Alternative titles; symbols
SNOMEDCT: 238047006; ORPHA: 118; DO: 3633;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q24 | Mannosidosis, beta | 248510 | Autosomal recessive | 3 | MANBA | 609489 |
A number sign (#) is used with this entry because beta-mannosidosis (MANSB) is caused by homozygous or compound heterozygous mutation in the gene encoding beta-mannosidase (MANBA; 609489) on chromosome 4q.
Beta-mannosidosis is an autosomal recessive lysosomal storage disease of glycoprotein catabolism caused by a deficiency of lysosomal beta-mannosidase activity. The most severely affected patients show developmental delay and mental retardation, but there are differing levels of severity and some patients may have comparatively mild disease (Bedilu et al., 2002) The disorder was first described in goats (Jones and Dawson, 1981), who have a more severe neurodegenerative disorder than that seen in humans.
Wenger et al. (1986) described a 46-month-old boy with a severe deficiency in beta-mannosidase activity, whose parents had an intermediate level of enzyme consistent with autosomal recessive inheritance. Beta-mannosidase activity levels near zero were found in all available samples from the patient, including leukocytes, plasma, and cultured skin fibroblasts. In addition to the deficiency of beta-mannosidase, this patient also had a low level of heparin sulfamidase activity in cultured skin fibroblasts. The patient's urine contained excess disaccharide that was identified as mannosyl(1-4)-N-acetylglucosamine and heparan sulfate. The patient showed coarsening facial features, mild bone disease, delayed speech development, hyperactivity, and mental retardation. Many of the findings resembled those found to have defects in the catabolism of the oligosaccharide chains of glycoproteins such as fucosidosis (230000), sialidosis (256550), and aspartylglucosaminuria (208400). The deficiency of heparin sulfamidase and the excess of heparan sulfate in the urine, both findings consistent with Sanfilippo syndrome type A (252900), suggested the presence of 2 disorders. Hu et al. (1990) used complementation studies to show that the patient reported by Wenger et al. (1986) had both Sanfilippo syndrome and beta-mannosidosis.
Cooper et al. (1986) reported an Indian-Hindu man with beta-mannosidosis; his parents were not related. Intellectual impairment was first observed when the patient began to attend school. Clinical assessment at the age of 44 years showed mental retardation but no other neurologic signs; CT scan of the brain was normal. The patient had angiokeratomas on the scrotum and the shaft of the penis and marked tortuosity of conjunctival vessels. He did not have facial dysmorphism, hepatosplenomegaly, or radiologic changes of the bones. The urine was free of albumin, red cells, and casts. The patient's 19-year-old mentally retarded brother had similar skin lesions. Both brothers had deficiency of beta-mannosidase, and the parents had intermediate levels. Cooper et al. (1988) found markedly decreased beta-mannosidase activity in plasma, white cells, fibroblasts, and urine obtained from the 2 affected Indian brothers (the younger brother was stated to be 29 years old); all other lysosomal enzymes measured, including sulfamidase, showed normal activity. Biopsy of a skin lesion from the 'bathing trunk' area showed marked cytoplasmic vacuolization. Urinary mucopolysaccharide excretion was normal, but thin-layer chromatography of urinary oligosaccharides showed an abnormal band shown to be a disaccharide. Cooper et al. (1988) noted that the difference in storage material in the caprine disease may account for the clinical differences; a trisaccharide accumulates in the goat.
By analyzing urinary oligosaccharides and by measuring enzyme activity in leukocytes and plasma, Dorland et al. (1988) diagnosed beta-mannosidosis in 2 sons of a first-cousin Turkish couple. Behavioral abnormalities and deafness with speech retardation were the main clinical features. Kleijer et al. (1990) reported 2 affected sibs from a Czech Gypsy family with beta-mannosidosis. The girl was severely affected; an older brother had milder manifestations. Heterozygous levels of beta-mannosidase were found in the fibroblasts and/or plasma of the parents and a sister. Cooper et al. (1991) reported a female infant with severe beta-mannosidosis. She had no dysmorphic features except brachycephaly. She showed moderate developmental delay, developed refractive seizures at age 12 months, and died at age 15 months. Urinary analysis showed mannose disaccharides.
