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Biomedical subjects

R D Steiner

Publications and source records attributed to R D Steiner.

34 records · Page 2Linked to original sources
PubMed1998

Eye findings in 8 children and a spontaneously aborted fetus with RSH/Smith-Lemli-Opitz syndrome.

We evaluate the ophthalmologic findings in 8 children with RSH/Smith-Lemli-Opitz syndrome (SLOS) and document abnormal concentrations of cholesterol and cholesterol precursors in the ocular tissues in a case of SLOS. The most common ophthalmologic finding was blepharoptosis, which was found in 6 of 8 patients, with the severity ranging from mild to moderate. None of the patients in the present study demonstrated cataracts; none had amblyopia from blepharoptosis. One patient had a right hypertropia with overaction of the inferior oblique muscle. This patient also had optic atrophy and a second patient had bilateral optic nerve hypoplasia. The importance of these findings to the visual function remains to be defined. Sterol analysis from ocular tissues of an aborted fetus with SLOS showed increased 7- and 8-dehydrocholesterol and a low cholesterol concentration in the retinal pigment epithelium, lens, cornea, and sclera. Routine ophthalmologic examination is indicated in SLOS because of the high incidence of abnormalities, most likely due to the abnormal synthesis of cholesterol and cholesterol precursors in the ocular tissues of these patients, as evidenced by sterol analysis of the ocular tissues in a case of SLOS.

Child, Preschool↗
PubMed1998

Bilateral radial ray hypoplasia with multiple epiphyseal dysplasia.

We describe a 5-4/12-year-old girl with the unique combination of bilateral radial ray hypoplasia and multiple epiphyseal dysplasia (MED). Radial ray hypoplasia was diagnosed at birth. MED was documented at age 4-3/12 years when she presented with leg pain and short stature and was found to have femoral anteversion and tibial torsion giving rise to severe genu valgum deformity and intoeing. She has no facial anomalies and is developmentally normal. Family history is unremarkable and chromosomal analysis was normal. Investigation of mineral metabolism showed idiopathic hypercalciuria. Surgical lengthening of her severely hypoplastic left radius at age 19 months was successful. Bilateral femoral and tibial osteotomies at age 5-4/12 years corrected her lower limb deformities. This combination of two distinctive but rare skeletal abnormalities may represent a new syndrome.

Abnormalities, Multiple↗
PubMed1998

Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome.

The Smith-Lemli-Opitz syndrome (SLOS; also known as "RSH syndrome" [MIM 270400]) is an autosomal recessive multiple malformation syndrome due to a defect in cholesterol biosynthesis. Children with SLOS have elevated serum 7-dehydrocholesterol (7-DHC) levels and typically have low serum cholesterol levels. On the basis of this biochemical abnormality, it has been proposed that mutations in the human sterol Delta7-reductase (7-DHC reductase; E.C.1.3.1.21) gene cause SLOS. However, one could also propose a defect in a gene that encodes a protein necessary for either the expression or normal function of sterol Delta7-reductase. We cloned cDNA encoding a human sterol Delta7-reductase (DHCR7) on the basis of its homology with the sterol Delta7-reductase from Arabidopsis thaliana, and we confirmed the enzymatic function of the human gene product by expression in SLOS fibroblasts. SLOS fibroblasts transfected with human sterol Delta7-reductase cDNA showed a significant reduction in 7-DHC levels, compared with those in SLOS fibroblasts transfected with the vector alone. Using radiation-hybrid mapping, we show that the DHCR7 gene is encoded at chromosome 11q12-13. To establish that defects in this gene cause SLOS, we sequenced cDNA clones from SLOS patients. In three unrelated patients we have identified four different mutant alleles. Our results demonstrate both that the cDNA that we have identified encodes the human sterol Delta7-reductase and that mutations in DHCR7 are responsible for at least some cases of SLOS.

Alleles↗
PubMed1997

Black children deficient in galactose 1-phosphate uridyltransferase: correlation of activity and immunoreactive protein in erythrocytes and leukocytes.

