33 years old in 1981 when he presented with pancytopenia. He was first seen at age 26 years with massive gingival hypertrophy, severe mental retardation, and bowed femurs. Mannose-laden histiocytes were demonstrated in the gingiva. An autoimmune basis of the pancytopenia was demonstrated by the presence of antiplatelet and antineutrophil antibodies and a low haptoglobin level. The authors speculated that abnormal accumulation of mannose-rich glycoproteins and oligosaccharides in the membranes of blood cells was responsible for the genesis of neoantigenic determinants. Michelakakis et al. (1992) described a 13-year-old Greek boy and his 24-year-old sister with type II mannosidosis. Both had mental retardation, sensorineural deafness, and reduced mannosidase levels in plasma and white blood cells. The boy had normal physical and psychomotor development until age 2 when progressive mental regression set in. He also had frequent respiratory infections. He had coarse facial features with thick eyebrows, widely spaced incisors, prognathism, and a low hairline anteriorly. Radiologic survey of the skeleton showed spondylolysis with spondylolisthesis of L5 on S1. The sister had heavy eyebrows and prognathism. Bennet et al. (1995) reported 2 unrelated patients with different presentations of mannosidosis. One had onset in early childhood with a severe phenotype characteristic of type I mannosidosis, whereas the other was diagnosed in late adulthood after the onset of progressive neurologic deterioration, consistent with type II mannosidosis. Both were detected by urinary screening of oligosaccharides. Lysosomal alpha-mannosidase activity was markedly reduced in lymphoblasts transformed from both patients' blood cells. Kinetic analyses showed that the enzyme from the type I patient had a 400-fold reduction in affinity, while that from the type II patient was reduced 40-fold. All 4 parents had reduced alpha-mannosidase activity in lymphoblasts. The type I patient had a large hydrocele and bilateral inguinal hernias at birth. Coarse facial appearance and delays in speech development prompted referral at age 13 months. At that time, hepatosplenomegaly and cataracts were noted, together with a broad forehead, frontal bossing, flat occiput, midfacial hypoplasia, epicanthal folds, hypertrichosis, and an anterior hair whorl. Brain scans showed increased ventricular size and macrocephaly. Foamy cytoplasm within vacuolated lymphocytes were demonstrated by bone marrow studies. The woman with type II mannosidosis was said to have a normal phenotype during early childhood, but required special education from the second grade onward. She learned to read and write and was independent until age 25 years when she developed bowel incontinence. Evidence of corticospinal and spinocerebellar tract disease progressed over the ensuing 15 years and was more pronounced in the lower limbs. Cerebrocortical atrophy was first documented at age 35. The diagnosis of mannosidosis was made at the age of 40. Gotoda et al. (1998) reported a Japanese woman with alpha-mannosidosis confirmed by genetic analysis (609458.0002). From the age of 1 year she had suffered from recurrent infections, such as bronchitis and otitis media. Hearing loss and delayed psychomotor development were noted at age 2 years. At the age of 9 years she entered a school for the deaf, where she did poorly. She gradually developed gait disturbance. Physical examination at the age of 36 years showed an IQ of 19, coarse facies, retinal degeneration, sensorineural hearing loss, increased deep tendon reflexes, spastic gait, and mild limb ataxia. There were vacuolated lymphocytes in her peripheral blood. Similar vacuoles were also found in biopsied muscle cells and fibroblasts. Lysosomal alpha-mannosidase activity of peripheral leukocytes was decreased to less than 1% of normal controls, whereas other lysosomal enzyme activities were all within the normal range. Thin-layer chromatography showed increased urinary excretion of oligosaccharides. A younger sister, aged 42, had a clinical history and features similar to those of the patient; pathologic examination of muscle from this sister had been reported by Kawai et al. (1985). In a patient with alpha-mannosidosis originally reported by Autio et al. (1973), Gotoda