Mannosidosis

Raphael Schiffmann MD (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.)
Originally released April 19, 1995; last updated December 18, 2016; expires December 18, 2019

This article includes discussion of mannosidosis, mannosidase deficiency, alpha-mannosidosis type 1, alpha-mannosidosis type 2, and beta-mannosidosis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Alpha- and beta-mannosidosis are autosomal recessive “storage” disorders associated with excretion of mannose-rich oligosaccharides. Alpha-mannosidosis can present as anything between the severe (infantile or type I) phenotype, with rapidly progressive mental retardation, hepatosplenomegaly, severe dysostosis multiplex, and often death between 3 and 12 years of age, and the milder (juvenile-adult or type II) form of slowly progressive course, with survival into adulthood. Early hematopoietic stem cell transplantation provides significant benefit, and its effect may be followed using magnetic resonance spectroscopy. GFAP, oligosaccharides, and other neuronal biomarkers are elevated in the CSF of most patients. Beta-mannosidosis is rarer and ranges from severe epilepsy, intellectual disability, hearing loss, quadriplegia, and early death to a pure spinocerebellar atrophy and even isolated angiokeratomas.

Key points

 

• Alpha-mannosidosis is characterized by facial dysmorphism, mental retardation, cataracts, corneal opacity, and hearing loss.

 

• Patients with beta-mannosidosis, on the other hand, are mildly dysmorphic and suffer from mental retardation and skin angiokeratomas, but have no eye abnormality.

 

• Correct diagnosis requires measurement of enzyme activity in serum, plasma, or cells.

 

• Important biomarkers can be identified in most patients, which include elevated mannose complexes in MR spectroscopy and elevated oligosaccharides, GFAP, and biomarkers of neurodegeneration in CSF.

 

• Alpha-mannosidosis can be treated by early hematopoietic stem cell transplantation.

Historical note and terminology

Two distinct genotypes are included under the heading of mannosidosis: alpha-mannosidosis and beta-mannosidosis. Both are rather rare, and the phenotype is variable. Alpha-mannosidosis was first described by Ockerman in 1967 in Scandinavia; the proband was a young, mildly retarded child with a coarse body and face (Ockerman 1969). In 1973 Ockerman described 3 additional cases of boys, aged 4, 5, and 10, with psychomotor mental retardation, coarse facies, osteoporotic long bones with poor trabeculation and somewhat thick calvaria, and recurrent infections (Autio et al 1973). This is the most typical clinical presentation (Borgwardt et al 2014). Neurodegenerative alpha-mannosidosis in cattle and cats was subsequently described (Jolly et al 1981; Vite et al 2001). The disease in cattle is of interest because the symptoms were similar to those of normal cattle that had ingested "loco weed." The neurotoxic component of loco weed is an indolizidine alkaloid, "swainsonine," an inhibitor of alpha-mannosidases, including the lysosomal alpha-mannosidase involved in mannosidosis. Similar intoxication in goats was caused by Sida carpinifolia (Driemeier et al 2000). Obligate carrier cattle were shown to have 50% of normal alpha-mannosidase activity, verifying it as a genetic rather than a toxic defect.

Animals with beta-mannosidosis, first described in Nubian goats in 1981 (Jones and Dawson 1981) and subsequently in cattle (Chen et al 1995), develop central nervous system hypomyelination and hypothyroidism. Affected animals die in the neonatal period if intensive care is not provided. Human cases, first described in 1986, are caused by a combined deficiency of beta-mannosidase and sulfamidase leading to mental retardation, coarse facial features, and mild skeletal changes reminiscent of the mucopolysaccharidoses (Wenger 1986). In 1988, Cooper and colleagues described 2 mildly retarded brothers, aged 29 and 44, with normal facies and no skeletal abnormalities, and who had totally deficient beta-mannosidase activity and normal activity of other lysosomal hydrolases, including sulfamidase (Cooper et al 1988). This phenotype appears to be more typical because most subsequent cases of beta-mannosidosis have shown mild but progressive mental degeneration with normal CT scan. However, there is a report of severely affected siblings with seizures in early childhood. Thus, diagnosis of beta-mannosidosis should be considered in any mildly retarded child with progressive neurodegeneration and either mild skeletal abnormalities or mild hepatosplenomegaly. Human beta-mannosidosis is much milder than beta-mannosidosis in goats and cattle, which involves extensive central nervous system demyelination, ataxia, tremor, and early death (Jones et al 1983; Patterson et al 1991).

The 2 forms of mannosidosis are both oligosaccharide lysosomal storage diseases and present as a wide range of phenotypes, in general being much slower in progression than the related lipidoses or mucopolysaccharidoses. Both mammalian genes have now been cloned, and the nature of the human mutations is actively being elucidated (Wu et al 2014). The animal models are being used for therapeutic endeavors involving bone marrow transplants and gene therapy.

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