Carrier Frequency of the Common Mutation IVS8-1G&gt;C in DHCR7 and Estimate of the Expected Incidence of Smith–Lemli–Opitz Syndrome

Battaile, K.P.; Battaile, Brian C.; Merkens, Louise S.; Maslen, Cheryl L.; Steiner, Robert D.

doi:10.1006/mgme.2000.3103

Cited by 84 publications

(72 citation statements)

References 25 publications

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“…With an estimated global incidence of 1 in 20,000 to 1 in 60,000 live births, SLOS is likely the fourth most common human recessive disease, after cystic fibrosis, phenylketonuria, and hemochromatosis (8,9). However, a recent study (10) estimates the SLOS carrier frequency to be 1 in 30, suggesting a much higher actual disease frequency, e.g. approximately 1 in 1,590 to 1 in 13,500.…”

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confidence: 99%

Partial Rescue of Retinal Function and Sterol Steady-State in a Rat Model of Smith-Lemli-Opitz Syndrome

Fliesler¹,

Vaughan

Jenewein

et al. 2007

Pediatr Res

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ABSTRACT:The Smith-Lemli-Opitz syndrome (SLOS) is the firstdescribed in a growing family of hereditary defects in cholesterol biosynthesis, and presents with a spectrum of serious abnormalities, including multiple dysmorphologies, failure to thrive, cognitive and behavioral impairments, and retinopathy. Using a pharmacologically induced rat model of SLOS that exhibits key hallmarks of the disease, including progressive retinal degeneration and dysfunction, we show that a high-cholesterol diet can substantially correct abnormalities in retinal sterol composition, with concomitant improvement of visual function, particularly within the cone pathway. Although histologic degeneration still occurred, a high-cholesterol diet reduced the number of pyknotic photoreceptor nuclei, relative to animals on a cholesterol-free diet. These findings demonstrate that cholesterol readily crosses the blood-retina barrier (unlike the blood-brain barrier) and suggest that cholesterol supplementation may be efficacious in treating SLOS-associated retinopathy. H ereditary abnormalities in cholesterol biosynthesis underlie a family of human birth defects associated with specific enzyme defects and phenotypes (1-3). The first described and most common of these is SLOS (4), a multiple congenital anomalies syndrome involving the inability to efficiently convert 7DHC to Chol (5,6). The enzyme responsible for catalyzing this biosynthetic step (3␤-hydroxysterol-⌬ 7 -reductase; DHCR7; EC 1.3.1.21) is encoded by the DHCR7 gene localized to human chromosome 11q12-q13 (7-9). More than 100 mutations in DHCR7 have been identified in association with SLOS; many result in abnormally low levels of cholesterol and abnormally high levels of 7DHC in bodily tissues (8,9). With an estimated global incidence of 1 in 20,000 to 1 in 60,000 live births, SLOS is likely the fourth most common human recessive disease, after cystic fibrosis, phenylketonuria, and hemochromatosis (8,9). However, a recent study (10) estimates the SLOS carrier frequency to be 1 in 30, suggesting a much higher actual disease frequency, e.g. approximately 1 in 1,590 to 1 in 13,500. The SLOS phenotype displays a spectrum of clinical manifestations, from mild to lethal, and may include such findings as moderate to severe mental retardation, autism, dysmorphic craniofacial and skeletal malformations, and failure to thrive (1-3).We previously reported progressive retinal degeneration in a pharmacological rat model of SLOS (11) characterized by shortening and eventual loss of retinal ROS, pyknosis and thinning of the ONL, accumulation of membranous inclusions and lipid droplets in the retinal pigment epithelium (RPE), defects in rod and cone photoresponses, together with SLOSlike accumulation of 7DHC and diminished cholesterol levels in retina, brain, liver, and serum. The SLOS rat model (11-13) is induced by treatment of pregnant rats and their progeny with AY9944, a selective inhibitor of 3␤-hydroxysterol-⌬ 7 -reductase (14,15), the enzyme defective in SLOS. The clinical relevance of the S...