A recent study found a high prevalence of a missense mutation (S135L) in the gene for galactose 1-phosphate uridyltransferase (GALT) in black children with galactosemia (J Pediatr 1996; 128:89-95). In the present study, GALT activity and GALT protein content were measured in erythrocytes and leukocytes of eight black and seven white galactosemic (GALT-deficient) children, for correlation with the presence of the S135L and Q188R (highly prevalent in white galactosemic children) missense mutations. The S135L mutation was found in 9 of 16 alleles of black children but not in white children; the Q188R mutation was found in 10 of 14 alleles examined in white galactosemic children and in 4 of 16 alleles in black galactosemic children. The GALT activity was near zero in the erythrocytes of white and black galactosemic children (0.26 +/- 0.28 vs 0.33 +/- 0.25 mumol/hr per gram of hemoglobin, respectively; p = 0.61) (normal 17 to 26 mumol/hr per gram), and no correlation of erythrocyte activity with genotype was observed. The GALT activity was higher in the leukocytes of black galactosemic children compared with white children (5 +/- 6 vs 1 +/- 2 mumol/hr per gram, respectively) (normal 172 to 374 mumol/hr per gram), but the difference was not statistically significant (p = 0.11). Analysis by genotype revealed that the two S135L homozygotes had much more leukocyte activity (9 and 17 mumol/hr per gram) than Q188R homozygotes or than all non-S135L allelic genotypes. Compound heterozygotes (S135L/G) had intermediate activity. The GALT protein was not detectable by Western blot in the erythrocytes of either white or black galactosemic children, as determined by antibodies specific for both C- and N-terminal sequences. The GALT protein was undetectable in the leukocytes of white galactosemic children, but leukocytes from black galactosemic children with the S135L mutation contained reduced but readily detectable GALT protein. Erythrocyte galactose 1-phosphate levels were significantly lower in galactosemic children with an S135L mutant allele (1.1 +/- 0.2 gm/dl) compared with children who had other mutations (3.1 +/- 0.9 mg/dl; p = 0.0001). The correlation of protein content data with activity levels in the blood cells suggests that the S135L missense mutation affects the stability of GALT protein to produce a deficiency state.

Adolescent↗
PubMed1996

Studies of collagen synthesis and structure in the differentiation of child abuse from osteogenesis imperfecta.

OBJECTIVE: To determine whether analysis of collagen synthesized by dermal fibroblasts could identify children with osteogenesis imperfecta (OI) among those suspected to have been abused. METHODS: We reviewed biochemical studies and clinical findings for all children who were referred to us to distinguish OI from abuse during a 4-year period. RESULTS: Cells from 6 of 48 children tested to distinguish OI from abuse had biochemical evidence of OI. In five of the six children with abnormal results on collagen studies, clinical signs of OI in addition to fractures were present on examination by a physician familiar with the condition. In those five cases, the diagnosis of OI was strongly suspected. CONCLUSIONS: OI can be diagnosed by biochemical studies in some cases of suspected abuse, but clinical evaluation by experienced physicians is usually sufficient to do so. When diagnostic uncertainty persists in cases of suspected child abuse, biochemical studies may be a useful adjunct, but routine biopsy for children suspected to have been abused is unwarranted.

Biomarkers↗
PubMed1996

Nonketotic hyperglycinemia: atypical clinical and biochemical manifestations.

A 16-year-old boy had intermittent chorea, delirium, and vertical gaze palsy precipitated by febrile illness. Nonketotic hyperglycinemia was confirmed by measurement of liver and lymphoblast glycine cleavage enzyme activity. Deficient but residual enzyme activity was demonstrated in both tissues, possibly accounting for the mild phenotype. Confirmation of an atypical variant of nonketotic hyperglycinemia with residual glycine cleavage enzyme activity has important implications for diagnosis and treatment.

Adolescent↗
PubMed1995

Klippel-Trenaunay-Weber syndrome associated with a 5:11 balanced translocation.

We report on a case of Klippel-Trenaunay Weber syndrome (KTWS) associated with a reciprocal translocation [46,XX,t (5;11) (q13.3;p15.1)]. The patient has developmental delay and minor anomalies in addition to classic findings of KTWS. These data support the notion that Klippel-Trenaunay-Weber syndrome may be due to a single gene defect and suggests the possible localization of a Klippel-Trenaunay-Weber gene(s) to 5q or 11p.

Child↗
PubMed1995

Asp187Asn mutation of gelsolin in an American kindred with familial amyloidosis, Finnish type (FAP IV).

Familial amyloidosis, Finnish type (FAP-IV) was identified clinically in an American kindred with Scandinavian ancestry. A polymerase chain reaction (PCR)-based DNA diagnostic assay was used to identify a G-to-A mutation at position 654 of the gelsolin cDNA (G654A) in this family. Molecular diagnostic testing demonstrated the mutation in individuals in three generations--the clinically affected proband, here deceased clinically affected father, and her presumably affected presymptomatic child. This report represents a rare example of FAP IV and the G654A mutation identified in a family outside Finland. The disease-associated haplotype was similar to that observed in Finnish FAP IV families (suggesting common distant ancestry).

Adult↗
PubMed1995

Corneal abnormalities in a mother and daughter with focal dermal hypoplasia (Goltz-Gorlin syndrome).

PURPOSE/METHODS: Focal dermal hypoplasia is an inherited dermatologic disorder commonly associated with skeletal and dental abnormalities. Ocular abnormalities frequently found in patients with focal dermal hypoplasia include microphthalmos, anophthalmos, and colobomas. Corneal abnormalities rarely have been described in patients with focal dermal hypoplasia. We examined a mother and daughter with focal dermal hypoplasia with distinctive corneal lesions. RESULTS/CONCLUSION: Several discrete vascularized peripheral subepithelial corneal opacifications were present bilaterally in both patients with focal dermal hypoplasia. No ocular abnormalities that would predispose to these abnormalities were found. These corneal lesions appear to represent an unusual manifestation of focal dermal hypoplasia.

Adolescent↗
PubMed1995

Hydrops fetalis: role of the geneticist.

