Biomedical subjects
Publications and source records attributed to D de Silva.
Meckel Gruber syndrome (MGS), an autosomal recessive disorder characterised by posterior encephalocoele, multicystic kidneys and post-axial polydactyly should be recognised by obstetricians and paediatricians to counsel parents regarding the 25% recurrence risk. We report a consanguineous family with MGS affecting three infants.
OBJECTIVE: To assess impact of long term psychotic disorders on caregivers. DESIGN: A questionnaire based, interviewer administered, cross-sectional survey using the translated version of a Burden Assessment scale (BAS). SETTING: Outpatient clinic of the University Psychiatry Unit, National Hospital, Sri Lanka. SAMPLE: 50 caregivers of patients suffering from psychotic disorders for more than 2 years. MEASUREMENTS: The BAS was administered to 50 caregivers to assess degree of distress and domains of concerns. RESULTS: 60% of caregivers felt very anxious and depressed. 54% experienced a financial decline, and 82% felt responsible for meeting the entire financial needs of the patient. 54% felt that their workload increased due to the illness. 58% of the caregivers were parents. CONCLUSIONS: Caregivers of patients with long term psychotic disorders are distressed, and have several concerns. Interventions focused on these will relieve the distress of caregivers and help patients. A majority of caregivers are parents. This has future implications, as many patients are not capable of independent living.
School children carry the heaviest burden of morbidity due to intestinal helminth infection. The objective of this investigation was to study geo-helminth infections in 349 school children aged 6 to 13 years living in a rural area of Sri Lanka. Stool samples were examined by direct saline smear in an initial survey to determine the prevalence of intestinal parasitic infections and thereafter the children were followed up over a two year period with cross sectional surveys of stool samples being carried out at yearly intervals. Following collection of a stool sample, all the subjects were treated with mebendazole 500 mg as a single dose. Weights and heights were measured using standardized procedures. 2 ml of venous blood were collected from each subject under aseptic conditions to determine hematological indices. The prevalence of geo-helminth infections was low, and the prevalence declined during the two-year period from 5.4% in 1997 to 2.2% in 1998 and 2.0% in 1999 following yearly mass anti-helminth treatment. The incidence density was 0.021 cases per child year. The reduction in the prevalence from the baseline to the second survey is probably due to the reduction of the reservoir of infection among children as a result of mass treatment at baseline. The prevalence of infection during the second and third surveys were almost the same probably due to infections originating from other segments of the untreated population.
The polymerase chain reaction (PCR) is usually analyzed by gel electrophoresis for size separation of PCR products. Additional separation techniques, such as single-stranded conformational polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE), temperature gradient gel electrophoresis (TGGE) and denaturing high-performance liquid chromatography (DHPLC), can also be used to scan for sequence alterations. These techniques are all based on the effect of PCR product hybridization on mobility. Hybridization can also be monitored with fluorescence during PCR without chromatographic or electrophoretic separation. Continuous monitoring of PCR allows the detection, quantification and sequence specificity of PCR products to be assessed, often without any need for further analysis. In such a closed system, PCR quantification with sensitivity to the single copy level can be achieved using either double-stranded DNA binding dyes or fluorescently labeled allele-specific oligonucleotide (ASO) probes. Melting curve analysis with ASO probes can be used to genotype various alleles, including single base alterations. The integration of rapid cycle PCR and ASO probes in an automated system greatly facilitates research and clinical applications of nucleic acid analysis in genetics, oncology, and infectious disease.
The most common cause of maturity-onset diabetes of the young (MODY) is a mutation in the hepatic nuclear factor 1alpha (HNF1alpha) gene (MODY3). We describe a family in which a missense mutation causing a Thr-Ile substitution at codon 620 has been found in all affected members. The mutation is not fully penetrant as two family members aged 87 and 46 have the mutation but do not have diabetes. The severity and age of diagnosis of diabetes varies widely within the family, and most presented over the age of 25. HNF1alpha mutation screening should be considered in any family with autosomal dominant inheritance of diabetes where one member has presented with diabetes before the age of 25. Predictive testing is now possible within the majority of MODY families, and is of clinical benefit, but the possibility of non-penetrance should be addressed during counselling and interpretation of results.