Poenaru et al. (1992) described a case in which speech impairment was the first symptom of infantile onset. The patient had mental retardation, recurrent infections, hyperactivity, and mild facial dysmorphism. Beta-mannosidase activity was completely lacking in the patient and a heterozygous level was found in the parents. Mannosyl-N-acetylglucosamine was identified in the patient's urine.
In a black African 14-year-old boy, Levade et al. (1994) described severe deficiency of beta-mannosidase activity manifested by bilateral thenar and hypothenar amyotrophy, electrophysiologically demonstrable demyelinating peripheral neuropathy, and cytoplasmic vacuolation of skin fibroblasts and lymphoid cells. The authors cited reports of 10 patients in 7 families.
Rodriguez-Serna et al. (1996) described a 22-year-old woman who since the age of 12 years had progressive angiokeratoma affecting the lower limbs and buttocks, with no other abnormalities. Enzyme studies revealed beta-mannosidase deficiency in cultured fibroblasts and in serum and leukocytes. The patient's parents exhibited intermediate enzyme levels, confirming autosomal recessive inheritance. Rodriguez-Serna et al. (1996) stated that a total of 11 cases of beta-mannosidase deficiency occurring in 8 families had been reported. Mental retardation and neurologic disorders were present in most reported patients.
Sedel et al. (2006) reported an 18-year-old male patient with beta-mannosidosis who exhibited motor and vocal tics since childhood, attention deficit, hyperactivity, impulsivity, and aggressiveness consistent with Gilles de la Tourette syndrome (GTS; 137580). He also had bilateral hearing loss and mild cognitive impairment. Molecular analysis identified compound heterozygosity for 2 mutations in the MANBA gene (609489.0003 and 609489.0004).
In 2 affected sibs from a Czech Gypsy family with beta-mannosidosis reported by Kleijer et al. (1990), Alkhayat et al. (1998) identified a homozygous null mutation in the MANBA gene (609489.0001).
In 2 patients with beta-mannosidosis, an Indian Hindu man originally reported by Cooper et al. (1986) and a Turkish woman originally reported by Wijburg et al. (1992), Bedilu et al. (2002) identified compound heterozygosity and homozygosity, respectively, for null mutations in the MANBA gene (608489.0007-608489.0009). Bedilu et al. (2002) noted that disease presentation in patients with null mutations is variable: the Czech Gypsy sibs described by Kleijer et al. (1990) had facial dysmorphism and skeletal involvement, whereas the Indian Hindu man and his affected younger brother did not have those features, and the Turkish woman had no apparent dysmorphology at 5 years of age but developed epicanthus, broad nasal bridge, and coarse facies by 18 years of age as well as a unilateral hip abnormality. Bedilu et al. (2002) concluded that beta-mannosidosis in humans may be milder than typical of other lysosomal storage disorders.
In a patient of European descent with severe beta-mannosidosis previously reported by Poenaru et al. (1992), Riise Stensland et al. (2008) identified compound heterozygosity for 2 mutations in the MANBA gene (609489.0005 and 609489.0006). Riise Stensland et al. (2008) stated that 20 patients from 16 families had been reported.
In goats, deficiency of beta-mannosidase causes a severe disorder that affects peripheral and central nervous system myelin, resulting in tremor, nystagmus, ataxia, and early death (Jones and Dawson, 1981; Malachowski and Jones, 1983; Lovell and Jones, 1983; Jones et al., 1983). Indeed, the caprine disorder was thoroughly described several years before the human disorder as a severe neurologic disease with CNS demyelination and early death. Although several laboratories sought the human equivalent, it was not found until 1986. Bovine beta-mannosidosis was reported in 1991 in neonatal Salers calves in North America and New Zealand (Jones and Abbitt, 1993).
Leipprandt et al. (1996) identified a single-base deletion at position 1398 in the beta-mannosidase DNA isolated from a goat with beta-mannosidosis. This deletion resulted in a shift in the reading frame and premature termination of translation, yielding a deduced peptide of 481 amino acids. Affected animals were homozygous for the mutation and obligate carriers were heterozygous. The assay for the presence or absence of the mutation was used for prenatal diagnosis using DNA collected from fetal fluids. The assay also confirmed chimerism in a goat with an atypically mild beta-mannosidosis phenotype.
