Treatment of Smith-Lemli-Opitz syndrome: Results of a multicenter trial

Irons, Mira; Elias, Ellen Roy; Abuelo, Diane; Bull, Marilyn J.; Greene, Carol L.; Johnson, Virginia P.; Keppen, Laura Davis; Schanen, Carolyn; Tint, G. S.; Salen, Gerald

doi:10.1002/(sici)1096-8628(19970131)68:3<311::aid-ajmg12>3.0.co;2-w

Cited by 126 publications

(64 citation statements)

References 5 publications

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“…The most noted growth-related role of cholesterol is that it is a major component of cellular membranes. As might then be expected in persons unable to synthesize significant amounts of cholesterol, SLOS infants and children have diminished growth rates [6], which can be improved with dietary cholesterol [60][61][62]. It would be expected that fetal growth rates are also reduced.…”

Section: Discussionmentioning

confidence: 96%

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

Yao

Jenkins

Horn

et al. 2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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SUMMARYThe requirement for cholesterol is greater in developing tissues (fetus, placenta, and yolk sac) as compared to adult tissues. Here, we compared cholesterol-induced suppression of sterol synthesis rates in the adult liver to the fetal liver, fetal body, placenta, and yolk sac of the Golden Syrian hamster. Sterol synthesis rates were suppressed maximally in non-pregnant adult livers when cholesterol concentrations were increased. In contrast, sterol synthesis rates were suppressed only marginally in fetal livers, fetal bodies, placentas, and yolk sacs when cholesterol concentrations were increased. To begin to elucidate the mechanism responsible for the blunted response of sterol synthesis rates in fetal tissues to exogenous cholesterol, the ratio of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) to Insig-1 was measured in these same tissues since the ratio of SCAP to the Insigs can impact SREBP processing. The fetal tissues had anywhere from a 2-to 6-fold greater ratio of SCAP to Insig-1 than did the adult liver, suggesting constitutive processing of the SREBPs. As expected, the level of mature, nuclear SREBP-2 was not different in the fetal tissues with different levels of cholesterol whereas it was different in adult livers. These findings indicate that the suppression of sterol synthesis to exogenous sterol is blunted in developing tissues and the lack of response appears to be mediated at least partly through relative levels of Insigs and SCAP.

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Section: Discussionmentioning

confidence: 96%

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

Yao

Jenkins

Horn

et al. 2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…8). Such putative conversion would explain the lack of increase in vitamin D3 concentrations in spite of 7-DHC tissue accumulation in patients with Smith-Lemli-Opitz syndrome [42]. Indeed, the skin (exposed to solar radiation) would be the site of choice for production of vitamin D3-like compound from 7-DHP or its hydroxy derivatives [43].…”

Section: Substrate Human P450sccmentioning

confidence: 99%

A novel pathway for sequential transformation of 7‐dehydrocholesterol and expression of the P450scc system in mammalian skin

Slominski¹,

Zjawiony

Wortsman

et al. 2004

European Journal of Biochemistry

225

343

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Following up on our previous findings that the skin possesses steroidogenic activity from progesterone, we now show widespread cutaneous expression of the full cytochrome P450 side-chain cleavage (P450scc) system required for the intracellular catalytic production of pregnenolone, i.e. the genes and proteins for P450scc enzyme, adrenodoxin, adrenodoxin reductase and MLN64. Functionality of the system was confirmed in mitochondria from skin cells. Moreover, purified mammalian P450scc enzyme and, most importantly, mitochondria isolated from placenta and adrenals produced robust transformation of 7-dehydrocholesterol (7-DHC; precursor to cholesterol and vitamin D3) to 7-dehydropregnenolone (7-DHP). Product identity was confirmed by comparison with the chemically synthesized standard and chromatographic, MS and NMR analyses. Reaction kinetics for the conversion of 7-DHC into 7-DHP were similar to those for cholesterol conversion into pregnenolone. Thus, 7-DHC can form 7-DHP through P450scc side-chain cleavage, which may serve as a substrate for further conversions into hydroxy derivatives through existing steroidogenic enzymes. In the skin, 5,7-steroidal dienes (7-DHP and its hydroxy derivatives), whether synthesized locally or delivered by the circulation, may undergo UVB-induced intramolecular rearrangements to vitamin D3-like derivatives. This novel pathway has the potential to generate a variety of molecules depending on local steroidogenic activity and access to UVB.

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“…Treatment with simvastatin, an HMG-CoA reductase inhibitor, has been shown to decrease HMGCoA reductase activity and lower the production of 7-DHC in SLOS (28). Supplementation with dietary cholesterol is another option for potentially treating SLOS (29)(30)(31). We hypothesized that measurement of urinary mevalonate excretion in subjects with SLOS can be used to monitor HMG-CoA reductase activity in vivo to determine whether feedback inhibition of the enzyme occurs in SLOS and whether the rationale for using dietary cholesterol to inhibit synthesis of 7-DHC and its metabolites is sound.…”

mentioning

confidence: 99%

Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion

Pappu

Steiner

Connor

et al. 2002

Journal of Lipid Research

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Smith-Lemli-Opitz syndrome (SLOS) is a genetic disorder characterized by low plasma cholesterol and high 7-dehydrocholesterol (7-DHC). Synthesis of cholesterol and 7-DHC and its metabolites is regulated by HMG-CoA reductase, whose activity can be measured by 24-h excretion of its product mevalonate. We devised a simple, non-invasive method for collecting 24-h urine in our subjects. With a background of a very low cholesterol diet, mean mevalonate excretion did not differ between controls and SLOS children, indicating that SLOS subjects have normal HMGCoA reductase activity. In a short term feeding study, the effects of a high cholesterol diet in SLOS subjects include a significant 55% increase in plasma cholesterol levels and 39% decrease in mevalonate excretion and no change in plasma 7-DHC levels. However, in four SLOS subjects, fed a high cholesterol diet for 2-3 years, plasma cholesterol levels continued to increase, urinary mevalonate excretion remained low and total 7-DHC decreased significantly, likely from decreased total sterol synthesis.Thus, in SLOS subjects, HMG-CoA reductase activity was normal and was subject to normal cholesterol induced feedback inhibition. However, total sterol synthesis in SLOS may still be decreased because of increased diversion of mevalonate into the shunt pathway away from sterol synthesis. -

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Treatment of Smith-Lemli-Opitz syndrome: Results of a multicenter trial

Cited by 126 publications

References 5 publications

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

A novel pathway for sequential transformation of 7‐dehydrocholesterol and expression of the P450scc system in mammalian skin

Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion

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