et al. (1998) identified compound heterozygosity for 2 mutations in the MAN2B1 gene (609458.0003; 609458.0004). The patient was the only child of healthy, nonconsanguineous parents. He had recurring infections during the first year of life. By age 17 months he was speaking only a few words and impaired hearing was suspected. He had coarse facial features, delayed psychomotor functions, and brisk tendon reflexes. Approximately 80% of his peripheral blood leukocytes were vacuolated, and his alpha-mannosidase activity was reduced to approximately 2% of normal. Gutschalk et al. (2004) reported 3 adult sibs, aged 38 to 47 years, with alpha-mannosidosis. In late adolescence, all 3 developed progressive cerebellar ataxia characterized by gait ataxia, impaired smooth pursuit, nystagmus, dysarthria, and extensor plantar responses. All also had sensorineural deafness from early childhood and developed progressive retinal degeneration during late adolescence. One patient reported delusions and hallucinations. MRI showed cerebellar atrophy and periventricular white matter changes. MR spectroscopy showed no evidence of demyelination, and Gutschalk et al. (2004) concluded that the neurodegeneration in adult mannosidosis results from lysosomal accumulation of storage material. Courtney and Pennesi (2011) described the ocular findings in 2 brothers with alpha-mannosidosis. In addition to corneal and lenticular changes, the brothers had fundus changes including slightly pale optic discs (mild optic atrophy), retinal vascular attenuation, and mottled retinal pigment epithelium (RPE), most notable in the macula and surrounding the fovea. Additionally, there were numerous nummular yellow-white deposits evident at the level of the RPE. No foveal light reflex, peripapillary sparing, or bone spicule pigmentary change was found in either eye. Spectral-domain optical coherence tomography revealed retinal thinning. Fundus autofluorescence showed granular areas of hypoautofluorescence in the macula as well as in the posterior pole surrounding the optic nerve where speckled hyperautofluorescence was intermixed with hypoautofluorescent areas.
In 2 Palestinian sibs with alpha-mannosidosis (248500) originally reported by Bach et al. (1978), Nilssen et al. (1997) identified a homozygous mutation in the MAN2B1 gene (609458.0001).
In 4 unrelated patients with alpha-mannosidosis, Gotoda et al. ... In 2 Palestinian sibs with alpha-mannosidosis (248500) originally reported by Bach et al. (1978), Nilssen et al. (1997) identified a homozygous mutation in the MAN2B1 gene (609458.0001). In 4 unrelated patients with alpha-mannosidosis, Gotoda et al. (1998) identified mutations in the MAN2B1 gene (609458.0001-609458.0005). All mutations were in either homozygous or heterozygous state. Riise Stensland et al. (2012) identified 96 different pathogenic mutations in the MAN2B1 gene, including 83 novel mutations, in 130 unrelated patients with alpha-mannosidosis from 30 countries. Most of the mutations were private, but R750W (609458.0004) was found in 50 patients from 16 countries and accounted for 27.3% of disease alleles. Other recurrent mutations included a splice site mutation in intron 14 (609458.0006), found in 13 disease alleles, and L809P (609458.0007), found in 8 disease alleles. Twenty-nine novel missense mutations were identified. Most did not show any residual enzyme activity when expressed in COS-7 cells, but 10 showed some activity, including 5 with 30% or more residual activity. There were no apparent genotype/phenotype correlations.
Riise Stensland et al. (2012) found that the R750W mutation in the MAN2B1 gene (609458.0004) was the most common mutation among 130 unrelated patients with alpha-mannosidosis from 30 countries. It was found in 50 patients from 16 countries ... Riise Stensland et al. (2012) found that the R750W mutation in the MAN2B1 gene (609458.0004) was the most common mutation among 130 unrelated patients with alpha-mannosidosis from 30 countries. It was found in 50 patients from 16 countries and accounted for 27.3% of disease alleles. Haplotype analysis indicated at least 4 independent events causing R750W, with 1 haplotype accounting for 95% of the alleles. Population-based analysis suggested that the mutant allele arose in eastern Europe.
