Lisosomas

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PART 4: LYSOSOMAL DISORDERS
Chapter 140: Disorders of Glycoprotein Degradation: α-Mannosidosis, β-Mannosidosis, Fucosidosis, and Sialidosis
George H. Thomas

Abstract
1. Most, if not all, glycoproteins are synthesized by one of two pathways. The glycosyl transferase pathway
synthesizes oligosaccharides linkedO-glycosidically to serine or threonine, whereas the dolichol, lipid-linked
pathway synthesizes oligosaccharides linked N-glycosidically to asparagine. Ultimately, the oligosaccharides are
degraded in lysosomes by a group of exoglycosidases acting at the nonreducing termini, and by
endo-β-N-acetylglycosaminidase and aspartylglucosaminidase at the reducing end. Specific deficiencies of these
enzymesresult in glycoprotein or oligosaccharide storage diseases. Four such human disorders are discussed in
this chapter.
2. Human α-mannosidosis (MIM 248500) is one of two disorders of glycoprotein catabolism associated with abnormal
levels and excretion of small mannose-rich oligosaccharides. The more severe (infantile or type I) phenotype
includes rapidly progressive mental retardation,hepatosplenomegaly, severe dysostosis multiplex, and often death
between 3 and 12 years of age. The milder (juvenile-adult or type II) phenotype, accounting for approximately
10–15 percent of cases, is characterized by a milder and more slowly progressive course with survival into
adulthood. While patients are generally placed into one of these two groups, there may in fact be a continuum of
clinicalfindings rather than a clear separation. The biochemical alterations in α-mannosidosis result from a
deficiency of the lysosomal enzyme α-mannosidase. The gene that codes for the precursors of the subunits of this
enzyme and maps to human chromosome 19p13.2–q12 has been isolated and sequenced. The mode of
inheritance is autosomal recessive.
3. Human β-mannosidosis (MIM 248510), a more recentlydescribed disorder of oligosaccharide catabolism, results
from a deficiency of β-mannosidase activity and is associated with increased storage and excretion of
Man(β1 → 4)GlnNAc. The clinical phenotype, based on the 13 patients described to date, remains unclear. The
most severe findings include status epilepticus, severe quadriplegia, and death by 15 months, while the mildest
findings have beenlimited to the presence of angiokeratomas. To date, the most frequent findings have been
mental retardation, respiratory infections, and hearing losses with associated speech impairments. In keeping with
data showing an autosomal mode of inheritance, the responsible gene has been mapped to human chromosome
4q21–25. A composite cDNA, consisting of an 87-nucleotide 5′-untranslated region, a2640-nucleotide coding
region, and a 556-nucleotide untranslated region, codes for a 3.7-kb transcript. The enzyme, a lysosomal protein,
has a molecular mass of 100 kDa.
4. Fucosidosis (MIM 230000) is an autosomal recessive disorder resulting from a deficiency of the lysosomal
hydrolase α-fucosidase. While at least two phenotypes have been described in this disorder, recent data suggest
thatindividual patients may actually represent a continuum within a wide spectrum of severity. The more severely
affected patients have, within the first year of life, the onset of psychomotor retardation, coarse facies, growth
retardation, dysostosis multiplex, neurologic retardation, and increase in sweat sodium chloride. In contrast, the
milder phenotypes are characterized by the presence ofangiokeratoma, longer survival, and more normal levels of
sweat sodium chloride. The enzyme defect results in the accumulation and excretion of a variety of glycoproteins,
glycolipids, and oligosaccharides containing fucoside moieties. Although the disorder is panethnic, the majority of
patients have been from Italy or the southwestern part of the United States. A high frequency of consanguinity
has...