Mira Irons

Markedly inhibited 7-dehydrocholesterol-delta 7-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes.

We investigated the enzyme defect in late cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome, a recessively inherited developmental disorder characterized by facial dysmorphism, mental retardation, and multiple organ congenital anomalies. Reduced plasma and tissue cholesterol with increased 7-dehydrocholesterol concentrations are biochemical features diagnostic of the inherited enzyme defect. Using isotope incorporation assays, we measured the transformation of the precursors, [3 alpha- 3H]lathosterol and [1,2-3H]7-dehydrocholesterol into cholesterol by liver microsomes from seven controls and four Smith-Lemli-Opitz homozygous subjects. The introduction of the double bond in lathosterol at C-5[6] to form 7-dehydrocholesterol that is catalyzed by lathosterol-5-dehydrogenase was equally rapid in controls and homozygotes liver microsomes (120 +/- 8 vs 100 +/- 7 pmol/mg protein per min, P = NS). In distinction, the reduction of the double bond at C-7 [8] in 7-dehydrocholesterol to yield cholesterol catalyzed by 7-dehydrocholesterol-delta 7-reductase was nine times greater in controls than homozygotes microsomes (365 +/- 23 vs 40 +/- 4 pmol/mg protein per min, P < 0.0001). These results demonstrate that the pathway of lathosterol to cholesterol in human liver includes 7-dehydrocholesterol as a key intermediate. In Smith-Lemli-Opitz homozygotes, the transformation of 7-dehydrocholesterol to cholesterol by hepatic microsomes was blocked although 7-dehydrocholesterol was produced abundantly from lathosterol. Thus, lathosterol 5-dehydrogenase is equally active which indicates that homozygotes liver microsomes are viable. Accordingly, microsomal 7-dehydrocholesterol-delta 7-reductase is inherited abnormally in Smith-Lemli-Opitz homozygotes.

Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome

OBJECTIVESnTo determine whether type I and the more severe type II variant of Smith-Lemli-Opitz syndrome have the same metabolic defect and to learn which plasma sterol measurements best predict survival.nnnMETHODSnPlasma sterols were measured in 33 individuals (24 type I, 9 type II) with a clinical diagnosis of the syndrome.nnnRESULTSnCholesterol levels were abnormally low (61 +/- 34 mg/dl) in type I subjects, whereas concentrations of the cholesterol precursor 7-dehydrocholesterol and its isomer 8-dehydrocholesterol were elevated 40- to 10,000-fold. Plasma cholesterol levels were significantly lower and total dehydrocholesterol levels higher in type II than in type I. Six children with the type II variant died by 13 weeks with mean plasma cholesterol levels 6.2 +/- 3.1 mg/dl, versus 17 +/- 11 mg/dl in the three surviving children with type II (p < 0.05). No child with a cholesterol level 7 mg/dl or less lived longer than 13 weeks.nnnCONCLUSIONSnPatients with type I and type II variants of Smith-Lemli-Opitz syndrome have markedly reduced activity of the enzyme that converts 7-dehydrocholesterol to cholesterol, but the extent of the block is far more complete in type II. Survival correlates strongly with higher plasma cholesterol concentrations.

Skeletal anomalies and deformities in patients with deletions of 22q11

Skeletal anomalies in patients with a 22q11.2 deletion are reported infrequently. We report the skeletal findings in 108 patients with a 22q11.2 deletion, of whom 37 (36%) had a skeletal anomaly. Twenty-two patients (20%) had anomalies of the limbs, 7 of the upper limb, including preaxial or postaxial polydactyly. An anomaly of the lower limb was found in 16 patients, including postaxial polydactyly, clubfoot, severely overfolded toes, and 2-3 toe cutaneous syndactyly. Chest films of 63 patients were examined; 30% of them had abnormal findings, most commonly supernumerary ribs (17%) or a butterfly vertebral body (11%). Hypoplastic vertebrae, hemivertebrae, and vertebral coronal clefts were also noted. Thus, skeletal anomalies are not uncommon in patients with a 22q11.2 deletion and may occur more frequently than recognized previously.

Fetal Smith-Lemli-Opitz syndrome can be detected accurately and reliably by measuring amniotic fluid dehydrocholesterols

The Smith–Lemli–Opitz syndrome, characterized by limb, face and organ abnormalities, and mental retardation, is caused by an inherited block in the step of cholesterol biosynthesis in which the Δ7 double bond of 7‐dehydrocholesterol is reduced. It is diagnosed by the presence of markedly elevated levels of 7‐dehydrocholesterol and 8‐dehydrocholesterol in plasma and tissue. We measured amniotic fluid sterols in 15 pregnancies in 13 women who had previously carried an affected fetus. Cholesterol, 7–dehydrocholesterol and 8‐dehydrocholesterol concentrations averaged 18±3, 9·8±2·9 and 5·0±1·7 μg/ml, respectively, in seven pregnancies with an affected fetus or child. In contrast, these levels were 19±3, 0·05±0·01 and <0·005 μg/ml, respectively, in eight increasedrisk pregnancies with normal outcomes and 16±2, 0·07±0·01 and <0·005 μg/ml in normal controls. 7‐dehydrocholesterol concentrations, 2·2–26 and 0·05–0·10 μg/ml in pregnancies with an affected and unaffected fetus, respectively, did not overlap. Thus, abnormally elevated amniotic fluid dehydrocholesterol concentrations are an accurate predictor of fetal Smith–Lemli–Opitz syndrome. A false‐positive or a false‐negative result is highly unlikely.

