No evidence for mevalonate shunting in moderately affected children with Smith-Lemli-Opitz syndrome

Jean-Baptiste Roullet, Louise S. Merkens, Anuradha Pappu, Megan D. Jacobs, Rolf Winter, William E. Connor, Robert D. Steiner

Research output: Contribution to journalArticle

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Abstract

Smith-Lemli-Opitz syndrome (SLOS) is caused by a genetic deficiency in 7-dehydrocholesterol (7-DHC) reductase (EC 1.3.1.21), the last enzyme of the cholesterol synthetic pathway. In SLOS, plasma cholesterol concentration is reduced and immediate precursor concentration (7-DHC) is elevated. Surprisingly, total sterol synthesis is reduced but HMG-CoA reductase activity, a rate-limiting enzyme in cholesterol synthesis is unaltered as judged by normal urinary excretion of mevalonic acid (MVA) (Pappu et al. J Lipid Res 43:1661-1669, 2002). These findings raise the possibility of increased diversion of MVA into the MVA shunt pathway away from sterol synthesis, by activation of the shunt pathway enzymes. To test this hypothesis, we measured the urinary excretion of 3-methylglutaconic acid (U-3MGC), a by-product of the shunt pathway, in 19 mildly to moderately severely affected SLOS subjects (ten males, nine females) receiving either a cholesterol-free or a high cholesterol diet, and in 20 age-and sex-matched controls. U-3MGC was similar in SLOS and controls, and was unaffected by dietary cholesterol intake. Further, no change in U-3MGC was observed in a subset of SLOS subjects (n=9) receiving simvastatin. In contrast, U-MVA was reduced by cholesterol supplementation (∼54%, p

Original languageEnglish (US)
Pages (from-to)859-869
Number of pages11
JournalJournal of Inherited Metabolic Disease
Volume35
Issue number5
DOIs
StatePublished - Sep 2012

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Smith-Lemli-Opitz Syndrome
Mevalonic Acid
Cholesterol
Sterols
Enzymes
Hydroxymethylglutaryl CoA Reductases
Dietary Cholesterol
Simvastatin
Diet
Lipids

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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No evidence for mevalonate shunting in moderately affected children with Smith-Lemli-Opitz syndrome. / Roullet, Jean-Baptiste; Merkens, Louise S.; Pappu, Anuradha; Jacobs, Megan D.; Winter, Rolf; Connor, William E.; Steiner, Robert D.

In: Journal of Inherited Metabolic Disease, Vol. 35, No. 5, 09.2012, p. 859-869.

Research output: Contribution to journalArticle

Roullet, Jean-Baptiste ; Merkens, Louise S. ; Pappu, Anuradha ; Jacobs, Megan D. ; Winter, Rolf ; Connor, William E. ; Steiner, Robert D. / No evidence for mevalonate shunting in moderately affected children with Smith-Lemli-Opitz syndrome. In: Journal of Inherited Metabolic Disease. 2012 ; Vol. 35, No. 5. pp. 859-869.
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