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Biomedical subjects

L Sheffield

Publications and source records attributed to L Sheffield.

At least 19 recordsLinked to original sources

Autosomal dominant Klippel-Feil anomaly with cleft palate.

Klippel-Feil anomaly is characterized by the fusion of two or more cervical vertebrae. Most cases are sporadic but dominant and recessive inheritance are well described. Associated anomalies such as a cleft palate are common. We describe a unique family with autosomal dominantly inherited Klippel-Feil anomaly in six individuals associated with a cleft palate in four. One patient, a child, has a cleft palate only but may develop radiological cervical fusion with time, as documented in two other family members.

Adult↗

Modified Method for the Detection of the CAG Repeat Expansion in Huntington's Disease and Application to a Predictive Testing Protocol.

Background: The identification of the CAG trinucleotide repeat expansion as the cause of Huntington's disease (HD) has dramatically altered the ease and uptake of testing. The direct test for the mutation allows testing of many more consultands, particularly those individuals whose family structure is not suitable for linkage analysis. Therefore, protocols that can rapidly handle a number of samples and give accurate reliable results are essential. Methods and Results: The HD1/HD2 set of primers, which amplify the variable CAG and polymorphic CCG repeats, and the HD1/HD3 set of primers, which amplify only the variable CAG repeat, were used. Comparison of internally labeled with end-labeled polymerase chain reaction product was made. "Lysates" made from blood were investigated as suitable material for the HD polymerase chain reaction. Conclusions: The conditions used for detection of the CAG repeat in the huntingtin gene by end labeling of one of the primers that amplifies only the CAG repeat were improved, and an efficient protocol that reduces sample preparation and storage by using lysates from blood rather than extracted purified genomic DNA was developed.

Journal Article↗

A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy.

X-linked recessive chondrodysplasia punctata (CDPX) is a congenital defect of bone and cartilage development characterized by aberrant bone mineralization, severe underdevelopment of nasal cartilage, and distal phalangeal hypoplasia. A virtually identical phenotype is observed in the warfarin embryopathy, which is due to the teratogenic effects of coumarin derivatives during pregnancy. We have cloned the genomic region within Xp22.3 where the CDPX gene has been assigned and isolated three adjacent genes showing highly significant homology to the sulfatase gene family. Point mutations in one of these genes were identified in five patients with CDPX. Expression of this gene in COS cells resulted in a heat-labile arylsulfatase activity that is inhibited by warfarin. A deficiency of a heat-labile arylsulfatase activity was demonstrated in patients with deletions spanning the CDPX region. These data indicate that CDPX is caused by an inherited deficiency of a novel sulfatase and suggest that warfarin embryopathy might involve drug-induced inhibition of the same enzyme.

Abnormalities, Drug-Induced↗

Charting infant distress: an aid to defining colic.

The value of a 24-hour distress diary, previously validated against a voice-activated audiotape record, was investigated in 30 infants with colic and 30 control infants. The infants with colic had significantly more distress behavior (300.0 minutes vs 102.5 minutes; p < 0.001), although overlap of duration of distress was noted. On the basis of a clinical definition of colic--total distress lasting 180 minutes in a 24-hour period--the diary had a sensitivity of 77% and a specificity of 87%. The sensitivity of the chart was confirmed in a separate study of another 90 infants with colic.

Child Behavior↗

Evidence that Rieger syndrome maps to 4q25 or 4q27.

We report a baby with the features of Rieger syndrome and a de novo interstitial deletion of 4q which includes band 4q26 and an adjoining GTL light band, either q25 or q27. Rieger syndrome is provisionally mapped to 4q23----q27 but band 4q26 has been excluded as a possible site, suggesting that Rieger syndrome must map to a band, either 4q25 or 4q27, adjoining 4q26.

Anodontia↗

Duplications of the X chromosome in males: evidence that most parts of the X chromosome can be active in two copies.

We have analysed two duplications of the X chromosome in male patients using chromosome replication and DNA methylation patterns as determinants of the functional status of the duplicated segments. In both cases, the large duplicated regions, Xq12-q22 and Xq26.3-qter, were not inactivated. A review of previously reported male cases revealed that these duplications were also not subject to inactivation. Taken together, the examined duplications cover almost the entire X chromosome except the pericentromeric region and Xq25-26. Thus, most regions of the X chromosome can be present in two functional copies without lethal consequences.

Blotting, Southern↗

Glyceryl ethers in peroxisomal disease.

1-O-Alkyl and 1-O-alk-1-enyl (plasmalogens) glyceryl ether lipid levels were measured in post-mortem brain and/or liver biopsies from 7 patients with ultrastructural and biochemical evidence of a defect in peroxisomal biogenesis and/or enzymological evidence of a disturbance in ether lipid synthesis. Near normal levels of both species of glyceryl ether lipids were found in neonatal adrenoleukodystrophy and infantile Refsum's disease but marked deficiencies were found in Zellweger's syndrome and rhizomelic chondrodysplasia punctata, the latter manifesting the most profound reduction in ether lipid levels. These observations suggest that little ether lipid biosynthesis occurs in vivo in rhizomelic chondrodysplasia punctata or Zellweger's syndrome. However, in some phenotypes with apparently gross reductions in peroxisomal numbers, e.g. neonatal adrenoleukodystrophy and infantile Refsom's disease, there is significant ether lipid synthesis in liver and brain.