Accumulation of galactose-1-phosphate in the galactosemic fetus despite maternal milk avoidance

below the requirement, 6 and suggest that the leucine intake was not the major factor in the rapid rise of the plasma leucine level. Our results, as well as all but one of those previously reported, indicate that newborn screening for maple syrup urine disease may be successful even when the infant is discharged from the newborn nursery early. However, until more data are available, it would seem wise to exercise caution in the interpretation of results obtained during the first hours of life, especially if there has been any intravenously administered fluid therapy. Although not important for screening purposes, the presence of measurable quantities of alloisoleucine in the blood of all three of these infants by 48 hours of age is of interest. This finding is very useful in confirming the diagnosis, because alloisoleucine is not normally detectable in blood. Its presence in a blood sample should alert the physician to the possibility of maple syrup urine disease.

The Smith—Lemli—Opitz Syndrome: A Potentially Fatal Birth Defect Caused by a Block in the Last Enzymatic Step in Cholesterol Biosynthesis

The Smith-Lemli-Opitz or “RSH” syndrome, first described in 1964 (Smith et al., 1964), is a severely debilitating and frequently fatal birth defect syndrome with an autosomal recessive mode of inheritance (Dellaire, 1969). Original estimates suggested an incidence of one in 20,000 births (Lowry and Yong, 1980) and a probable carrier frequency of about 1% (Chasalow, 1985). However, newer studies from the Czech Republic may place its true prevalence closer to 1 in 9,000, with as many as one in 45–50 inviduals carrying the defect (Opitz et al., 1997). Although all of the above estimates were made in case that were not biochemically confirmed, if the most recent observations prove to be correct, then the syndrome is as least as common as medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (Zaideh et al., 1995) and may well be the fourth most common recessively inherited disorder in Caucasians following cystic fibrosis, phenylketonuria, and hemochromatosis. Until the discovery in 1993 of the cholesterol biosynthesis defect in children with the syndrome (Irons et al., 1993; Tint et al., 1993; Tint et al., 1994), its cause was entirely unknown (Gorlin et al., 1990).

The prenatal sono raphic diagnosis of lethal multiple pterygium syndrome: A heritable cause of recurrent abortion

Presumably, a large number of recurrent abortions are caused by lethal recessive syndromes whose diagnosis depends either on a known family history or on the identification of characteristic fetal phenotypic features on pathologic examination. Because these conditions are rare, family histories are seldom helpful, and nondirected postmortem examinations on degenerating samples are seldom enlightening. Serial ultrasonography beginning early in pregnancy may provide important information in the evaluation of recurrent abortion caused by lethal recessive disorders. Reported is the accurate prenatal sonographic diagnosis of lethal multiple pterygium syndrome in a patient with a history of recurrent abortions. This syndrome is characterized by multiple limb contractures with pterygia, facial clefting, intracranial abnormalities, cystic hygroma, progressive fetal edema, and fetal death by midgestation. Inheritance may be X-linked recessive. Lethal multiple pterygium syndrome should be considered in patients with a history of recurrent midtrimester losses.

Screening for metabolic disorders. How are we doing

Routine screening for phenylketonuria and congenital hypothyroidism has become an integral part of pediatric practice in the United States. Screening for several other metabolic disorders is now entering the second or third decade of use. New information is available for the pediatrician for both groups of disorders that will be of help in caring for children in the years to come.

THE NEONATAL PHENOTYPE OF GALACTOSEMIA

Galactosemia (GAL), due to Gal-1-PO4 uridyltransferase deficiency, is an inborn error of galactose metabolism causing neonatal morbidity and mortality. The general features of GAL are not specific, and the particular characteristics that may better define GAL in the neonate have not been systematically studied. We have analyzed the clinical and biochemical findings prior to treatment in all 23 neonates with GAL identified by routine screening during the past 21 years. At the time of newborn screening identification, only one infant had been diagnosed clinically as having GAL, although 18 were symptomatic; 3/5 asymptomatic infants were biochemically variant. Among all affected neonates 6 (26%) had bacterial infections, 5 with bacteremia and 1 with urinary tract infection; 5/6 infections were due to E. coli. Hyperbilirubinemia during the first week of life was almost exclusively unconjugated, while the conjugated fraction tended to rise only during the second week. Serum transaminase elevations were associated with conjugated hyperbilirubinemia. Coagulopathy was the most distinguishing feature of liver dysfunction, and was disproportionate to the severity of other biochemical indications of liver disease. Of 11 infants studied by slit-lamp ophthalmologic examination, 7 (64%) had “water-droplet cataracts”.GAL produces severe physiologic disturbances which are often unsuspected from a deceptively milder clinical presentation. These disturbances may be related to the long-term sequelae now recognized in early-treated galactosemics.

CORRELATION OF CLINICAL PHENOTYPE AND BIOCHEMICAL DEFECT IN SMITH-LEMLI-OPITZ SYNDROME (SLOS). • 480

SLOS is caused by an inborn error of cholesterol biosynthesis. Affected patients have growth and developmental retardation, congenital anomalies, and a characteristic facial appearance. Prior to discovery of the biochemical defect, diagnosis was based on clinical examination alone. Confirmation of the clinical diagnosis can now be accomplished by demonstration of the characteristic abnormal sterol pattern in plasma or other tissues.