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confidence: 99%

Partial Rescue of Retinal Function and Sterol Steady-State in a Rat Model of Smith-Lemli-Opitz Syndrome

Fliesler¹,

Vaughan

Jenewein

et al. 2007

Pediatr Res

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“…The Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive disorder with an incidence of at least one in 20,000 and a carrier frequency of 1 in 30 (1)(2)(3)(4). This metabolic disorder is characterized clinically by specific facial dysmorphism, severe growth and feeding abnormalities, multiple congenital malformations, and endocrine and neurological dysfunction, including often-severe mental retardation (2)(3)(4).…”

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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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“…As might be expected, SLOS is characterized by a reduction in cholesterol and an increase in cholesterol precursors, including 7-and 8-DHC. Recent studies demonstrate that the incidence of this syndrome may be much greater than previously believed at a predicted incidence of 1:1590-1:13,500 [9,10], though observed incidence is lower (perhaps 1 in 20,000 births). The discrepancy in observed versus predicted incidence is likely due in part to pregnancy loss as well as undiagnosed mild cases.…”

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confidence: 82%

Enhanced placental cholesterol efflux by fetal HDL in Smith–Lemli–Opitz syndrome

Jenkins

Merkens

Tubb

et al. 2008

Molecular Genetics and Metabolism

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Previous studies from this laboratory have shown that maternal-derived cholesterol can be effluxed from trophoblasts to fetal HDL and plasma. We had the opportunity to study for the first time the ability of HDL and plasma from a fetus with the Smith-Lemli-Opitz syndrome (SLOS) to efflux cholesterol from trophoblasts. It was unclear whether cholesterol could be effluxed to fetuses with SLOS since lipoprotein levels are often very low. To answer this question, cord blood was collected from the placentas of an SLOS fetus and unaffected fetuses just after delivery. Plasma cholesterol concentrations were very low in the affected fetus; cholesterol, 7-dehydrocholesterol, and 8-dehydocholesterol concentrations were 14.1, 4.5, and 5.2 mg/dl, respectively. The HDL from the fetal SLOS effluxed ≈50% more cholesterol from a trophoblast cell line, were smaller in size, and had a lower cholesterol to phospholipid ratio as compared to HDL from unaffected fetuses or adults. Plasma from the SLOS fetus effluxed cholesterol to a similar percentage as unaffected fetal plasma or adult plasma, possibly due to fewer HDL particles as demonstrated in previous SLOS patients. These novel data demonstrate that the cholesteroldeficient SLOS fetus is able to obtain cholesterol from trophoblasts at a time when cholesterol is playing a critical role in development, and has implications for design of treatments for cholesterol deficiency syndromes as well as understanding of prenatal cholesterol transport in humans. KeywordsFetus; Trophoblast; BeWo cells; Pregnancy; Cholesterol transport Smith-Lemli-Opitz syndrome (SLOS) is a metabolic disorder that presents with a spectrum of congenital abnormalities. Individuals with a severe phenotype have many congenital abnormalities and mental retardation whereas those with a mild phenotype may have only subtle learning disorders and minor dysmorphic features [1][2][3]. The biochemical cause of this syndrome is a reduction in the activity of the enzyme 7-dehydrocholesterol-Δ7- [4,5], which converts 7-dehydrocholesterol (7-DHC) to cholesterol, due to mutations in DHCR7 [6][7][8]. As might be expected, SLOS is characterized by a reduction in cholesterol and an increase in cholesterol precursors, including 7-and 8-DHC. Recent studies demonstrate that the incidence of this syndrome may be much greater than previously believed at a predicted incidence of 1:1590-1:13,500 [9,10], though observed incidence is lower (perhaps 1 in 20,000 births). The discrepancy in observed versus predicted incidence is likely due in part to pregnancy loss as well as undiagnosed mild cases. Nevertheless, SLOS is probably the second most prevalent, potentially lethal, recessive genetic condition behind cystic fibrosis with an incidence of 1:2500 [11]. The congenital malformations associated with this disease can begin to appear as early as 3 weeks postconception when Sonic Hedgehog (SHH) is needed for patterning of the forebrain [12,13], since sterols activate SHH [14][15][16] and sterol deficiency is thought to play a rol...

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Carrier Frequency of the Common Mutation IVS8-1G>C in DHCR7 and Estimate of the Expected Incidence of Smith–Lemli–Opitz Syndrome

Cited by 84 publications

References 25 publications

Partial Rescue of Retinal Function and Sterol Steady-State in a Rat Model of Smith-Lemli-Opitz Syndrome

Partial Rescue of Retinal Function and Sterol Steady-State in a Rat Model of Smith-Lemli-Opitz Syndrome

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

Enhanced placental cholesterol efflux by fetal HDL in Smith–Lemli–Opitz syndrome

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