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Mucolipidosis IIIC (MLIIIC) is a rare autosomal recessive lysosomal storage disease resulting from defective mannose 6-phosphate-dependent lysosomal enzyme trafficking; mutations of the γ subunit of N-acetylglucosamine-1 phosphotransferase (GINAcPT) were recently found to cause its pathogenesis. We report here for the first time prenatal diagnosis (PND) for MLIIIC by means of chorionic villous sampling (CVS). A fetus in a large Bedouin-Moslem family was found to be homozygous for the founder haplotype and the mutational SSCP pattern of MLIIIC. The diagnosis was confirmed by markedly reduced lysosomal enzyme activities in cultured chorionic villi. The molecular identification of the disease-causing mutation in this large Bedouin-Moslem kindred permitted, for the first time, identification of carriers and couples at risk. The feasibility of early PND for a progressive disabling disease is important for its prevention. Nevertheless, the feasibility of PND raises a serious dilemma since affected individuals might have a variable phenotype and the disease is progressive and non-lethal. In addition, religious and social constraints are important factors to be taken into consideration in the genetic counseling of couples at risk. Copyright © 2003 John Wiley & Sons, Ltd.

Wolman disease results from an inherited deficiency of lysosomal acid lipase (LAL; EC 3.1.1.13). This enzyme is essential for the hydrolysis of cholesteryl esters and triacylglycerols derived from endocytosed lipoproteins. Because of a complete absence of LAL activity, Wolman patients accumulate progressive amounts of cholesteryl esters and triacylglycerols in affected tissues. To investigate the nature of the genetic defects causing this disease, mutations in the LAL gene from three subjects of Moslem-Arab and Russian descent living in Israel were determined. Two homozygotes for a novel 1-bp deletion introducing a premature in-frame termination codon at amino acid position 106 (S106X) were identified. A third subject was a homozygote for a G-5R signal peptide substitution and a G60V missense mutation. The functional significance of these mutations was tested by in vitro expression of single and double mutants in Spodoptera frugiperda cells. Single mutants G60V and S106X and double mutant G-5R/G60V displayed a virtual absence of lipase activity in cell extracts and culture medium. Signal peptide mutant G-5R retained lipase activity in cell extracts and showed a drastically reduced enzyme activity in culture supernatant, indicating that the mutation may affect secretion of active enzyme from cells. These results support the notion that Wolman disease is a genetically heterogeneous disorder of lipid metabolism.

Analysis of Ashkenazi families with Hunter patients in Israel demonstrated the complete absence of new mutations among the probands' mothers. Furthermore, in these families a significant deviation of the segregation ratio between the Hunter gene and the normal allele was demonstrated among offspring of heterozygous mothers or siblings of affected children. This may be due to pre- or postzygotic prenatal selection, favoring the X chromosome carrying the Hunter gene among Ashkenazi Jews.

The cellular localization of glycoprotein and ganglioside sialidases in normal and I-cell-disease cultured fibroblasts has been investigated. Cellular organelles have been separated on a colloidal silica gradient. The subcellular distribution of these enzymes indicated that the glycoprotein sialidase is mainly a lysosomal hydrolase, whereas the ganglioside sialidase is primarily located in the plasma membranes. The latter isoenzymes is tightly bound to these membranes and thus could not be extracted by homogenization in the presence of Triton X-100. The interpretation of this finding and its relation to the pathochemistry of sialidase-deficient disorders is discussed.

Among all the Jewish families with Hunter patients in Israel, 10 were Ashkenazi or Moroccan in origin. In those families, there was a paucity of new mutations. In addition, a significant deviation of the segregation ratio between the Hunter gene and the normal allele was demonstrated among the offspring of heterozygous mothers or siblings of affected children in these families. These results confirm and extend our previous observations suggesting selection in favor of the X chromosome carrying the Hunter allele among Ashkenazi and Moroccan Jews.

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