Adrenoleukodystrophy↗

Unusual X chromosome inactivation in a mentally retarded girl with an interstitial deletion Xq27: implications for the fragile X syndrome.

A de novo interstitial deletion (X)(q27.1q27.3), between the loci DXS 105 and F8, has been found in a mentally retarded female. The deleted X chromosome is preferentially early replicating in fibroblasts, B cells and T cells, suggesting that the missing region plays a role in inactivation of the X chromosome. None of the available DNA probes except DXS 98 maps to the deleted region of about 10,000 kb. The locus FRAXA is either included in the deletion, or located close to the distal break point.

Blotting, Southern↗

Non-allelic mutations in X-linked retinitis pigmentosa.

Using RFLP studies, the disease locus in two X-linked retinitis pigmentosa families was found to be centromeric to DXS7 in one family and telomeric to DXS7 in another, suggesting non-allelic heterogeneity.

Blotting, Southern↗

Linkage heterogeneity between X-linked retinitis pigmentosa and a map of 10 RFLP loci.

In nine families in which X-linked retinitis pigmentosa (XLRP) is segregating, the lod scores of XLRP in a map of 10 RFLP loci were obtained by multipoint linkage analysis. The XLRP locus was located telomeric to DXS7 in seven of the families and centromeric to DXS7 in two of the families. Under the hypothesis of two XLRP loci, a heterogeneity (admixture) test was performed, providing significant evidence of heterogeneity in XLRP (P less than .01). No correlation was detected between the clinical manifestations of XLRP and the two different disease loci.

Chromosome Mapping↗

Rhizomelic chondrodysplasia punctata: clinical, pathologic, and biochemical findings in two patients.

The clinical, pathologic, and biochemical features of rhizomelic chondrodysplasia punctata are described in two patients. Although both patients had clinical and radiologic similarities, one patient survived for only 13 days and the other is still alive at 8 years. The most prominent pathologic feature was the marked degenerative change in the chondrocytes from resting cartilage. Fibroblast alkyldihydroxyacetone phosphate synthase activity was markedly reduced in both patients (approximately 10% of control mean); in contrast, dihydroxyacetone phosphate acyltransferase activity was only moderately reduced (50% of control mean). Alkyl and alk-l-enyl ether (plasmalogens) levels were very low in brain and liver. The accumulation of phytanic acid observed in plasma or liver was paralleled by a reduced ability of the patients' fibroblasts to oxidize phytanic acid. Our data indicate that the genetic defect in rhizomelic chondrodysplasia punctata results in abnormalities in two apparently unrelated pathways (i.e., phytanic acid oxidation and ether lipid biosynthesis.

Brain↗

Variable distributions of serum creatine kinase reference values. Relationship to exercise activity.

Although the effect of exercise on serum creatine kinase (CK: EC 2.7.3.2) activity is well known, no standard protocol for blood collection conditions has been developed. Variable frequency distributions of CK activities have been reported for reference range samples from different laboratories and have been attributed to laboratory differences. In this study the frequency distributions of creatine kinase activities (CK: EC 2.7.3.2) in serum samples obtained from the same groups of volunteers varied from a normal Gaussian distribution, to skewed distributions, on different occasions. In one collection extremely high CK values followed the performance of an eccentric exercise step test 5-8 days previously. In 2 students serum CK activities had not returned to resting values 12 and 15 days later. Peak serum CK values occurred within 24 h of other types of exercise. Serum CK frequency distributions in blood samples obtained from a group of nurses was skewed, whereas the distribution in mothers of school children was Gaussian. When repeat samples were obtained from the nurses after instruction to avoid exercise, the distribution became Gaussian. In view of the increasing levels of physical activity in the community, a standard protocol for serum CK analysis is required, in which exercise activity over the previous three weeks should be documented. Test subjects should be counselled to avoid unusual eccentric exercise and sampling should include 3 tests at least 1 week apart.

Adolescent↗

Fronto-ethmoidal meningoencephaloceles: morphology and treatment.

Twenty-five cases of fronto-ethmoidal meningoencephaloceles have been studied. The relationship to other sincipital meningoencephaloceles is explored. In all cases the exit holes from the anterior cranial fossa are at the site of the foramen caecum. The facial component of the defect determines the sub-classification: naso-frontal, naso-ethmoidal and naso-orbital. The cranio-facial deformity may consist of hypertelorism, orbital dystopia, elongation of the face and dental malocclusion. These reflect the distorting influence of the extruded intracranial contents on facial growth. Early removal of the meningoencephalocele by the cranio-facial route is recommended to allow normal growth forces to be re-established. In older patients with established deformities translocation of the orbits may be necessary.

Adolescent↗