Possible abnormalities of steroid secretion in children with Smith-Lemli-Opitz syndrome and their parents

doi:10.1016/0039-128X(85)90032-7

Steroids

Volume 46, Issues 4–5, October–November 1985, Pages 827-843

https://doi.org/10.1016/0039-128X(85)90032-7 Get rights and content

Abstract

In early infancy, two unrelated children with Smith-Lemli-Opitz syndrome were found to have elevated levels of androgen sulfates. When the steroid conjugates in the serum of normal infants were hydrolyzed and chromatographed on Sephadex LH-20, 4 androgen containing peaks (I, II, III, IV) were found. In the serum from these two infants with Smith-Lemli-Opitz syndrome, Peaks I and III were increased, but Peaks II and IV were absent. The parents of the two children, and of three additional unrelated children with Smith-Lemli-Opitz syndrome, had exaggerated 17-hydroxyprogesterone responses to an intravenous bolus of ACTH. These findings suggest that a defect in steroid metabolism may be linked to the Smith-Lemli-Opitz syndrome.

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Cited by (51)

Ionotropin is the mammalian digoxin-like material (DLM). It is a phosphocholine ester of a steroid with 23 carbon atoms
2018, Steroids
Citation Excerpt :
Our laboratory evaluated patients with potential steroid biosynthetic defects. In 1983, one patient, in addition to the morphology characteristic of SLO, had potassium wasting and extremely high levels of steroids detected with antibodies to DHEA-sulfate and 17-hydroxyprogesterone [26,27]. This was the first report of a possible steroid defect in patients with this syndrome.
We describe a novel steroid, which we have named “Ionotropin”. Its unique features are: [1] it has 23 carbon atoms and [2] it is a phosphocholine ester. There are no other known mammalian steroids with either structural feature. Ionotropin cross reacts with digoxin-specific antibodies and may be the long-sought, endogenous, mammalian digoxin-like material (DLM). Using LC–MS, we identified three other phosphocholine steroids in serum. Two of these steroids also cross-react with digoxin specific antibodies.
In adrenal extracts, we found both phosphocholine esters and corresponding phospho-ethanolamine steroid esters. There are no other known phosphoethanolamine steroid esters. Together, these 8 compounds define a biosynthetic pathway from 7-dehydropregnenolone to Ionotropin. Ionotropin may be the only steroid hormone not synthesized with cholesterol as a precursor. Finally, we propose that Ionotropin serves as the endogenous potassium sparing hormone. Ionotropin provides a new understanding of renal, cardiac, gonadal and placental function.
Lowered DHCR7 activity measured by ergosterol conversion in multiple cell types in Smith-Lemli-Opitz syndrome
2004, Molecular Genetics and Metabolism
Smith–Lemli–Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol metabolism characterized by multiple congenital anomalies and mental retardation. SLOS results from mutations in 7-dehydrocholesterol Δ⁷ reductase (DHCR7), the gene encoding the final enzyme involved in cholesterol biosynthesis. The resulting cholesterol deficiency and excessive 7- and 8-dehydrocholesterol (7-DHC, 8-DHC) in plasma and tissues are almost always diagnostic for SLOS. We measured DHCR7 activity in fibroblasts, amniocytes, and chorionic villi from controls, heterozygotes, and SLOS subjects. The enzyme activity (expressed as percent conversion of substrate) was significantly lower in untransformed fibroblasts from SLOS subjects (4.47% ± 0.72) compared to untransformed fibroblasts from heterozygotes (26.6% ± 4.6, p < 0.01) or controls (50.6% ± 5.3, p < 0.001). We also measured plasma cholesterol and 7-DHC, determined the severity score and identified DHCR7 mutations for most of the subjects. There was no significant correlation of enzyme activity with severity score, plasma cholesterol level, plasma 7-DHC level, or the 7-DHC:cholesterol ratio. We conclude that even though enzyme activity as measured by the ergosterol assay may not correlate with severity, this assay has the potential to distinguish SLOS cells from carrier or unaffected cells in a variety of cell types, and should prove useful in confirming a diagnosis in atypical cases where sterol levels are equivocal. Additionally, it may be important to measure residual enzyme activity in SLOS subjects being considered for a trial of statins, as this treatment could theoretically be detrimental in subjects with little or no DHCR7 activity. Finally, the data suggest a threshold enzyme activity of 8% conversion, below which disease occurs.
Smith-Lemli-Opitz syndrome: The first malformation syndrome associated with defective cholesterol synthesis
2000, Molecular Genetics and Metabolism
Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive condition with multiple malformations, mental retardation, and growth failure, results from markedly reduced activity of the final enzyme in the cholesterol biosynthetic pathway, 7-dehydrocholesterol reductase (DHCR7). Clinical signs vary in severity, ranging from fetal loss to holoprosencephaly with multiple malformations to isolated syndactyly. The biochemical defect in SLOS is a deficiency of DHCR7, which results in an abnormally low cholesterol level, and increased amounts of intermediates of sterol biosynthesis. Animal models currently exist through the use of cholesterol biosynthesis inhibitors, from which a great deal has been learned. Pregnant rats treated with inhibitors of DHCR7 yield pups that have abnormal sterol profiles and craniofacial abnormalities characteristic of severe SLOS. Biochemical testing of human patients can be performed using gas chromatography/mass spectroscopy (GC/MS) to analyze the sterol content of tissues, amniotic fluid, or cell culture lysate. Numerous mutations have been identified in DHCR7 but seven individual mutations account for 67% of the total mutations reported in the literature. Clinical trials with SLOS are underway, with the goal of increasing the cholesterol concentration in the plasma and tissues through the administration of dietary cholesterol. Thus far, this approach has shown limited efficacy. Nevertheless, the recent identification of the biochemical and molecular genetic basis for SLOS is reason for optimism that the condition may one day yield to treatment.
RSH/Smith-Lemli-Opitz syndrome: A multiple congenital anomaly/mental retardation syndrome due to an inborn error of cholesterol biosynthesis
2000, Molecular Genetics and Metabolism
The RSH/Smith–Lemli–Opitz syndrome (RSH/SLOS) is an autosomal recessive multiple congenital anomaly/mental retardation syndrome caused by an inborn error of cholesterol biosynthesis. The RSH/SLOS phenotypic spectrum is broad; however, typical features include microcephaly, ptosis, a small upturned nose, micrognathia, postaxial polydactaly, second and third toe syndactaly, genital anomalies, growth failure, and mental retardation. RSH/SLOS is due to a deficiency of the 3β-hydroxysterol Δ⁷-reductase, which catalyzes the reduction of 7-dehydrocholesterol (7-DHC) to cholesterol. This inborn error of cholesterol biosynthesis results in elevated serum and tissue 7-DHC levels. The 3β-hydroxysterol Δ⁷-reductase gene (DHCR7) maps to chromosome 11q12-13, and to date 66 different mutations of this gene have been identified in RSH/SLOS patients. Identification of the biochemical basis of RSH/SLOS has led to development of therapeutic regimens based on dietary cholesterol supplementation and has increased our understanding of the role cholesterol plays during embryonic development.
Neonatal urinary steroids in Smith-Lemli-Opitz syndrome associated with 7-dehydrocholesterol reductase deficiency
1999, Steroids
The biosynthetic abnormality in Smith-Lemli-Opitz syndrome (SLOS) is a deficiency of 7-dehydrocholesterol (7DHC) reductase, the enzyme responsible for catalyzing the final step in the Kandutsch-Russell pathway for cholesterol synthesis. Because the disposition of 7DHC and 8-dehydrocholesterol [8DHC; cholesta-5,8(9)-dien-3β-ol] produced in this syndrome is little understood, we have analyzed urine from three young infants by gas chromatography/mass spectrometry to characterize its steroid metabolites. All steroid metabolites of adrenal origin found in normal infant urine were also found in urine from the patients with SLOS but in reduced amount. Quantitatively, the major steroids in these SLOS patients were identified by mass spectrometry as homologs of normal neonatal steroids possessing an additional double bond. Generally, two forms of each steroid were present in a similar amount. Because of the markedly increased levels of 7DHC and 8DHC in SLOS, these almost certainly represented the 5,7 and 5,8(9) unsaturated forms of each metabolite. The most abundant steroids were tentatively identified as 3β,16α-dihydroxy-5,7-pregnadien-20-one and 3β,16α-dihydroxy-5,8(9)-pregnadien-20-one, although similar 21-hydroxylated steroids and homologs of 16α-hydroxyDHEA were also found. This study shows that all enzymatic steps used by cholesterol in the DHEA synthetic pathway are also functional for 7DHC and 8DHC.
Synthesis of [3α-<sup>3</sup>H]7-dehydrocholesterol via stable tritiated 4- phenyl-1,2,4-triazoline-3,5-dione derivative
1997, Steroids
Synthesis of [3α-³H]7-dehydrocholesterol is described via protection of the 5,7-diene system in 7-dehydrocholesterol as the Diels-Alder adduct with 4-phenyl-1,2,4-triazoline-3,5-dione followed by oxidation of the hydroxyl group to give the 3-oxo adduct. Reduction of the keto adduct with [³H]sodium borohydride produced the adduct of [3α-³H]7-dehydrocholesterol from which the radiolabeled sterol was obtained via treatment with lithium aluminum hydride. The advantage of the method is that highly labeled [3α-³H]7-dehydrocholesterol can be prepared. Further, unlike 7-dehydrocholesterol, its adduct with 4-phenyl-1,2,4-triazoline-3,5-dione is stable and can be stored. This allows the preparation of small batches of [3α-³H]7-dehydrocholesterol for immediate use in biological experiments, and losses due to decomposition of excess radiolabeled 7-dehydrocholesterol are minimized.

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Possible abnormalities of steroid secretion in children with Smith-Lemli-Opitz syndrome and their parents

Abstract

J. Pediatr.

J. Biol. Chem.

J. Pediatr.

J. Pediatr.

Steroids

Z. Kinderheilk.

J. Med. Genet.

Clin. Endocrinol.

J. Clin. Endocrinol. Metab.

Anal. Letters.

Clin. Endocrinol.

Clin. Endocrinol.

Clin. Genet.