Zhu et al. (2006) reported that Manba-null mice were viable, fertile, and showed no differences in general appearance or behavior from wildtype mice at over 12 months of age. Histologic evidence of storage material, manifest as intracytoplasmic vacuoles, was present in several organs, including epididymis, liver, kidney, and thyroid, although the accumulated amounts were small. All Manba-null animals examined had cytoplasmic vacuolation in the central nervous system, but there was variation in severity and distribution. Affected areas included pyramidal cells in the dorsolateral cerebral cortex, choroid plexus, hippocampus, and spinal cord, among others. The storage material was a disaccharide, similar to that found in humans with beta-mannosidosis. Biochemical studies showed that the mutant mice had increased alpha-mannosidase activity. The clinical and biochemical phenotype was distinct from that seen in ruminants.
Alkhayat, A. H., Kraemer, S. A., Leipprandt, J. R., Macek, M., Kleijer, W. J., Friderici, K. H. Human beta-mannosidase cDNA characterization and first identification of a mutation associated with human beta-mannosidosis. Hum. Molec. Genet. 7: 75-83, 1998. [PubMed: 9384606] [Full Text: https://doi.org/10.1093/hmg/7.1.75]
Bedilu, R., Nummy, K. A., Cooper, A., Wevers, R., Smeitink, J., Kleijer, W. J., Friderici, K. H. Variable clinical presentation of lysosomal beta-mannosidosis in patients with null mutations. Molec. Genet. Metab. 77: 282-290, 2002. [PubMed: 12468273] [Full Text: https://doi.org/10.1016/s1096-7192(02)00172-5]
Cooper, A., Hatton, C., Thornley, M., Sardharwalla, I. B. Human beta-mannosidase deficiency: biochemical findings in plasma, fibroblasts, white cells and urine. J. Inherit. Metab. Dis. 11: 17-29, 1988. [PubMed: 3128685] [Full Text: https://doi.org/10.1007/BF01800054]
Cooper, A., Sardharwalla, I. B., Roberts, M. M. Human beta-mannosidase deficiency. (Letter) New Eng. J. Med. 315: 1231, 1986. [PubMed: 3762648]
Cooper, A., Wraith, J. E., Savage, W. J., Thornley, M., Noronha, M. J. Beta-mannosidase deficiency in a female infant with epileptic encephalopathy. J. Inherit. Metab. Dis. 14: 18-22, 1991. [PubMed: 1861456] [Full Text: https://doi.org/10.1007/BF01804383]
Dorland, L., Duran, M., Hoefnagels, F. E. T., Breg, J. N., Fabery de Jonge, H., Cransberg, K., van Sprang, F. J., van Diggelen, O. P. Beta-mannosidosis in two brothers with hearing loss. J. Inherit. Metab. Dis. 11 (suppl. 2): 255-258, 1988. [PubMed: 3141715] [Full Text: https://doi.org/10.1007/BF01804251]
Hu, P., Wenger, D. A., van Diggelen, O. P., Klejer, W. J. Complementation studies in human and caprine beta-mannosidosis. J. Inherit. Metab. Dis. 14: 13-17, 1990.
