Mannosidosis, Alpha B, Lysosomal

A number sign (#) is used with this entry because alpha-mannosidosis (MANSA) is caused by homozygous or compound heterozygous mutation in the MAN2B1 gene (609458) on chromosome 19p13.

Description

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).

Clinical Features

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.

Central Nervous System Abnormalities

Borgwardt et al. (2016) studied central nervous system abnormalities in 34 MANSA patients ranging in age from 6 to 35 years. Ten patients underwent brain MRI and magnetic resonance spectroscopy (MRS). Brain imaging showed occipital white matter signal abnormalities in 5 of the 10 patients, and age-inappropriate myelination in 6. MRS demonstrated significantly elevated mannose complex in gray and white matter, consistent with gliosis. All 34 patients were analyzed for cerebrospinal fluid (CSF) markers: there were elevated concentrations of tau (MAPT; 157140), GFAP (137780), and NEFL (162280) in 97%, 74%, and 41% of CSF samples, respectively. There was a negative correlation between CSF-biomarkers and cognitive function and CSF-oligosaccharides and cognitive function. The data indicated that the disorder is associated with early neuropathologic changes.

Diagnosis

Prenatal Diagnosis

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.

Clinical Management

Investigators have demonstrated that zinc can stimulate residual alpha-mannosidase activity in cultured cells from patients with mannosidosis (Kistler et al., 1977). Wong et al. (1993) reported a trial of oral zinc therapy for 3 years in a 4-year-old boy with alpha-mannosidosis. However, after almost 10 years of follow-up of the patient on and off zinc therapy, they concluded that there was no substantial clinical improvement.

Biochemical Features

Ockerman et al. (1973) found that normal liver alpha-mannosidase exists in at least 3 forms, separable by DEAE cellulose chromatography. The lysosomal A and B forms were most active at pH 4.4, whereas form C was most active at pH 6.0. In 2 cases of mannosidosis, Carroll et al. (1972) found that forms A and B were missing. Cheng et al. (1986) found that although mannosidase A and B differed in their subunit compositions, they were immunologically identical. The authors suggested that the differences in A and B were due to differences in processing, and that both forms arise from a single locus.

Ben-Yoseph et al. (1982) found that mannosidase activity was normal in the medium of cultured fibroblasts from patients with mannosidosis. However, incubation of the mannosidosis extracellular enzyme with either normal or patient cell lysates resulted in a partial loss of activity, whereas an additive value was observed with the normal extracellular enzyme. Ben-Yoseph et al. (1982) suggested that the enzymatic defect in mannosidosis is expressed only after the enzyme has been delivered to lysosomes and presumably has undergone some form of processing there. However, Cheng et al. (1986) provided evidence that the enzyme secreted by mannosidosis fibroblasts was not related immunologically to lysosomal mannosidase.

Molecular Genetics

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.

Population Genetics

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.

Animal Model

Hocking et al. (1972) described recessive inheritance of mannosidosis in cattle. The disease is manifest by head tremor, aggressive tendency, ataxia, failure to thrive, and early death.

Berg et al. (1997) identified a 4-bp deletion in the feline Man2b1 gene in a Persian cat with mannosidosis; the deletion resulted in a frameshift from codon 583 and premature termination at codon 645. No enzyme activity could be detected in the liver of the cat. A domestic long-haired cat expressing a milder phenotype had enzyme activity of 2% of normal; this cat did not possess the 4-bp deletion.

In the Man2b1 cDNA of alpha-mannosidosis-affected Angus cattle, Tollersrud et al. (1997) found a 961T-C transition, resulting in a phe321-to-leu amino acid substitution. In affected Galloway cattle, they found a 662G-A transition that caused an arg221-to-his substitution. Phe321 and arg221 are conserved among the alpha-mannosidase class-2 family.

Crawley et al. (1999) identified alpha-mannosidosis in the guinea pig.

Therapeutic Strategies

Walkley et al. (1994) studied the effects of bone marrow transplantation (BMT) in alpha-mannosidosis in cats where the disease shows clinical, morphologic, and biochemical features closely resembling those in the human disease. BMT-treated animals showed little or no progression of neurologic signs 1 to 2 years after transplant, whereas untreated cats became severely impaired and reached end-stage disease by 6 months of age. Increased lysosomal alpha-mannosidase activity was found in brain tissue of the treated animals, and electron microscopy demonstrated no evidence of lysosomal storage within most neurons. Histochemical localization of acidic alpha-D-mannosidase showed that functional enzyme was present in neurons, glial cells, and cells associated with blood vessels. This study provided direct evidence that bone marrow transplantation can lead to significant replacement of lysosomal hydrolase within neurons of the central nervous system and can compensate for the genetic metabolic defect.

Roces et al. (2004) reported correction of storage of neutral oligosaccharides in a mouse model of alpha-mannosidosis after intravenous administration of Man2b1 from bovine kidney and human and mouse recombinant MAN2B1. The bovine and human enzymes were barely phosphorylated, whereas the bulk of the mouse Man2b1 contained mannose 6-phosphate recognition markers. Clearance and apparent half-life of the internalized enzyme was dependent on the enzyme source as well as tissue type. The corrective effect was time-, tissue- and dose-dependent, and the effects were observed to be transient. After a single dose injection of MAN2B1, the maximum corrective effect was observed between 2 and 6 days. Injection of 250 microU of human MAN2B1 per gram of body weight followed by a subsequent injection 3.5 days later was sufficient to clear liver, kidney, and heart of neutral oligosaccharides. A decrease in mannose-containing oligosaccharides was also observed in the brain, with storage levels in treated mice less than 30% of levels found in control mice.

Blanz et al. (2008) demonstrated that the neuropathology of a mouse model for alpha-mannosidosis could be efficiently treated using recombinant human alpha-mannosidase (rhLAMAN). After intravenous administration of various doses (25-500 U/kg), rhLAMAN was widely distributed among tissues, and immunohistochemistry revealed lysosomal delivery of the injected enzyme. Whereas low doses (25 U/kg) led to a greater than 70% clearance of stored substrates in visceral tissues and doses of 250 U/kg were sufficient for clearance in peripheral neurons of the trigeminal ganglion, repeated high-dose injections (500 U/kg) were required to achieve a greater than 50% reduction of brain storage. Successful transfer across the blood-brain barrier was evident as the injected enzyme was found in hippocampal neurons, leading to nearly complete disappearance of storage vacuoles. In addition, the decrease in neuronal storage in the brain correlated with an improvement of the neuromotor disabilities found in untreated alpha-mannosidosis mice. Uptake of rhLAMAN seemed to be independent of mannose-6-phosphate receptors, consistent with the low phosphorylation profile of the enzyme.