Ellen Roy Elias

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

BACKGROUND The Smith-Lemli-Opitz syndrome (frequency, 1:20,000 to 1:40,000) is defined by a constellation of severe birth defects affecting most organ systems. Abnormalities frequently include profound mental retardation, severe failure to thrive, and a high infant-mortality rate. The syndrome has heretofore been diagnosed only from its clinical presentation. METHODS Using capillary-column gas chromatography-mass spectrometry, we measured the sterol composition of plasma, erythrocytes, lens, cultured fibroblasts, and feces from five children with the syndrome (three girls and two boys). RESULTS Plasma cholesterol levels were abnormally low (8 to 101 mg per deciliter [0.20 to 2.60 mmol per liter]) in every patient, being well below the 5th percentile for age- and sex-matched controls. Concentrations of the cholesterol precursor 7-dehydrocholesterol (cholesta-5,7-dien-3 beta-ol), which was not detectable in most of our controls, were elevated (11 to 31 mg per deciliter) more than 2000-fold above normal and were similar to the levels of cholesterol in all tissues from all patients. An isomeric dehydrocholesterol with a structure similar to that of 7-dehydrocholesterol was also detected. CONCLUSIONS The combination of abnormally low plasma cholesterol levels and a high concentration of the cholesterol precursor 7-dehydrocholesterol points to a major block in cholesterol biosynthesis at the step in which the C-7(8) double bond of 7-dehydrocholesterol is reduced, forming cholesterol. The block may be sufficient to deprive an embryo or fetus of cholesterol and prevent normal development, whereas the incorporation of 7-dehydrocholesterol into all membranes may interfere with proper membrane function.

Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups

OBJECTIVE To use the technique of complementation analysis to help define genotype and classify patients with clinical manifestations consistent with those of the disorders of peroxisome assembly, namely the Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). STUDY DESIGN Clinical findings, peroxisomal function, and complementation groups were examined in 173 patients with the clinical manifestations of these disorders. RESULTS In 37 patients (21%), peroxisome assembly was intact and isolated deficiencies of one of five peroxisomal enzymes involved in the beta-oxidation of fatty acids or plasmalogen biosynthesis were demonstrated. Ten complementation groups were identified among 93 patients (54%) with impaired peroxisome assembly and one of three phenotypes (ZS, NALD, or IRD) without correlation between complementation group and phenotype. Forty-three patients (25%) had impaired peroxisome assembly associated with the RCDP phenotype and belonged to a single complementation group. Of the 173 patients, 10 had unusually mild clinical manifestations, including survival to the fifth decade or deficits limited to congenital cataracts. CONCLUSIONS At least 16 complementation groups, and hence genotypes, are associated with clinical manifestations of disorders of peroxisome assembly. The range of phenotype is wide, and some patients have mild involvement.

Care coordination in the medical home: Integrating health and related systems of care for children with special health care needs

Care coordination is a process that facilitates the linkage of children and their families with appropriate services and resources in a coordinated effort to achieve good health. Care coordination for children with special health care needs often is complicated because there is no single point of entry into the multiple systems of care, and complex criteria frequently determine the availability of funding and services among public and private payers. Economic and sociocultural barriers to coordination of care exist and affect families and health care professionals. In their important role of providing a medical home for all children, primary care physicians have a vital role in the process of care coordination, in concert with the family.

Sexuality of Children and Adolescents With Developmental Disabilities

Children and adolescents with developmental disabilities, like all children, are sexual persons. However, attention to their complex medical and functional issues often consumes time that might otherwise be invested in addressing the anatomic, physiologic, emotional, and social aspects of their developing sexuality. This report discusses issues of puberty, contraception, psychosexual development, sexual abuse, and sexuality education specific to children and adolescents with disabilities and their families. Pediatricians, in the context of the medical home, are encouraged to discuss issues of sexuality on a regular basis, ensure the privacy of each child and adolescent, promote self-care and social independence among persons with disabilities, advocate for appropriate sexuality education, and provide ongoing education for children and adolescents with developmental disabilities and their families.

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.

