The Neuraminidase Defect

In a patient classified as mucolipidosis I, Ckmzetal (1977) and Spranger /. (1977) demonstrated a severe deficiency of an acid neuraminidase (sialidase N-acetyl neuraminic acid hydrolase, E.C. 3.2.1.18) in his cultured fibroblasts. The patient had a neurodegenerative disorder with myoclonus, skeletal changes like in Hurler disease, and cherry-red spots in the maculae of his eyes. In addition to the neuraminidase defect, the fibroblasts of the patient accumulated abnormal amounts of sialic acid-containing compounds. The patient excreted excessive quantities of sialyloligosaccharides in the urine (Michalski etal 1977). Fibroblasts from the parents of another such patient had activities of neuraminidase which were intermediate between patients and controls (Cantz and... 

It should be remembered, that a defect of lysosomal neuraminidase is likely to be the immediate cause of I-cell disease, but the fundamental error is in the phosphorylation of several hydrolases, of which the neuraminidase will simply be the first to act in normal degradation. 

In addition to these two types of sialidosis, there are patients with a combined defect of neuraminidase and p-galactosidase (Wenger etal. 1978, Andria etal. 1978, OK.ADAetal. 1979), possibly caused by a common defect in the biosynthetic processing of the two enzymes (Hoogeveen etal. 1980). A neuraminidase deficiency has also been observed in patients with mucolipidosis II (I-cell disease) and mucolipidosis III (Strecker etal. 1976, Thomas etal. 1976). In these disorders, however, the neuraminidase deficiency is but one of many lysosomal hydrolase deficiencies, presumably due to a defect in the proper compart-mentalization of these enzymes (Neufeld 1974). 

The combined p-galactosidase/neuraminidase deficiency, on the other hand, presents a clinical picture which seems intermediate in severity between the mild and severe forms of isolated neuraminidase deficiency. Whereas it is not yet clear whether the neuraminidase deficiency in this disorder is secondary to an unknown processing defect, a defect in such a mechanism has been shown to be responsible for the deficiency of numerous lysosomal hydrolases, including neuraminidase, in patients with mucolipidoses II and III. 

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... 

Figure 6.5 Transferrin glycoform patterns for serum samples from CDG-II patients by HPLC. HPLC traces for (a) a control serum sample from a light drinker (solid line) and from a heavy drinker with elevated asialo- and disialotransferrin and a measurable monosialotransferrin (broken hne), (b, c) serum samples from two CDG-II patients with uncharacterized defects showing elevated mono- and trisialotransferrin and a reduced tetrasialotransferrin, and also two unknown peaks (A and B) and (e) a control serum before, and at different times after, treatment with neuraminidase. Parts (a), (b) and (d) reproduced from A. Helander, J. Bergstrom and H.H. Freeze, Clin. Chem., 50, 954-958 (2004), by permission of the American Association of Chnical Chemistry...

These allowed distinction between types of neuraminidase activities. Results confirmed, inter alia, the hypothesis of a specific defect of a-(2 -> 6)-neuramini-dase in the case of a sialidosis B. 

Neuraminidase Deficiency. A simple defect in lysosomal neuraminidase has only recently come to light (Lowden and O Brien, 1979 Kuriyama etal, 1979). Patients with this storage disease put out sialo-oligosaccharides in their urine. Fibroblasts from the patient of Kuriyama et al, (1979) showed an extreme deficiency in neuraminidase activity towards a2,3-sialyl lactose, a2,6-sialyl lactose and fetuin. Hence more than one enzyme might be involved. 

The fibroblasts from a patient with mucolipidosis I were found to be severely deficient in an acid neuraminidase. Since normal levels of other glycoside hydrolases were found, the basic metabolic lesion appears to involve a defect in the degradation of compounds containing 5-acetamido-3,5-dideoxy-D-gf/yc ro-D-galacto-nonxxiosonic acid. 

One possibility is impaired liberation of N-acetyl-galactosamine as proposed by Svennerholm (1957b). A defective removal of a carbohydrate moiety from a mono-sialoganglioside is also assumed by Rouser et al. (1965), since other gangliosides can be degraded to the Tay-Sachs ganglioside by neuraminidase. 

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