Chapter 140

## Abstract

1. Most, if not all, glycoproteins are synthesized by one of two pathways. The glycosyl transferase pathway synthesizes oligosaccharides linked O-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 enzymes result 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 clinical findings 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 recently described 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 been limited 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, a 2640-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 that individual 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 of angiokeratoma, 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 been seen in affected families. The gene symbol for α-fucosidase (FUCA1) that codes for the common subunit that makes up the multiple forms of α-fucosidase has been isolated sequenced, and mapped to chromosome 1p24. At least 23 mutations causing fucosidosis have been reported. Of these, only four result in an amino acid substitution, with the remaining mutations presumed to result in unstable or defective mRNA, e.g. premature stop codons, frameshifts, defective splicing, large deletions.

5. Sialidosis (MIM 256550), the final disorder reviewed in this chapter, is also an autosomal recessive lysosomal storage disorder. Type I sialidosis, the milder form of this disorder, is characterized by the development of ocular cherry-red spots and generalized myoclonus in the second or third decade of life. Additional findings, reported in more than 50 percent of patients, include seizures, hyperreflexia, and ataxia. Type II sialidosis is distinguished from this milder form by the early onset of a progressive, rather severe, mucopolysaccharidosis-like phenotype with visceromegaly, dysostosis multiplex, and mental retardation. Both forms of the disease result from deficiency of the neuraminidase that normally cleaves terminal α2 → 3 and α2 → 6 sialyl linkages of several oligosaccharides and glycopeptides that are found in increased amounts in tissues and fluids of affected patients. The gene coding for this neuraminidase maps to human chromosome 6p21 in the region containing the HLA locus. A 1.9-kb cDNA, containing an open reading frame of 1245 nucleotides, is predicted to code for a protein containing 415 amino acids. Direct evidence that this gene is responsible for isolated deficiencies of sialidase is provided by the detection of mutations in this locus in at least nine sialidosis patients.

6. No definitive treatment is currently available for these lysosomal enzyme deficiencies. Identification of affected fetuses by biochemical analysis is reliable and has been demonstrated for each of these abnormalities by means of chorionic villus samples or cultured amniotic fluid cells.

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