Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease characterized by multiple episodes of cholestasis without progression to chronic liver disease. The gene was previously assigned to chromosome 18q21, using a shared segment analysis in three families from the Netherlands. In the present study we report the linkage analysis of an expanded sample of 14 BRIC families, using 15 microsatellite markers from the 18q21 region. Obligate recombinants in two families place the gene in a 7-cM interval, between markers D18S69 and D18S64. All intervening markers had significant LOD scores in two-point linkage analysis. Moreover, we identified one family in which the BRIC gene seems to be unlinked to the 18q21 region, or that represents incomplete penetrance of the BRIC genotype. IntroductionBenign recurrent intrahepatic cholerstasis (BRIC) is a rare autosomal recessive liver disease (De Koning et al. 1995) characterized by intermittent attacks of cholestasis without extrahepatic bile duct obstruction (Summerskil and Walshe 1959;Brenard et al. 1989). Each cholestatic attack starts with rising serum bile acid levels, usually followed by hyperbilirubinemia and overt cholestasis (Bijleveld et al. 1989;Brenard et al. 1989). The attacks vary in duration (weeks to months) and resolve spontaneously. No biochemical abnormalities are found in patients between attacks. The initial episode can occur at any age from infancy to adulthood, although most patients present before the age of 25 years. The frequency of attacks varies from several times a year to less than once per decade (Brenard et al. 1989). Progression to chronic liver disease has not been observed, but cholestatic episodes result in substantial morbidity, including pronounced weight loss and deficiency of fat-soluble vitamins. No established treatment is available, although cholestyramine may alleviate symptoms in some patients. Development of an effective therapy is hampered because the basic defect in BRIC is unknown.The gene for BRIC was originally mapped to chromosome 18q21 through the identification of a shared chromosomal segment in three distantly related patients from an isolated community in the Netherlands (Houwen et al. 1994). The region shared in these patients extended from D18S363 to D18S55, a genetic distance of more than 20 cM. To facilitate future molecular genetic studies we subsequently started to delimit the region of interest by studying additional BRIC families with a more densly spaced set of markers. We now present an analysis of 14 BRIC families from different ethnic sources with microsatellites selected primarily from the Généthon map, with the addi- Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64
Two male relatives with Fabry disease presented striking differences in clinical symptoms and age of onset. The propositus had retarded statural growth and skeletal dysplasia while his nephew suffered mainly from aggravating acroparesthesia and celiac disease. Fabry disease is an X-linked inborn error of glycosphingolipid metabolism resulting from deficient activity of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal A) enzyme. The alpha-Gal A gene is located at Xq22.1. Efforts to establish genotype-phenotype correlations have been limited because most patients have private mutations. In previous clinical studies performed in families with Fabry disease, marked differences in phenotype are described between affected relatives. This family also demonstrates the difficulty in predicting the clinical phenotype in patients and relatives with the same alpha-Gal A mutation. Furthermore, in the absence of a family history, the diagnosis may be easily missed.
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