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

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

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 < 0.05) and by simvastatin (~50%, p < 0.04). There was no correlation between U-3MGC and either plasma sterol concentrations, urinary isoprenoids, or the subjects’ clinical severity score. However U-3MGC was inversely correlated with age (p < 0.04) and body weight (p < 0.02), and higher in females than in males (~65%, p < 0.025). The data show that DHCR7 deficiency does not result in 3MGC accumulation in SLOS and suggest that the MVA shunt pathway is not activated in patients with the condition.

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Abbreviations

3MGC:

3-methylglutaconic acid

7-DHC:

7-dehydrocholesterol

8-DHC:

8-dehydrocholesterol

BSTFA:

N,O-bis(trimethylsilyl)trifluoroacetamide

DHCR7:

7-dehydrocholesterol reductase (Δ7-sterol reductase)

HMG-CoA:

3-methyl-3-glutarylcoenzyme A

CoQ:

Coenzyme Q

GCMS:

Gas chromatography-mass spectrometry

MVA:

Mevalonic acid or mevalonate

SLOS:

Smith-Lemli-Opitz syndrome

SLOS-HI:

Group of SLOS subjects receiving a high cholesterol diet

SLOS-LO:

Group of SLOS subjects receiving a cholesterol-free diet

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Acknowledgments

The authors gratefully acknowledge the assistance of Sylvia Hathaway for editorial assistance, Jennifer Penfield, PA and Carrie Phillipi, MD, PhD for patient care, and the nurses and staff of the OHSU Pediatric Clinical and Translational Research Center, as well as health care providers of the SLOS subjects for patient referral and expert care of the patients, and the patients and their families for participation in these studies. We will be ever grateful to the late Dr. Connor for his inspiration and contribution to this work.

Details of funding

This work was supported by a grant from NIH (R01 HL073980). This publication was made possible with support from the Oregon Clinical and Translational Research Institute (OCTRI), grant number UL1 RR024140 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.

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Authors and Affiliations

  1. Department of Pediatrics, Oregon Health & Science University, 707 S.W. Gaines St., Portland, OR, 97239-2998, USA

    Jean-Baptiste Roullet, Louise S. Merkens, Anuradha S. Pappu & Megan D. Jacobs

  2. Department of Physiology and Pharmacology, Oregon Health & Science University, 707 S.W. Gaines St., Portland, OR, 97239-2998, USA

    Anuradha S. Pappu

  3. Antimalarial Drug Discovery Laboratory, Portland VA Medical Center, Portland, OR, USA

    Rolf Winter

  4. Department of Medicine, Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health & Science University, 707 S.W. Gaines St., Portland, OR, 97239-2998, USA

    William E. Connor

  5. Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Oregon Clinical and Translational Research Institute, Doernbecher Children’s Hospital, Oregon Health & Science University, 707 S.W. Gaines St., Portland, OR, 97239-2998, USA

    Robert D. Steiner

  6. Division of Research, CDRC-P, Department of Pediatrics, Oregon Health & Science University, 707 S.W. Gaines St., Portland, OR, 97239-2998, USA

    Jean-Baptiste Roullet

Authors
  1. Jean-Baptiste Roullet
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  2. Louise S. Merkens
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  3. Anuradha S. Pappu
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  4. Megan D. Jacobs
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  5. Rolf Winter
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  6. William E. Connor
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  7. Robert D. Steiner
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Correspondence to Jean-Baptiste Roullet.

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Communicated by: K. Michael Gibson

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Roullet, JB., Merkens, L.S., Pappu, A.S. et al. No evidence for mevalonate shunting in moderately affected children with Smith-Lemli-Opitz syndrome. J Inherit Metab Dis 35, 859–869 (2012). https://doi.org/10.1007/s10545-012-9453-6

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  • DOI: https://doi.org/10.1007/s10545-012-9453-6

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