Defective Cholesterol Biosynthesis Associated with the Smith-Lemli-Opitz Syndrome

Tint, G. S.; Irons, Mira; Elias, Ellen Roy; Batta, Ashok K.; Frieden, Roger; Chen, T S; Salen, Gerald

doi:10.1056/nejm199401133300205

Cited by 764 publications

(527 citation statements)

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“…For example, we found no similarities in the sterol pattern observed with HCV G3 to the metabolite patterns seen with enzyme dysfunction in well-characterized hereditary sterol disorders, such as 3b-hydroxysterol D 7 -reductase (Smith-Lemli-Opitz syndrome and desmosterolosis), 3b-hydroxysterol D 24 -reductase (desmosterolosis), 3b-hydroxysteroid-D 5 -desaturase (lathosterolosis), and 3b-hydroxysteroid-D 8 D 7 -isomerase (X-Linked Dominant Conradi-Hünermann syndrome; CDPX2). 21,30 Eradication of HCV G3 resulted in increased distal metabolite levels but no change in the lanosterol level, further suggesting that viral perturbation of the sterol pathway may occur at a point(s) distal from lanosterol and proximal to 7-DHC/cholesterol. Similar results were obtained when the changes before and after treatment metabolites were compared between SVR and non-SVR patients, and only postlanosterol metabolite changes differed with viral eradication.…”

Section: Discussionmentioning

confidence: 99%

“…20 Metabolomics has been successfully used to identify hereditary sterol defects, where enzyme deficiencies perturb key processes causing elevated levels of preceding sterols and decreased downstream cholesterol synthesis. 21,22 All cholesterol synthesis must pass through the final steps of the isoprenoid metabolic pathway, which are exclusively dedicated to cholesterol synthesis (Fig. 1).…”

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confidence: 99%

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Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner

et al. 2012

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Hepatitis C virus (HCV) subverts host cholesterol metabolism for key processes in its lifecycle. How this interference results in the frequently observed, genotype-dependent clinical sequelae of hypocholesterolemia, hepatic steatosis, and insulin resistance (IR) remains incompletely understood. Hypocholesterolemia typically resolves after sustained viral response (SVR), implicating viral interference in host lipid metabolism. Using a targeted cholesterol metabolomic platform we evaluated paired HCV genotype 2 (G2) and G3 patient sera for changes in in vivo HCV sterol pathway metabolites. We compared HCV genotypic differences in baseline metabolites and following antiviral treatment to assess whether sterol perturbation resolved after HCV eradication. We linked these metabolites to IR and urine oxidative stress markers. In paired sera from HCV G2 (n 5 13) and G3 (n 5 20) patients, baseline sterol levels were lower in G3 than G2 for distal metabolites (7-dehyrocholesterol (7DHC) 0.017 versus 0.023 mg/dL; P adj 5 0.0524, cholesterol 140.9 versus 178.7 mg/dL; P adj 5 0.0242) but not the proximal metabolite lanosterol. In HCV G3, SVR resulted in increased levels of distal metabolites (cholesterol [D55.2 mg/dL; P adj 5 0.0015], 7DHC [D0.0075 mg/dL; P adj 5 0.0026], lathosterol [D0.0430 mg/dL P adj 5 0.0405]). In contrast, lanosterol was unchanged after SVR (P 5 0.9515). Conclusion: HCV G3, but not G2, selectively interferes with the late cholesterol synthesis pathway, evidenced by lower distal sterol metabolites and preserved lanosterol levels. This distal interference resolves with SVR. Normal lanosterol levels provide a signal for the continued proteolysis of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which may undermine other host responses to increase cholesterol synthesis. These data may provide a hypothesis to explain why hypocholesterolemia persists in chronic HCV infection, particularly in HCV G3, and is not overcome by host cholesterol compensatory mechanisms. (HEPATOLOGY 2012;56:49-56)

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner

et al. 2012

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“…SLO is an autosomal-recessive disorder due to mutations in the gene for D7-dehydrocholesterol reductase, 63,64 leading to increased serum levels of 7-dehydrocholesterol. The incidence has been estimated to be one in 10 000 to one in 60 000.…”

Section: Single Gene Disorders Associated With Admentioning

confidence: 99%

The genetics of autistic disorders and its clinical relevance: a review of the literature

2006

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Twin and family studies in autistic disorders (AD) have elucidated a high heritability of the narrow and broad phenotype of AD. In this review on the genetics of AD, we will initially delineate the phenotype of AD and discuss aspects of differential diagnosis, which are particularly relevant with regard to the genetics of autism. Cytogenetic and molecular genetic studies will be presented in detail, and the possibly involved aetiopathological pathways will be described. Implications of the different genetic findings for genetic counselling will be mentioned.

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“…42, No. 3, 1997 biosynthesis (Tint et aL, 1994). CNS anomalies are common in Smith-Lemli-Opitz syndrome.…”

Section: Discussionmentioning

confidence: 99%

Mevalonic acidemia: First case of Japan

et al. 1997

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SummaryMevalonic acidemia is a rare metabolic disorder due to mevalonate kinase deficiency which affects the biosynthesis of cholesterol and nonsterol isoprenes. We report the first case of Japan. The clinical course is characterized by intrauterine growth retardation, postnatal growth failure, intractable diarrhea, liver dysfunctions and death at three months of age. Dysmorphic features including triangular face, protrusion of forehead, hypertelorism, low set ears and micrognathism were noted. High mevalonic acid level was found by GC/MS.

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Defective Cholesterol Biosynthesis Associated with the Smith-Lemli-Opitz Syndrome

Cited by 764 publications

References 30 publications

Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner

Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner

The genetics of autistic disorders and its clinical relevance: a review of the literature

Mevalonic acidemia: First case of Japan

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