Lysosomal Enzyme Deficiency

Lysosomal enzyme deficiencies, which frequently result in disease due to accumulation of the substrate for the missing enzyme, are suitable targets for enzyme replacement therapy (ERT). 

By taking advantage of the carbohydrate specificity of glycoprotein clearance and uptake, the attachment of carbohydrates to enzymes could provide a basis for rational, target organ-direeted, replacement-therapy, particularly for lysosomal-enzyme deficiencies. The attachment of the appropriate carbohydrate would promote the uptake of the enzyme by a particular tissue, or at least limit the sites where it would be cleared. The attachment of the carbohydrate might also improve the stability of the enzyme, both in the circulation and intracellularly. 

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)... 

Explain why lysosomal enzyme deficiencies and glycosaminoglycan accumulation result in clinical signs/symptoms. 

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

EC 3.1.6.1) is a lysosomal enzyme that hydrolyzes sulfuric acid ester bonds. The enzyme exists in two forms, arylsulfatases A and B, that differ in substrate specificity and in sensitivity toward inhibitors [142][143]. Human tissues contain more arylsulfatase A than arylsulfatase B. The natural substrates of these enzymes are complex lipids such as cerebroside 3-sulfate, and gly-cosaminoglycans such as chondroitin 4-sulfate and derman sulfate [144], Deficiencies of these enzymes are associated with a number of lysosomal disorders. 

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

Hurler syndrome (MPS type I) is caused by deficiency of a-iduronidase, a lysosomal enzyme involved In degradation of dermatan sulfate and heparan sulfate, which accumulate in the cells of all tissues and spill over into the urine. 

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. 

The biochemical defect In Tay-Sachs disease is an inherited deficiency of -hexosaminidase, a lysosomal enzyme responsible for hydrolysis ofGM2 ganglioside, which accumulates abnormally in the lyso-somes. 

Laronidase (Aldurazyme) is recombinant-L-idu-ronidase. In mucopolysaccharidosis I (Hurler syndrome) there is a deficiency of the lysosomal enzyme a -L-iduronidase. Laronidase is employed for the non-neurological manifestations of Hurler syndrome. After intravenous infusion laronidase is eliminated with a half-life of 1.5-3.6 hours. Infusion related side effects are seen frequently. Hypersensitivity reactions may occur. 

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