Mucolipidosis deficiency

Pseudo-Hurler polydystrophy (mucolipidosis III, ML-III) is related to l-cell disease, but cells of these patients retain some activity of the deficient enzyme. 

The answer is D. As this patient ages, a variety of skeletal defects and short stature that are consistent with a lysosomal storage disease (mucolipidosis), either I-cell disease or pseudo-Hurler polydystrophy, are developing. Both diseases arise from a deficiency of an enzyme involved in synthesis of the Man-6-P marker on lysosomal enzymes. Such misaddressed proteins are secreted rather than trafficked to the lysosomes. The degradative function of lysosomes is impaired as a result and the organelles tend to accumulate waste products (hence, the term storage disease ). It is these inclusion bodies or dense structures that would be visible by microscopic examination of the patient s cells in a biopsy specimen. 

Fig. 4.1.9 Electrophoresis pattern of different types of MPS (indicated beneath the corresponding band). Standards (STD) and normal controls (N) were also run on each gel. GAGs are labeled on the left side of the figure. The picture was kindly provided by Dr. E Buerger, Metabolic Center Heidelberg, Germany. GM1 GM1-gangliosidosis, MSD multiple sulfatase deficiency ML II mucolipidosis II, LZ loading zone of the gel...

For disorders characterized by an underlying enzyme deficiency (e.g., Gaucher disease, Fabry disease, Tay-Sachs, Hurler syndrome), assays of enzyme activity in blood and/or tissues is generally available (Meikle et al., 2004). Mutation analysis is also available, particularly for populations in whom the common disease alleles are known (e.g., mutations among Ashkenazi Jews for Gaucher, Tay-Sachs, Niemann-Pick type A, and mucolipidosis type IV Ostrer, 2001). In other cases, analysis of the gene defect responsible for rare subtypes is available through specialized laboratories. 

Fucosidosis, being a so-called mucolipidosis, can be grouped among the mucopolysaccharidoses. It is due to a-fucosidase deficiency (localized on chromosome Ip 34). The storage products are deposited in the form of granular or lamellar inclusions in the lysosomes. This autosomal recessive disorder was first observed by P. Durand et al. in 1967 and clarified by F. Van Hoof et al. in 1968. Besides hepatomegaly, splenomegaly may also sometimes occur. 

By cell fusion and a new single cell hydrolase assay technique, the complementation was observed between mucolipidosis II and two other hereditary lysosomal 3-D-galactosidase-deficient disorders in humans Gj j-gangliosidosis type II and /3-D-galactosidase deficient-type mucolipidosis. The possible mechanisms with which abnormal ML-II jS-D-galactosidase was modified and normalized by the other two different cell strains were discussed. 

Fibroblasts, cultured from the skin of patients with the genetic diseases mucolipidosis I and mucolipidosis II, were found to be deficient in a neuraminidase specific for both (2 3) and (2 6) linkages of a-neuraminosyl groups in... 

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. 

Mucolipidosis I has been shown to be associated with the excretion of O- and A -glycopeptides, a finding which is in agreement with a report on a neuraminidase deficiency for this disease. 360 MHz H N.m.r. spectra have been recorded for ten urinary sialyl-oligosaccharides isolated from patients with mucolipidosis I and II, 3 -sialyl-lactose has been isolated from normal... 

Mucolipidosis 11 (1-cell disease) N-acetylglucosamine 1-phosphotransferase (secondary multiple lysosomal enzyme deficiencies) 4q21-q23 252500... 

The diagnosis of oligosaccharidoses and related disorders relies upon the assay of the deficient enzymatic activities. For all of them DNA analysis is also available and, if required, can be used. For mucolipidosis IV an enzymatic assay is not available, but molecular analysis is feasible and can be ... 

The isolation of kallikrein (mol. wt. 3.2 x 10 ), a protease that releases kinin from kininogen, from rat urine has been reported. Kallikrein contains five residues of 2-amino-2-deoxy-D-glucose per molecule. Excessive amounts of oligosaccharides rich in sialic acid have been detected in the urine of patients with I-cell disease or mucolipidosis, indicating that there is a deficiency of a-neuraminidase in these diseases. ... 

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... 

Messer 1979). This gene dosage effect indicated that the neuraminidase deficiency was primary. A similar neuraminidase deficiency was demonstrated in an infant with clinical symptoms suggestive of mucolipidosis I (Kelly and Graetz 1977) and in patients with nephrosialidosis , a combination of the symptoms of mucolipidosis I with renal disease (Maroteaux etal. 1978 a). In these patients, there was likewise a massive excretion of sialyloligosaccharides in the urine. 

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). 

Bach, G., Zeigler, M., Shaap, T., and Kohn, G., 1979, Mucolipidosis Ganglioside sialidase deficiency, Biochem. Biophys. Res. Commun. 90 1341-1347. 

---