Chronic diarrhea and juvenile cataracts: think cerebrotendinous xanthomatosis and treat.

Cerebrotendinous xanthomatosis is an autosomal recessive disease of bile acid synthesis caused by 27-hydroxylase deficiency. Treatment with chenodeoxycholic acid normalizes cholestanol concentrations and abrogates progression of the disease. We present 4 patients with cerebrotendinous xanthomatosis within 1 family who were treated with chenodeoxycholic acid for 14 years. Two young sisters started treatment at the preclinical stage before the appearance of major symptoms. Their 2 older uncles, who had already developed the complete phenotypic form of cerebrotendinous xanthomatosis when diagnosed, commenced treatment at the same time as the sisters, thus establishing a natural control group. After 14 years of chenodeoxycholic acid therapy, the cholestanol levels of all 4 patients decreased to normal levels (<6 microg/mL). Both sisters remained asymptomatic. Only moderate improvement in symptoms was observed in their uncles. In this long-term study, prompt preclinical administration of chenodeoxycholic acid in early childhood completely prevented the cerebrotendinous xanthomatosis phenotype in 2 sisters. Pediatricians should be aware of this diagnostic possibility of cerebrotendinous xanthomatosis in children presenting with chronic diarrhea and juvenile cataracts. Prevention is particularly significant in light of the availability of early genetic diagnosis and the devastating effects of this illness if not treated.

Population screening in a Druze community: the challenge and the reward.

PURPOSE: The Druze community is characterized by consanguinity and endogamy, and by reluctance to genetic testing and technological interventions for the prevention of birth defects. Multiple patients with four rare and severe inborn errors of metabolism cerebrotendinous xanthomatosis, prolidase deficiency, argininosuccinate lyase deficiency, and carbamyl phosphate synthetase I deficiency were identified in an isolated Druze village in northern Israel. The aims of this study were to identify couples at risk for four inherited diseases, and to prevent birth defects in a community presenting religious and cultural obstacles to genetic testing. METHODS: A genetic screening and counseling program in a high-risk community. RESULTS: The 1425 residents who attended group genetic counseling sessions between 2003 and 2007 consented to genetic testing. We identified 217 carriers for either one or two disease causing mutations. High carrier frequencies for cerebrotendinous xanthomatosis, prolidase deficiency, argininosuccinate lyase deficiency, and carbamyl phosphate synthetase I deficiency were identified as 1:11, 1:21, 1:41, and 1:95, respectively. Fifty-eight percent (125) of the carriers' spouses agreed to genetic counseling and testing. Ten couples at risk for affected offspring were identified and offered prenatal genetic counseling and diagnosis. CONCLUSIONS: The genetic screening program, the first of its kind reported in a Druze community, was well received. We expect this program to increase awareness of genetic counseling, to contribute to disease prevention, and to serve as a model for other isolated communities.

Cockayne syndrome type II in a Druze isolate in Northern Israel in association with an insertion mutation in ERCC6.

Cockayne syndrome (CS) (OMIM #133540) is a rare autosomal recessive disease characterized by severe growth and developmental retardation, progressive neurological dysfunction and symptoms of premature aging. The underlying cause of the disease is a defect in transcription-coupled DNA repair, specifically the nucleotide excision repair (NER) pathway. To date, about half of the reported CS cases have an altered cellular response to UV resulting from mutations in either the CSA or the CSB genes. We have identified a large, highly consanguineous, Druze kindred descended from a single ancestor, with six CS cases. All six of them presented with the congenital severe phenotype that includes severe failure to thrive, severe mental retardation, congenital cataracts, loss of adipose tissue, joint contractures, distinctive face with small, deep-set eyes and prominent nasal bridge, and kyphosis. They had no language skills, could not sit or walk independently, and died by the age of 5 years. Cellular studies of the fibroblasts from three patients showed a significant defect in transcription-coupled DNA repair (TCR) and a marked correction of the abnormal cellular phenotype with a plasmid containing the cDNA of the ERCC6 gene. Molecular studies led to identification of a novel insertion mutation, c.1034-1035insT in exon 5 of the ERCC6 gene (p.Lys345Asnfs*24). This mutation was identified in 1:15 healthy individuals from the same village, indicating an extremely high carrier frequency. Identification of the causative mutation enables comprehensive genetic counseling among the population at risk from this village.

[Clinical, biochemical and molecular characterization of rare genetic disorders, related to nucleotide excision repair (NER) system].

All living organisms are equipped with DNA repair systems that can cope with a wide variety of DNA lesions. Among these repair pathways, nucleotide excision repair (NER) is quite versatile, involved in the removal of a variety of bulky DNA lesions induced by ultraviolet light and chemical carcinogens and mutagens. The importance of NER for human health is illustrated mainly by the occurrence of rare life-threatening disorders such as Xeroderma Pigmentosum (XP), Cockayne Syndrome (CS) and Trichthiodystrophy (TTD). XP, CS and most TTD patients exhibit increased sensitivity to UV light and premature aging. XP is associated with a high incidence of skin tumors, CS is primarily a developmental disorder associated with failure to thrive, and psychomotor retardation. The authors report the clinical, biochemical and molecular aspects of the NER pathway in individuals suspected to have a DNA repair, NER type-related disease. These diseases are rare worldwide, but are frequent in Israel, probably due to the high rate of consanguinity among certain Arab, Druze and Jewish populations. Our laboratory is the only one in Israel, and one of very few labs world-wide that is performing DNA repair evaluation as a diagnostic test for DNA repair-deficient inherited diseases. Identification of the causative genes and proteins in suspected families will facilitate accurate diagnosis, genetic counseling, identification of couples at risk and prenatal diagnosis.