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• CTX causes neurologic disease which can be prevented with chenodeoxycholate. • Sitosterolemia causes premature ASCVD which can be prevented with ezetimibe. • SLOS causes mental disability which can be treated with diet and bile acids. • Gerald Salen (1935–2020) developed treatments for CTX, sitosterolemia, and SLOS. Cerebrotendinous xanthomatosis (CTX), sitosterolemia, and Smith-Lemli Opitz syndrome (SLOS) are rare inborn errors of metabolism. The diagnoses of CTX and sitosterolemia are often delayed for many years because of lack of physician awareness, often resulting in significant and unnecessary progression of disease. CTX may present with chronic diarrhea, juvenile onset cataracts, strikingly large xanthomas, and neurologic disease in the setting of a normal serum cholesterol, but markedly elevated serum or plasma cholestanol levels. These patients have a defect in producing the bile acid chenodoxycholate, and oral chenodeoxycholate therapy is essential for these patients in order to prevent neurologic complications. Sitosterolemia can present with xanthomas, anemia, thrombocytopenia, splenomegaly, very premature heart disease, and serum cholesterol levels that may be normal or elevated, along with marked elevations of plasma β-sitosterol. These patients have a defect causing overabsorption of β-sitosterol, and the treatment of choice is oral ezetimibe. SLOS presents with growth delay, intellectual disability, multiple structural anomalies, and low serum cholesterol levels, and the defect is reduced cholesterol production. Treatment consists of dietary cholesterol supplementation and oral bile acid therapy which raises serum cholesterol levels and may improve symptoms. The metabolic and genetic defects in these disorders have been defined. There is no one in our field that has contributed more to the diagnosis and treatment of these disorders than Gerald Salen, MD, who died in late 2020 at 85 years of age. He will be greatly missed by his family, friends, and colleagues from around the world. [ABSTRACT FROM AUTHOR]

Abstract: Data obtained from recent studies in humans, rodents, and cell culture demonstrate that circulating maternal cholesterol can be transported to the fetus. The two major cell types responsible for the transport are trophoblasts and endothelial cells of the fetoplacental vasculature. Maternal lipoprotein-cholesterol is initially taken up by trophoblasts via receptor-mediated and receptor-independent processes, is transported by any number of the sterol transport proteins expressed by cells, and is effluxed or secreted out of the basal side via protein-mediated processes or by aqueous diffusion. This cholesterol is then taken up by the endothelium and effluxed to acceptors within the fetal circulation. The ability to manipulate the mass of maternal cholesterol that is taken up by the placenta and crosses to the fetus could positively impact development of fetuses affected with the Smith-Lemli-Opitz Syndrome (SLOS) that have reduced ability to synthesize cholesterol and possibly impact growth of fetuses unaffected by SLOS but with low birthweights. [Copyright &y& Elsevier]

Disorders of androgen production can occur in all steps of testosterone biosynthesis and secretion carried out by the foetal Leydig cells as well as in the conversion of testosterone into dihydrotestosterone (DHT). The differentiation of Leydig cells from mesenchymal cells is the first walk for testosterone production. In 46,XY disorders of sex development (DSDs) due to Leydig cell hypoplasia, there is a failure in intrauterine and postnatal virilisation due to the paucity of interstitial Leydig cells to secrete testosterone. Enzymatic defects which impair the normal synthesis of testosterone from cholesterol and the conversion of testosterone to its active metabolite DHT are other causes of DSD due to impaired androgen production. Mutations in the genes that codify the enzymes acting in the steps from cholesterol to DHT have been identified in affected patients. Patients with 46,XY DSD secondary to defects in androgen production show a variable phenotype, strongly depending of the specific mutated gene. Often, these conditions are detected at birth due to the ambiguity of external genitalia but, in several patients, the extremely undervirilised genitalia postpone the diagnosis until late childhood or even adulthood. These patients should receive long-term care provided by multidisciplinary teams with experience in this clinical management. [Copyright &y& Elsevier]

Summary: The Smith–Lemli-Opitz (SLO) syndrome is an autosomal recessive disorder caused by a mutation in the 7-dehydrocholesterol reductase gene, which in turn provokes a defect in cholesterol biosynthesis. SLO is characterised by a specific physical, behavioural and developmental pattern, and the main clinical features include minor facial anomalies, multiple congenital anomalies, failure to thrive and mental retardation. This report describes a case in a newborn child with the typical clinical signs and symptoms of SLO syndrome, who was also affected by profound bilateral sensorineural deafness, and revises the literature suggesting that audiological examination of patients with SLO syndrome may be useful. [Copyright &y& Elsevier]

Abstract: Cholesterol is an important sterol in mammals. Defects in cholesterol synthesis or intracellular routing have devastating consequences already in utero: the Smith–Lemli–Opitz syndrome, desmosterolosis and Niemann–Pick C1 disease provide examples of severe human inherited diseases caused by mutations in cholesterol metabolism genes. On the other hand, elevated plasma cholesterol concentrations are associated with the development of atherosclerosis which represents a major health risk in Western societies. Moreover, several studies indicate that development of atherosclerosis may already start during fetal life. Hence, a carefully balanced regulation of cholesterol metabolism appears of critical importance for both the development of the fetus and health of the adult. In the adult, the liver X receptor is a key regulator of cholesterol metabolism. Its target genes regulate cellular cholesterol efflux and thereby modulate whole-body cholesterol fluxes. LXR and several of its target genes have recently been demonstrated to be expressed in the placenta, which would provide a means to control delivery of maternal cholesterol to the fetus. Here we discuss the potential role of the placenta in the regulation of fetal cholesterol homeostasis and strategies to influence maternal–fetal cholesterol transfer. [Copyright &y& Elsevier]