Causal heterogeneity in isolated lissencephaly

We report clinical, cytogenetic, and molecular studies in 65 patients with isolated lissencephaly sequence (ILS). All had type I lissencephaly of varying severity and a grossly normal cerebellum. Some had additional brain abnormalities. Facial appearance was essentially normal. All had severe to profound mental retardation, seizures, hypotonia that evolved into spasticity, and feeding difficulties. Clinical and laboratory studies demonstrated etiologic heterogeneity. Molecular studies detected microdeletions in chromosome band 17p13.3 in six of 44 patients tested, confirming that deletion of all or part of this “critical region” is the cause of ILS in some cases. There were slightly larger deletions in the same region in a majority of patients with Miller-Dieker syndrome. One patient had an apparently balanced, de novo reciprocal translocation with breakpoints at Xq22 and 2p25. Four sibs from two families had a new, autosoma1 recessive syndrome of ILS with neonatal death. Other causes supported by clinical observations include autosoma1 recessive inheritance, intrautenne infection, and intrauterine perfusion failure. Those ILS probands in whom no etiology could he established had 41 sibs of whom three were affected, giving an empiric recurrence risk of 7%.

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

OBJECTIVES To 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. METHODS Plasma sterols were measured in 33 individuals (24 type I, 9 type II) with a clinical diagnosis of the syndrome. RESULTS Cholesterol 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. CONCLUSIONS Patients 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.

Treatment of Smith-Lemli-Opitz syndrome: Results of a multicenter trial

Patients with the RSH or Smith-Lemli-Optiz syndrome (SLOS) have an inborn error of cholesterol biosynthesis which results in a deficiency of cholesterol and an elevation of the cholesterol precursor, 7-dehydrocholesterol. A treatment protocol consisting of administration of cholesterol +/- bile acids was initiated in an attempt to correct the biochemical abnormalities seen. Fourteen patients (8 female, 6 male: ages 2 months to 15 years) have now been treated for 6-15 months. Three patients received cholesterol alone, while 11 patients received cholesterol and one or more bile acids. Biochemical improvement in sterol levels and in the ratio of cholesterol to total sterols was noted in all patients. The most marked improvement was noted in patients presenting with initial cholesterol levels < 40 mg/dl. No toxicity was observed. Clinical improvement in growth and neurodevelopmental status was also observed.

Utilization and Costs for Children Who Have Special Health Care Needs and Are Enrolled in a Hospital-Based Comprehensive Primary Care Clinic

Objective. When deciding how much hospital resources should be allocated to comprehensive primary care clinics for children with multisystem disorders, it is important to consider all of the non-primary care revenue streams associated with these children as well as the effects of a comprehensive primary care program on access and quality. The objectives of this study were, first, to determine costs as well as the payments associated with hospital ambulatory and inpatient services for children with multisystem disorders followed by a comprehensive primary care clinic; and, second, to determine the effect of enrollment in a hospital-based comprehensive primary care clinic on ambulatory and inpatient utilization patterns and expenditures for children with multisystem disorders. Methods. The study population for the payment analysis consisted of 1012 children of all ages who were seen in the Special Primary Care Clinic (SPCC) in 2001. For these children, outcomes included direct costs, total (direct plus allocated overhead) costs, and payments per patient per 365 days after their first SPCC visit in 2001. A total of 175 of these patients were 4 years of age or older and had no SPCC visit before their first visit in 2001. We compared utilization and expenditures for the 175 children during the year before enrollment in SPCC with those in the year after enrollment. The Childrens Hospital administrative database was used to document direct costs, total costs, and payments by type of service for 365 days after an index visit. Ambulatory services included medical and surgical ambulatory, inpatient, emergency department (ED), and ancillary services. We determined the proportion of children who had visits; the visit rates per 100 child-years; and the average total and direct costs per visit, per child with a visit, and per child-year. Inpatient services data included non-intensive care and intensive care hospitalization rates per 100 child-years; the proportion of children hospitalized; their average length of stay; and the average total and direct costs per hospitalization, per patient hospitalized, and per child-year of total patients in the cohort. Results. For 1012 children who were seen in SPCC in 2001, the hospital overall loss per child-year was

Home Care of Children and Youth With Complex Health Care Needs and Technology Dependencies

956. The loss per child-year for outpatient services was