Jones, M. Z., Abbitt, B. Animal model of human disease: bovine beta-mannosidosis. Am. J. Path. 142: 957-960, 1993. [PubMed: 8456950]
Jones, M. Z., Cunningham, J. G., Dade, A. W., Alessi, D. M., Mostosky, U. V., Vorro, J. R., Benitez, J. T., Lovell, K. L. Caprine beta-mannosidosis: clinical and pathological features. J. Neuropath. Exp. Neurol. 42: 268-285, 1983. [PubMed: 6842266]
Jones, M. Z., Dawson, G. Caprine beta-mannosidosis: inherited deficiency of beta-D-mannosidase. J. Biol. Chem. 256: 5185-5188, 1981. [PubMed: 7228876]
Kleijer, W. J., Hu, P., Thoomes, R., Boer, M., Huijmans, J. G. M., Blom, W., Van Diggelen, O. P., Seemanova, E., Macek, M. Beta-mannosidase deficiency: heterogeneous manifestation in the first female patient and her brother. J. Inherit. Metab. Dis. 13: 867-872, 1990. [PubMed: 2079835] [Full Text: https://doi.org/10.1007/BF01800211]
Leipprandt, J. R., Kraemer, S. A., Haithcock, B. E., Chen, H., Dyme, J. L., Cavanagh, K. T., Friderici, K. H., Jones, M. Z. Caprine beta-mannosidase: sequencing and characterization of the cDNA and identification of the molecular defect of caprine beta-mannosidosis. Genomics 37: 51-56, 1996. [PubMed: 8921369] [Full Text: https://doi.org/10.1006/geno.1996.0519]
Levade, T., Graber, D., Flurin, V., Delisle, M.-B., Pieraggi, M.-T., Testut, M.-F., Carriere, J.-P., Salvayre, R. Human beta-mannosidase deficiency associated with peripheral neuropathy. Ann. Neurol. 35: 116-119, 1994. [PubMed: 8285582] [Full Text: https://doi.org/10.1002/ana.410350119]
Lovell, K. L., Jones, M. Z. Distribution of central nervous system lesions in beta-mannosidosis. Acta Neuropath. 62: 121-126, 1983. [PubMed: 6659869] [Full Text: https://doi.org/10.1007/BF00684928]
Malachowski, J. A., Jones, M. Z. Beta-mannosidosis: lesions of the distal peripheral nervous system. Acta Neuropath. 61: 95-100, 1983. [PubMed: 6637401] [Full Text: https://doi.org/10.1007/BF00697387]
Poenaru, L., Akli, S., Rocchiccioli, F., Eydoux, P., Zamet, P. Human beta-mannosidosis: a 3-year-old boy with speech impairment and emotional instability. Clin. Genet. 41: 331-334, 1992. [PubMed: 1623631] [Full Text: https://doi.org/10.1111/j.1399-0004.1992.tb03408.x]
Riise Stensland, H. M. F., Persichetti, E., Sorriso, C., Hansen, G. M, Bibi, L., Paciotti, S., Balducci, C., Beccari, T. Identification of two novel beta-mannosidosis-associated sequence variants: biochemical analysis of beta-mannosidase (MANBA) missense mutations. Molec. Genet. Metab. 94: 476-480, 2008. [PubMed: 18565776] [Full Text: https://doi.org/10.1016/j.ymgme.2008.04.010]
Rodriguez-Serna, M., Botella-Estrada, R., Chabas, A., Coll, M.-J., Oliver, V., Febrer, M.-I., Aliaga, A. Angiokeratoma corporis diffusum associated with beta-mannosidase deficiency. Arch. Derm. 132: 1219-1222, 1996. [PubMed: 8859034] [Full Text: https://doi.org/10.1001/archderm.1996.03890340083013]
Sedel, F., Friderici, K., Nummy, K., Caillaud, C., Chabli, A., Durr, A., Lubetzki, C., Agid, Y. Atypical Gilles de la Tourette syndrome with beta-mannosidase deficiency. Arch. Neurol. 63: 129-131, 2006. [PubMed: 16401745] [Full Text: https://doi.org/10.1001/archneur.63.1.129]
Wenger, D. A., Sujansky, E., Fennessey, P. V., Thompson, J. N. Human beta-mannosidase deficiency. New Eng. J. Med. 315: 1201-1205, 1986. [PubMed: 2945113] [Full Text: https://doi.org/10.1056/NEJM198611063151906]
Wijburg, H., de Jong, J., Wevers, R., Bakkeren, J., Trijbels, F., Sengers, R. Beta-mannosidosis and ethanolaminuria in a female patient. Europ. J. Pediat. 151: 311 only, 1992. [PubMed: 1499588] [Full Text: https://doi.org/10.1007/BF02072238]
Zhu, M., Lovell, K. L., Patterson, J. S., Saunders, T. L., Hughes, E. D., Friderici, K. H. Beta-mannosidosis mice: a model for the human lysosomal storage disease. Hum. Molec. Genet. 15: 493-500, 2006. [PubMed: 16377659] [Full Text: https://doi.org/10.1093/hmg/ddi465]