Hurler disease

Fig. 9. Pfaundier-Hurler disease. Liver. EnlargemeDt 210-fold. Liver cells store glycogen and show a light, slightly ballooned cytoplasm. KupfPer cells (middle) store a glycolipid which is PAS-positive.

Pig. 10. Pfaundler-Hurler disease, infantile form. Ballooning of the ganglion cells of the cerebrum and storage of protein-bound gangliosides. (Reproduced by courtesy of Prof. P. B. Diezel)... 

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... 

Pseudo-Hurler polydystrophy is another genetic disease closely related to I-ceU disease. It is a milder condition, and patients may survive to adulthood. Smdies have revealed that the GlcNAc phosphotransferase involved in I-cell disease has several domains, including a catalytic domain and a domain that specifi-... 

Mucolipidosis type 11 (I-cell disease) Mucolipidosis type IIIA (pseudo-Hurler s)... 

Gaucher s disease type I Fabry s disease Hurler s disease Pompe s disease Hurler s syndrome... 

Krivit, W., Peters, C. and Shapiro, E. G. Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachro-matic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. Curr. Opin. Neurol. 12 167-176,1999. 

Several disorders that lead to Impaired lysosome function Include the mucolipidoses l-cell disease and pseudo-Hurler polydystrophy. 

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. 

First described in 1919 by Hurler, mucopolysaccharidosis I (MPS I, the Hurler syndrome) leads to accumulation of partially degraded dermatan and heparan sulfates (Fig. 4-11).317,352 353 A standard procedure in the study of diseases of this type is to culture fibroblasts from a skin biopsy. Such cells cultured from patients with the Hurler syndrome accumulate the polysaccharide, but when fibroblasts from a normal person are cultured in the same vessel the defect is "corrected." It was shown that a protein secreted by the normal fibroblasts is taken up by the defective fibroblasts, permitting them to complete the degradation of the stored polysaccharide. 

Some hereditary diseases are characterized by lack of two or more lysosomal enzymes. In I-ceII disease (mucolipidosis II), which resembles the Hurler syndrome, at least ten enzymes are absent or are present at much reduced levels.350,361 The biochemical defect is the absence from the Golgi cisternae of the N-acetylglucosaminyl phosphotransferase that transfers P-GlcNAc units from UDP-GlcNAc onto mannose residues (Eq. 20-22) of glycoproteins marked for use in lysosomes. 

Lysosomal storage abnormalities, such as glycogenosis (Pompe s disease). Tay-Sachs, Krabbe s. Gaucher s, and Fabry s diseases, as well as melachromatic leukodystrophy, aspariylgiycosaminuria, and Niemann-Pick disease. Also included in this category are mucopolysaccharidoses. Hunter s, Scheie s, and Hurler s syndromes. 

The deficiency of any lysosomal enzyme results in accumulation of its substrate in lysosomes. Some of these diseases include Hurler syndrome, Hunter syndrome, I-cell disease, Niemann-Pick disease,... 

Komfeld, S., and Sly, W. S. (1995) I-Cell Disease and Pseudo-Hurler Polydystrophy Disorders of Lysosomal Enzyme Phosphorylation and Localization, in The Metabolic and Molecular Bases of Inherited Disease, 7th ed., ed. C. R. Scriver A. L. Beaudet, W S. Sly, and D. Valle, McGraw-Hill, New York, pp.2495-2508. 

There are numerous inherited disorders of lysosomal metabolism in humans. These disorders result from the lack of a specific acid hydrolase and have several clinical manifestations. A variety of substances may accumulate that interfere with normal cell functions, as is the case with the lipidoses (Chapter 9) or mucopolysaccharides (glycosaminoglycans) in the Hurler s disease (gargoylism). 

I-cell disease is suspected clinically by the phenotype and is confirmed biochemically (cf. Biochemical Perspectives section). The infant with I-cell disease is usually small for gestational age and is clinically differentiated from having Hurler s syndrome by earlier onset of signs and symptoms, the absence of excessive mu-copolysacchariduria, short stature, and the rapidly progressive course, leading to death usually by age 4 years. 

By 6 months of age, psychomotor retardation is usually obvious. Joint immobility progresses with development of claw-hand deformities and kyphoscoliosis. Hepatomegaly is prominent, but splenomegaly is minimal. Corneal haziness may be present but is subtle, and corneal opacities due to the accumulation of storage material are not as striking as in Hurler syndrome. Examination of peripheral blood smears reveals the presence of abnormal inclusions in cells such as lymphocytes, and increased lysosomal enzyme activity in whole blood as well as cultured fibroblasts is confirmatory of I-cell disease. 

Biochemically, I-cell disease is characterized by excessive secretion of newly synthesized lysosomal enzymes into body fluids and concomitant loss of respective intracellular activities in fibroblasts. Shown in Table 17-1 are representative lysosomal enzyme activity levels in serum from patients with I-cell disease and those with the closely related disorder pseudo-Hurler poly dystrophy, indicating significantly increased levels of lysosomal enzyme activity. Germane to the biochemical diagnosis is the characteristic pattern of lysosomal enzyme deficiency in cultured fibroblasts, that is, an increase in the ratio of extracellular to intracellular enzyme activity (Table 17-2). It is interesting to note that not all lysosomal (i.e. intracellular)... 

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