Sialidosis

The term sialidosis refers to a series of disorders, probably allelic, caused by genetic abnormalities in the lysosomal sialidase which removes the terminal sialic acids from carbohydrate chains of glycoproteins. The activity of the sialidase which cleaves the sialic acid moieties from some of the gangliosides, such as GM3 and polysialogangliosides, is not defective (see appropriate section in Scriver et al., 1995). Review of the earlier literature on sialidosis requires exceptional care. Some of the earlier cases reported as sialidosis may well have been cases of galactosialidosis, another distinct genetic disorder recognized much more recently (see below). 

Clinical and Pathological Aspects. The disease is inherited as an autosomal recessive trait. Two major clinical forms are known. The more severe form, previously also known as mucolipidosis I, primarily occurs in infants and juvenile age groups. The less severe form is known as the cherry-red spot-myoclonus syndrome and occurs primarily in juvenile and older patients. Patients with the most severe form of mucolipidosis I may exhibit congenital 

In mucolipidosis I patients, vacuolated lymphocytes and foamy bone marrow cells are common. Cellular vacuolation is often seen in the enlarged liver (more extensive in the Kupffer cells than in the hepatocytes) and spleen, CNS neurons, peripheral nerves, and the neurons in the myenteric plexus. Pathology is generally milder in the late-onset cherry-red spot-myoclonus form than in the more severe mucolipidosis I and is confined to the nervous system. CNS neurons prominently contain lipofuscin pigments. 

Deficient activity in lysosomal acid sialidase (a-neuraminidase) is the genetic defect underlying sialidosis. Sialic acid occurs at the nonreducing terminus of the carbohydrate chains of many glycoproteins and also as a characteristic component of gangliosides. However, there is no biochemical or enzymological 

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Sialin was first identified as the product of the gene defective in sialidosis, a lysosomal storage disorder. The transporter mediates the movement of sialic acid out of lysosomes by coupling to the proton electrochemical gradient across the lysosomal membrane. Unlike the vesicular neurotransmitter transporters which are antiporters, sialin is a sympoiter with sialic acid and protons both moving out of the lysosome. 

Table 47-17. Major features of some diseases (eg, a-mannosidosis, 3-mannosidosis, fucosidosis, sialidosis, aspartylglycosaminuria, and Schindler disease) due to deficiencies of glycoprotein hydrolasesJ...

MIM numbers a-mannosidosis, 248500 3-mannosidosis, 248510 fucosidosis, 230000 sialidosis, 256550 aspartylglycosaminuria, 208400 Schindler disease, 104170. 

Mucolipidoses Sialidosis MU Sialidase (neuraminidase) Glycoprotein fragments... 

The term mucolipidosis was introduced to denote diseases that combined features common to both mucopolysaccharidoses and sphingolipidoses (Chapter 24). Three mucolipidoses are listed in Table 48—7. In sialidosis (mucolipidosis I, ML-I), various oligosaccharides derived from glycoproteins and certain ganglio-sides can accumulate in tissues. I-cell disease (ML-II)... 

Sialidosis II Autosomal recessive Stabilizing protein of the a-neurominidase (3-galactosidase complex... 

Patients with sialidosis show a striking syndrome characterized by action myoclonus, cerebellar ataxia and a macular cherry red spot similar to that in Tay-Sachs disease but with preserved intellect. 

Figure 4.2.2 depicts the urinary oligosaccharide patterns of sialidosis (a-neur-aminidase deficiency), GM1 gangliosidosis and mucopolysaccharidosis type IVB (/3-galaclosidase deficiency) compared to a normal urine and standards of raffinose, lactose and glucose. In patients with sialidosis, a densely staining band close to the... 

Fig. 4.2.2 TLC of urinary oligosaccharides. Left to right standards of raf-finose (lower), lactose (middle) and glucose (upper), sialidosis, GM1 gangliosidosis, mucopolysaccharidosis IVB and a control...

Thomas GH (2001) Disorders of glycoprotein degradation a-mannosidosis, / -mannosidosis, fucosidosis and sialidosis. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, vol III, 8th edn. McGraw-Hill, New York, pp 3507-3533... 

Three different rare genetic metabolic defects in sialic acid metabolism are known, as indicated in Fig. 4.3.2 [3, 21] (1) free sialic acid storage disease (SASD Online Mendelian Inheritance in Man, OMIM 604369, 269920), a lysosomal membrane transporter defect (2) sialuria (OMIM 269921), a feedback inhibition defect in sialic acid biosynthesis (3) sialidosis (OMIM 256550), a breakdown defect of sialyloli-gosaccharides caused by a defect of lysosomal sialidase. In all these genetic defects, an increased amount of sialic acid can be found in tissues and or body fluids, either bound to OGSs as in (3), or in its free state as in (1) and (2). 

SASD must be discriminated from other disorders of sialic acid storage [3] (1) sialidosis and galactosialidosis, defects respectively in lysosomal sialidase and both sialidase and /1-galactosidase. (OMIM 256550 and 256540) (2) nonlysosomal sialuria (OMIM 269921). 

Table 4.3.6 Normal and pathological values of sialidase and f-galactosidase activity in cultured fibroblasts of controls and patients with sialidosis or galactosialidosis...

Fig. 27.—Structure of Oligosaccharides Isolated from Sialidosis Urine (continued on pp. 192 and 93).,7,-,7e...

Compound 22 is a mono-antennary, lower-branch, sialo oligosaccharide, isolated in admixture with 21 from the urine of a patient with sialidosis. The 500-MHz, H-n.m.r. spectrum of the mixture is given in Fig. 20 the set of lower-intensity signals belongs to 22. The n.m.r. parameters for 22 are summarized in Table IX. For the interpretation of the n.m.r. spectrum, comparison with the spectra of 18 and 21 is appropriate. 

Compounds 36 and 37 are diantennary, monosialo oligosaccharides, each containing an a-(2- 3)-linked NeuAc group. They were obtained in a mixture (together with a small amount of 27) from the urine of a patient with sialidosis.52,72 The 500-MHz, H-n.m.r. spectrum of this mixture, containing 36 and 37 in the ratio of 3 1, is presented in Fig. 28. The n.m.r. data for both oligosaccharides are given in Table XI. 

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