The causes of hydrops fetalis are myriad. As a result of the advent of routine Rh screening, most cases are not currently related to Rh incompatibility. Genetic, metabolic, chromosomal, and syndromic causes are among the most frequently identified causes of nonimmune hydrops. The importance of determining the underlying cause of hydrops becomes evident once issues such as prognosis, specific treatment, and risk of recurrence are considered. The medical geneticist is highly qualified to assist in the evaluation of hydrops. Clinical geneticists have undergone training in a primary care specialty followed by intensive training in the diagnosis, management, and counseling of individuals and families with genetic, chromosomal, or multifactorial syndromes or birth defects. This training prepares the medical geneticist well to serve as a consultant when hydrops is diagnosed. As knowledge of the molecular genetic and metabolic basis of disease increases, utilization of genetics laboratories continues to increase dramatically. In addition to examining the child to look for dysmorphic features, the clinical geneticist can assist with the laboratory evaluation by coordinating testing with the cytogeneticist, molecular geneticist, and biochemical geneticist as appropriate. Increased awareness of the role of the geneticist in the evaluation of such patients should prove helpful to the physicians caring for such patients and the patients' families.

Bone Diseases, Developmental↗
PubMed1994

A novel mutation in medium chain acyl-CoA dehydrogenase causes sudden neonatal death.

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common known genetic disorder of fatty acid oxidation. Most (approximately 80%) cases are homozygous for a single mutation: A to G replacement at nucleotide 985 (A985G). MCAD deficiency typically presents in the second year of life as hypoketotic hypoglycemia associated with fasting and may progress to liver failure, coma, and death. Prompt diagnosis and management may prevent long-term sequelae. MCAD deficiency was verified by analysis of urinary acylglycine and serum acylcarnitine species from two neonates referred for diagnosis. Full-length cDNA and MCAD exon 7 and 11 genomic clones were prepared for sequence analysis. Normal and mutant cDNAs were expressed in bacteria, and enzymatic activity was assayed by the ferricenium hexaflurophosphate method. Four compound heterozygote individuals from two unrelated families with A985G on one allele and a novel G to A mutation at nucleotide 583 (G583A) as the second mutant allele presented with MCAD deficiency in the first week of life. The expressed G583A mutant protein lacks enzymatic activity. This novel mutation, G583A, is associated with severe MCAD deficiency causing hypoglycemia or sudden, unexpected neonatal death. This previously unrecognized phenotype of MCAD deficiency may contribute significantly to preventable infant deaths.

Acyl-CoA Dehydrogenase↗
PubMed1992

Osteogenesis imperfecta.

Recent biochemical, linkage, and molecular genetic studies have demonstrated that, in almost every instance, osteogenesis imperfecta results from mutations in the genes that encode the chains of type I collagen. Such studies have done much to improve our understanding of the molecular basis of brittle bone disease, and have provided significant inroads into molecular diagnosis and prognostic counseling. Nonetheless, further investigation is needed urgently to identify forms of medical therapy that will decrease morbidity in osteogenesis imperfecta.

Chromosome Aberrations↗
PubMed1992

Autosomal dominant transmission of acrodysostosis.

A mother and daughter with acrodysostosis are described. This documented parent-to-child transmission supports the hypothesis of autosomal dominant inheritance of acrodysostosis. The daughter exhibited many features of acrodysostosis by two months of age, demonstrating that acrodysostosis may be diagnosed in infancy.

Adult↗
PubMed1984

Cytochalasin B facilitates the inhibition of human polymorphonuclear leukocyte generation of superoxide by verapamil.

Several functions of the human neutrophil are dependent upon extracellular calcium for optimal activation. We studied the calcium dependency of human polymorphonuclear leukocyte (PMN) superoxide generation in response to opsonized zymosan particles and its modulation by the calcium channel antagonist verapamil. PMNs were isolated from anticoagulated blood after Ficoll-Hypaque density centrifugation. The isolated PMNs were incubated with opsonized zymosan particles. The superoxide anion generated was measured by a cytochrome C reduction assay. When PMNs were incubated with opsonized zymosan in a calcium-free buffer, there was 0.45 +/- 0.06 nmol of cytochrome C reduced per 1 X 10(6) PMN per minute. This increased to 0.76 +/- 0.12 nmol per 1 X 10(6) PMN per minute when 0.6 mmol/L Ca++ was present. Moreover, if the PMNs were incubated with cytochalasin B (5 micrograms/ml), the generation of superoxide anion was further enhanced. If the same experiments were conducted in the presence of verapamil, 100 mumol/L, superoxide generation was inhibited by 51.5% +/- 8.4%. For verapamil to inhibit superoxide generation, cytochalasin B was necessary. Our results suggest that verapamil-sensitive calcium channels may exist in human PMNs, and the demonstration of their presence is cytochalasin B-dependent.

Calcium↗
PubMedDate not supplied

Smith-Lemli-Opitz syndrome: the first malformation syndrome associated with defective cholesterol synthesis.

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.

Animals↗