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Chapter 138

### Abstract

1. I-cell disease (mucolipidosis II, or ML-II alpha/beta) and pseudo-Hurler polydystrophy (mucolipidosis III, or ML-III alpha/beta and ML-III gamma) 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 developmental delay, 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 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 plasma 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-acetylglucosamine-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 α/β subunits mediate the catalytic activity and the specific recognition of lysosomal enzymes, while the γ subunits facilitate the phosphorylation of a subset of lysosomal enzymes.

6. Over 125 mutations in the GNPTAB gene and 24 mutations in the GNPTG gene have been identified to date. Almost all patients with ML-II have nonsense, frameshift, or splice site alterations in GNPTAB (ML-II alpha/beta), whereas ML-III alpha/beta patients carry missense mutations or at least one hypomorph allele resulting in residual phosphotransferase activity. The majority of the ML-III gamma patients have splicing, deletions or insertions or nonsense mutations in the GNPTG gene.

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 pathways that function in the transport of lysosomal enzymes. The nature of the alternate pathways in these cell types is incompletely understood.

8. Diagnosis of ML-II and ML-III can be made biochemically by estimation of plasma 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. Sequencing of the GNPTAB and GNPTG coding regions detects disease-causing mutations in over 95% of patients. In general, ML-II and ML-III can be distinguished on clinical criteria and on progression of the disease. Prenatal diagnosis of at-risk pregnancies is dependent on prior identification of disease-causing mutations in the family. Carrier detection is also possible.

9. There is no definitive treatment.

In 1967, a disease was described that resembled the Hurler syndrome but ...

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