Mutational Analysis of a Patient with Concomitant Cerebrotendinous Xanthomatosis and Smith-Lemli-Opitz Syndrome

Cerebrotendinous Xanthomatosis (CTX) is a rare recessively inherited disorder of bile acid synthesis caused by mutations in the sterol 27-hydroxylase gene (CYP27) located on human chromosome 2. The disease is characterized by tendon xanthomatosis, juvenile cataracts and progressive neurological dysfunction. Smith-LemliOpitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol metabolism caused by mutations in the gene for ∆-dehydrocholesterol reductase in chromosome 11. It is characterized by congenital malformations, mental retardation, dysmorphism of multiple organs, and delayed neuropsycomotor development. A patient was discovered with clinical history and signs consistent with CTX. Elevated levels of cholestanol were found using biochemical analysis, which confirmed the CTX disease. Elevated levels of 7-DHC consistent with SLOS were also found. To elucidate the molecular basis for this unusual biochemistry, we screened the CYP27 and DHCR7 genes for mutations. Genomic DNA was extracted from the patient’s blood and used to perform PCR amplification and sequencing of exons 1-9 and 3-9 for CTX and SLOS respectively, intron-exon boundaries. For CTX, we identified a previously reported 2 bp deletion in exon 6 (∆2bpC1201) and a novel mutation G276C in exon 1 that affects the splice site. Although no mutations were observed in DHCR7 gene, several polymorphisms were found in exon 6 at C703T (D146D), exon 9 at C1423T (D386D) and T1537C (G424G). Thus we have a genetic and biochemical configuration of CTX in our patient. There were no mutations identified in the DHCR7 gene. Our interpretation for the elevated 7DHC of presentation is that the upregulation of cholesterol biosynthesis resulted in an excess production of the precursors. Introduction Cerebrotendinous Xanthomatosis (CTX) is a rare, recessively inherited disorder of bile acid synthesis. CTX was first described in 1937 in individuals with neurological dysfunction and tendon xanthomas. Later studies demonstrated that cholesterol and the 5α-reduced form of cholesterol, cholestanol accumulate in neural and other tissues of CTX subjects [1]. CTX is caused by mutations of the mitochondrial enzyme sterol 27-hydroxylase (CYP27), located on human chromosome 2 [1, 2]. Clinical features include tendon xanthomas, juvenile cataracts, and nervous system dysfunction, i.e. mental retardation, behavioral and psychiatric problems, pyramidal tract paresis, cerebellar ataxia, and peripheral neuropathy. Other common features include osteoporosis, bone fractures, chronic diarrhea in children and premature atherosclerosis [2]. Long term bile acid therapy with Chenodeoxycholic acid (CDCA), the most deficient biliary bile acid, decreased cholestanol levels and improved neurologic function in most CTX subjects. More than 250 incidents of CTX have been discovered throughout the world [2]. About 37 different mutations of the