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  • Updated 06.20.2022
  • Released 04.19.1995
  • Expires For CME 06.20.2025

Mannosidosis

Introduction

Overview

Alpha- and beta-mannosidosis are autosomal recessive “storage” disorders associated with the excretion of mannose-rich oligosaccharides. Alpha-mannosidosis can present as either (1) a 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, or (2) a milder (juvenile-adult or type II) form of slowly progressive course, with survival into adulthood. Early hematopoietic stem cell transplantation provides significant benefit. Enzyme replacement therapy for alpha-mannosidosis has been developed and received approval in Europe. Glial fibrillary acidic protein, oligosaccharides, and other neuronal biomarkers are elevated in the CSF of most patients. Beta-mannosidosis is rarer and has a wide range of phenotypes, including (1) severe epilepsy, intellectual disability, hearing loss, quadriplegia, and early death; (2) spinocerebellar atrophy; and (3) isolated angiokeratomas.

Key points

• Alpha-mannosidosis can present as either (1) a 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 or (2) a milder (juvenile-adult or type II) form with a slowly progressive course and survival into adulthood.

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

• Hearing impairment is an early sign of alpha-mannosidosis in children with a mild phenotype.

• 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 and enzyme replacement therapy.

• Enzyme replacement therapy for alpha-mannosidosis has been developed and received approval in Europe.

• Beta-mannosidosis is rare and has a wide range of phenotypes, including (1) severe epilepsy, intellectual disability, hearing loss, quadriplegia, and early death; (2) spinocerebellar atrophy; and (3) isolated angiokeratomas.

Historical note and terminology

Two distinct genotypes are included under the heading of mannosidosis: alpha-mannosidosis and beta-mannosidosis. Both are rare, and the phenotype is variable for both genotypes. The two 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 (81). The animal models are being used for therapeutic endeavors involving bone marrow transplants and gene therapy.

Alpha-mannosidosis. Alpha-mannosidosis was first described by Per-Arne Ockerman (1933-) in 1967 in Sweden; the proband was a mildly intellectually disabled child with a coarse body and face (61; 62). Because the coarse facial features resembled those in Hurler syndrome, alpha-mannosidosis was originally classified as a mucopolysaccharidosis but was later shown to be a distinct entity (61). In 1973, Ockerman described three additional cases in boys, aged 4, 5, and 10 years, with delayed psychomotor development, coarse facies, osteoporotic long bones with poor trabeculation and somewhat thick calvaria, and recurrent infections (03). This is the most typical clinical presentation (08).

Neurodegenerative alpha-mannosidosis in cattle and cats was subsequently described (33; 77). Obligate carrier cattle were shown to have 50% of normal alpha-mannosidase activity, verifying the disorder as a genetic rather than a toxic defect. Nevertheless, symptoms of affected cattle resemble those of normal North American normal cattle that had ingested "loco weed" (ie, certain species of Astragalus and Oxytropis). The neurotoxic component of loco weed is an indolizidine alkaloid, "swainsonine," which is an inhibitor of alpha-mannosidases, including the lysosomal alpha-mannosidase involved in mannosidosis. Similar intoxication in goats was caused by Sida carpinifolia (23).

Structural formula of swainsonine

Swainsonine is a toxin present in certain plants (eg, "locoweed"), which when ingested by ruminants or horses produces a toxic form of mannosidosis. (Created by Jü on July 28, 2012. Public domain.)

Beta-mannosidosis. Animals with beta-mannosidosis, first described in Nubian goats in 1981 (35) and subsequently in cattle (14), develop extensive central nervous system hypomyelination and hypothyroidism, which is manifest by tremor, ataxia, and early death (34; 65). Affected animals die in the neonatal period if intensive care is not provided.

Human beta-mannosidosis is less severe than beta-mannosidosis in goats or cattle. The first human case of beta-mannosidosis, described in 1986, was caused by a combined deficiency of beta-mannosidase and sulfamidase, leading to intellectual disability, coarse facial features, and mild skeletal changes reminiscent of the mucopolysaccharidoses (79). In 1988, Cooper and colleagues described two mildly intellectually disabled brothers, aged 29 and 44 years, with normal facies and no skeletal abnormalities; they had totally deficient beta-mannosidase activity and normal activity of other lysosomal hydrolases, including sulfamidase (16). Most subsequent cases of beta-mannosidosis have shown mild but progressive mental degeneration; however, there is a report of severely affected siblings with seizures in early childhood. Thus, diagnosis of beta-mannosidosis should be considered in mildly intellectually disabled children with progressive neurodegeneration and either mild skeletal abnormalities or mild hepatosplenomegaly.

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