I cell disease

Man 6-P receptors, located in the Golgi apparatus, bind the Man 6-P residue of these enzymes and direct them to the lysosomes. Fibroblasts from patients with I-cell disease (see below) are severely deficient in the activity of the GIcNAc phosphotransferase. 

I-Cell Disease Results From Faulty Targeting of Lysosomal Enzymes... 

As indicated above, Man 6-P serves as a chemical marker to target certain lysosomal enzymes to that organelle. Analysis of cultured fibroblasts derived from patients with I-cell (inclusion cell) disease played a large part in revealing the above role of Man 6-P. I-cell disease is an uncommon condition characterized by severe progressive psychomotor retardation and a variety of physical signs, with death often occurring in the first decade. Cultured cells from patients with I-cell disease were found to lack almost all of the normal lysosomal enzymes the lysosomes thus accumulate many different... 

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-... 

Scriver CR et al (editors) The Metabolic and Molecular Bases of In-heritedDisease, 8th ed. McGraw-Hill, 2001.(Various chapters in this text give in-depth coverage of topics such as I-cell disease and disorders of glycoprotein degradation.)... 

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)... 

Methylmalonic aciduria (Bi2-reslstant) Mucolipidosis II (I-cell disease) Nlemann-Plck disease Sandhoff disease... 

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

Hickman, S. and Neufeld, E. F. A hypothesis for I-cell disease defective hydrolases that do not enter lysosomes. Biochem. Biophys. Res. Commun. 49 992-999,1972. 

Lysosomal enzymes phosphorylation of mannose by phosphotransferase in Golgi I-cell disease... 

Answer A. Characteristic symptoms of I-cell disease. Note release of lysosomal enzymes into serum, which would not be seen in the other deficiencies. 

Sphingolipids released when membrane is degraded are digested in endosomes after fusion with lysosomes. Lysosomes contain many enzymes, each of which removes specific groups from individual sphingolipids. Genetic deficiencies of many of these enzymes are known, and the diseases share some of the characteristics of I-cell disease discussed in Chapter 4. Table 1-16-1 summarizes these. 

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. 

For cells with /1-galactosidase deficiency (GM1 gangliosidosis or Morquio type as well as I-cell disease), the measured enzyme activity will be significantly lower than the true enzyme activity. In addition, cases of multiple sulfatase deficiency will also show low N-acetylgalactosamine-6-sulfatase activity. Therefore, arylsulfatase A or another sulfatase, as well as /1-galactosidase activities should also be determined in case of suspicious results. To exclude poor sample quality, the determination of a-mannosidase is recommended. 

To exclude I-cell disease in cases of low jS-galactosidase activity, this enzyme should also be assessed in serum. Furthermore, to evaluate the quality of the material it is recommended to determine the activity of a-mannosidase. 

In cases of low -glucuronidase activity, the activity of this enzyme in serum should also be assessed to avoid missing I - cell disease. 

Explain why fibroblasts from a patient with I-cell disease secrete lysosomal enzymes when grown in tissue culture. 

Patients with I-cell disease do not phosphorylate the mannose residues on the glycoproteins that are lysosome-bound. These lysosomal hydrolases are therefore secreted. 

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. 

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. 

Figure 17-1. A 9-month-old Hispanic male infant with I-cell disease. From the Division of Medical Genetics, Children s Hospital, Los Angeles.

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. 

Radiographically, I-cell disease is manifested in two successive stages of infancy, one... 

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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