INBORNERRORS OFSTEROLBIOSYNTHESIS

Abstract

The known disorders of cholesterol biosynthesis have expanded rapidly since the discovery that Smith-Lemli-Opitz syndrome is caused by a deficiency of 7-dehydrocholesterol. Each of the six now recognized sterol disorders-mevalonic aciduria, Smith-Lemli-Opitz syndrome, desmosterolosis, Conradi-Hünermann syndrome, CHILD syndrome, and Greenberg dysplasia-has added to our knowledge of the relationship between cholesterol metabolism and embryogenesis. One of the most important lessons learned from the study of these disorders is that abnormal cholesterol metabolism impairs the function of the hedgehog class of embryonic signaling proteins, which help execute the vertebrate body plan during the earliest weeks of gestation. The study of the enzymes and genes in these several syndromes has also expanded and better delineated an important class of enzymes and proteins with diverse structural functions and metabolic actions that include sterol biosynthesis, nuclear transcriptional signaling, regulation of meiosis, and even behavioral modulation.

Genetic testing in autism: how much is enough?

“…24 -26 Plasma sterol profiles are obtained in children suspected to have Smith-Lemli-Opitz syndrome (SLOS) or as a screening test. It has been reported that SLOS may present as autism in rare cases, 27,28 although a more recent study did not confirm these initial findings. 29 For children who lack speech, DNA methylation analysis is performed to exclude Angelman syndrome, with sequencing of the Angelman gene (UBE3A ligase) in classic cases if a normal pattern of DNA methylation is found.…”

Abnormalities of cholesterol metabolism in autism spectrum disorders

“…This is consonant with the epidemiology of SLOS and the distribution of DHCR7 alleles. As described by Kelley and Herman [2001], at least 80% of DHCR7 mutations are null …”

“…SLOS has a wide spectrum of clinical and biochemical severity, from functionally normal individuals to malformed fetuses that die in utero [Lowry and Yong, 1980;Kelley and Hennekam, 2000]. Although the combined carrier frequency for several common DHCR7 null alleles of about 1.25% predicts an incidence of 1 in 25,000 births in European-derived populations, about 50% of conceptuses appear to be lost early in pregnancy [Kelley and Herman, 2001]. Most SLOS individuals who survive the newborn period are compound heterozygotes for a common DHCR7 null mutation and a milder missense mutation, whereas the most mildly affected SLOS individuals carry two missense alleles with residual DHCR7 activity.…”

Cholesterol homeostasis in development: The role of Xenopus 7‐dehydrocholesterol reductase (Xdhcr7) in neural development

“…Furthermore, the highest expression of Xdhcr7 was detected by RT-PCR analysis from early gastrulation to early organogenesis stages, a time-window during which different tissue and organ identities are established. The general role of cholesterol in embryonic development is well described (Wolf, 1999;Moebius et al, 2000;Roux et al, 2000;Kelley and Herman, 2001). The early expression of Xdhcr7 is in accordance with the multiple developmental defects reported in DHCR7 mutations (Porter, 2000;Waterham and Wanders, 2000;Nowaczyk and Waye, 2001;WitschBaumgartner et al, 2001;Ciara et al, 2004), since the reported phenotypes may result from a failure of early patterning events.…”

“…Accumulating data provides evidence for a pivotal role played by cholesterol in development and pattern formation, mainly through its involvement in the maturation and transduction of the Hedgehog signal (Porter et al, 1996;Kuwabara and Labouesse, 2002;McCarthy et al, 2002;McCarthy and Argraves, 2003). Disorders of cholesterol biosynthesis are among the most severe human genetic diseases, since they are all characterised by dysmorphogenesis of multiple organs (Moebius et al, 2000;Kelley and Herman, 2001;Nwokoro et al, 2001;Cooper et al, 2003). The de novo cholesterol biosynthesis involves more than 30 enzyme-catalysed reactions, of which the NADPH-dependent reduction of hydroxymethyl glutaryl coenzyme A is rate limiting (Herman, 2003).…”