Alpha-mannosidosis should be suspected in individuals with intellectual disability, hearing loss, ataxia, skeletal abnormalities, and coarse facial features....
DiagnosisClinical DiagnosisAlpha-mannosidosis should be suspected in individuals with intellectual disability, hearing loss, ataxia, skeletal abnormalities, and coarse facial features.TestingAlpha-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 TestingGene. MAN2B1 is the only gene in which mutations are known to cause alpha-mannosidosis.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Alpha-MannosidosisView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityMAN2B1Sequence analysisSequence variants 2, 398.5%Clinical Deletion / duplication analysis 4, 5Partial- or whole-gene deletions1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.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, Pathologic 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 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, specificity, and other test characteristics can be found at www.eurogentest.org [Nilssen et al 2011; see full text].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a probandAssay 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.Genetically Related (Allelic) DisordersNo other phenotypes have been associated with mutations in MAN2B1.
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]....
Natural HistoryDevelopment 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 abnormalitiesType 2. Moderate form clinically recognized before age ten years, with myopathy, slow progression, and presence of skeletal abnormalitiesType 3. Severe form with obvious progression, leading to early death from primary central nervous system involvement or infectionMotor 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.OtherCommunicating 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].
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....
Differential DiagnosisThe 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Alpha-mannosidosis type 1, mild formAlpha-mannosidosis type 2, moderate formAlpha-mannosidosis type 3, severe form
To establish the extent of disease in an individual diagnosed with alpha-mannosidosis, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 painPhysical 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 infectionsAudiometry. If intellectual disability or young age makes cooperation difficult, brain stem evoked response testingOphthalmologic examination to evaluate for corneal opacities, myopia, hyperopia, and strabismusNeuropsychological testing to establish functional level and learning capacityBlood 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 sitesBone densitometry to detect osteopenia or osteoporosisCT 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 consultationTreatment of ManifestationsSome 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 measuresEarly 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 functioningInsertion of PE (pressure-equalizing) tubes to reduce the conductive/mechanical component of hearing loss from fluid in the middle earGlasses (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 jointsUse of a wheelchair if necessaryTreatment of osteoporosis or osteopenia identified on bone densitometry with palmidronate (Aredia®) monthly or zoledronic acid (Aclasta®) once a yearOrthopedic 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 considerationsUse of sign language in individuals with significant hearing lossEarly educational intervention for development of social skillsSpeech therapy to improve speechSpecial education to maximize learningPlanning housing for possible future wheelchair usePrevention of Primary ManifestationsMost 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 ComplicationsBecause 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].SurveillanceSuggested serial monitoring to evaluate severity and rate of disease progressionMedical 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 painPhysical 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 infectionsAudiometry. If intellectual disability makes cooperation difficult, brain stem evoked response testingOphthalmologic examination to detect corneal opacities, myopia, hyperopia, and strabismusNeuropsychological testing to establish functional level and learning capacitiesBlood 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 sitesBone densitometry every two to five years to assess osteopeniaCT 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 RiskAt-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 InvestigationBone 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 investigatedSearch ClinicalTrials.gov for access to information on clinical studies related to alpha-mannosidosis.OtherBecause 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].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMAN2B119p13.2Lysosomal alpha-mannosidaseMAN2B1 homepage - Mendelian genesMAN2B1Data 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) View in own window 248500MANNOSIDOSIS, ALPHA B, LYSOSOMAL; MANSA 609458MANNOSIDASE, ALPHA, CLASS 2B, MEMBER 1; MAN2B1Normal allelic variants. 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.Pathologic 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 Pathologic Allelic Variants Occurring in >5 FamiliesView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencec.1830+1G>C p.Val549_Glu610del 1NM_000528.2 NP_000519.2c.2248C>Tp.Arg750Trpc.2426T>Cp.Leu809ProBerg et al [1999]As determined from analyses of 130 unrelated patients [Riise Stensland et al 2012]See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).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.