Abstract

1. I-cell disease (mucolipidosis II, or ML-II) and pseudo-Hurler polydystrophy (mucolipidosis III, or ML-III) are related genetic diseases, with rare occurrence and autosomal recessive inheritance.

   
   

2. I-cell disease shows many of the clinical and radiographic features of Hurler syndrome but presents earlier and does not show mucopolysacchariduria. There is severe progressive psychomotor retardation, and death usually occurs in the first decade. Pseudo-Hurler polydystrophy is milder and presents later, and survival into adulthood is possible.

   
   

3. In both diseases, there is abnormal lysosomal enzyme transport in cells of mesenchymal origin. In these cells, newly synthesized lysosomal enzymes are secreted into the extracellular medium instead of being targeted correctly to lysosomes. Affected cells show dense inclusions filled with storage material, and lysosomal enzymes are present at elevated levels in the serum and body fluids of affected patients.

   
   

4. In normal cells, targeting of lysosomal enzymes to lysosomes is mediated by receptors that bind mannose 6-phosphate recognition markers on the enzymes. The recognition marker is synthesized in a two-step reaction in the Golgi complex, and it is the enzyme that catalyzes the first step in this process, UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosaminyl-1-phosphotransferase, which is defective in ML-II and ML-III.

   
   

5. The phosphotransferase is a low-abundance, membrane-bound enzyme complex of three subunits (α₂β₂γ₂) that are the products of two genes. Biochemical studies suggest that the enzyme possesses two domains, one of which is associated with its catalytic activity and the other with the specific recognition of lysosomal enzymes.

   
   

6. A variety of defects have been described in the genes encoding phosphotransferase. Fibroblasts from four patients with ML-II had no detectable transcript for the α/β subunit, and two patients with ML-III, complementation group A, had greatly reduced levels of this transcript. Both groups had the transcript for the γ-subunit gene. Patients from three families with ML-III, complementation group C, had a frameshift mutation in the γ-subunit gene. Their mutant enzyme is catalytically active but is defective in recognizing lysosomal enzymes as substrates.

   
   

7. While all cells and tissues of affected individuals are deficient in phosphotransferase activity, not all cells are deficient in lysosomal enzyme content. This indicates that some cell types have mannose 6-phosphate-independent pathway(s) that function in the transport of lysosomal enzymes. The nature of the alternate pathway(s) in these cell types is unknown.

   
   

8. Diagnosis of ML-II and ML-III can be made biochemically by estimation of serum lysosomal enzyme levels. The characteristic pattern of enzyme deficiencies in fibroblasts also can be used, as can the ratio of extracellular to intracellular enzyme activities. The phosphotransferase activity also can be measured. In general, ML-II and ML-III must be distinguished on clinical criteria and on progression of the disease. Prenatal diagnosis is reliable, and carrier detection is also possible.

   
   

9. There is no definitive treatment.

   
   

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