The clinical features and cytogenetic results of an 18 year old mentally handicapped female found to be a mosaic for a tandem duplication of chromosome 1 (46,XX,dup(1)(q12q22)/46,XX) are reported. The case is compared with the three previously described cases and possible mechanisms for the origin of the duplication are discussed. This patient was not found to have features of Proteus syndrome which was previously reported in a subject mosaic for a tandem duplication involving chromosome (1)(q11q25).
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The gene responsible for Friedreich's ataxia, a disease characterized by neurodegeneration and cardiomyopathy, has recently been cloned and its product designated frataxin. A gene in Saccharomyces cerevisiae was characterized whose predicted protein product has high sequence similarity to the human frataxin protein. The yeast gene (yeast frataxin homolog, YFH1) encodes a mitochondrial protein involved in iron homeostasis and respiratory function. Human frataxin also was shown to be a mitochondrial protein. Characterizing the mechanism by which YFH1 regulates iron homeostasis in yeast may help to define the pathologic process leading to cell damage in Friedreich's ataxia.
The FET3 gene product of Saccharomyces cerevisiae is an essential component of the high affinity iron transport system. Based on FET3 sequence homology to the multicopper oxidase family and iron oxidation studies in spheroplasts (De Silva, D. M., Askwith, C. C., Eide, D., and Kaplan, J. (1995) J. Biol. Chem. 270, 1098-1101), it was hypothesized that the Fet3 protein (Fet3p) was a cell surface ferroxidase. To further characterize the protein, we have isolated Fet3p from yeast membranes and purified the protein to apparent homogeneity. Consistent with its localization at the plasma membrane, Fet3p is a glycosylated protein. SDS-polyacrylamide gel electrophoresis analysis showed that the protein was present in two differentially glycosylated forms of approximately 120 and 100 kDa. Purified Fet3p is a copper-containing protein that is able to catalyze the oxidation of a variety of organic compounds in addition to ferrous iron. Azide and metal chelators strongly inhibited enzyme activity. Iron appeared to be the best substrate for the enzyme, and the apparent Km for ferrous oxidation was 2 microM. Interestingly, Fet3p was able to effectively catalyze the incorporation of iron onto apotransferrin. We conclude that Fet3p is a ferro-O2-oxidoreductase in yeast, homologous to the human plasma protein ceruloplasmin.
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OBJECTIVES: To determine knowledge about four genetic disorders (Down's syndrome (DS), haemophilia (haem), spinal muscular atrophy type 1 (SMA1) and Huntington's disease (HD)), attitudes towards counselling, acceptability of prenatal diagnosis and termination of pregnancies affected with these conditions. DESIGN: Questionnaire survey of a cohort of medical students and newly qualified doctors. SETTING: Faculty of Medicine, University of Ruhuna. RESULTS: 227 completed questionnaires (111 fourth year and 86 final year students, and 30 demonstrators) were analysed. Awareness of DS and haem, was higher than of SMA1 and HD, and was highest among the demonstrators. Over 80% of the cohort would not counsel directively about future pregnancies and would discuss the diseases with the family or at risk individuals. Prenatal diagnosis was found acceptable for DS, haem and SMA1 by a majority of the cohort. Attitudes to termination of affected pregnancies varied, 88%, 77%, 55% and 36% finding it acceptable for DS, SMA1, haem, and HD respectively, provided legal terminations were available and termination was requested by parents. CONCLUSIONS: This cohort of students and doctors appear to accept the principles of clinical genetics involving non-directive counselling, prenatal diagnosis and in some disorders, termination of pregnancy.
In recent years, significant advances have been made in our understanding of the mechanism and regulation of elemental iron transport in the eukaryote Saccharomyces cerevisiae. This organism employs two distinct iron-transport systems, depending on the bioavailability of the metal. In iron-replete environments, a low-affinity transport system (K(m) = 30 microM) is used to acquire iron. This system may also be used to acquire other metals including cobalt and cadmium. When environmental iron is limiting, a high-affinity (K(m) = 0.15 microM) iron-transport system is induced. Genetic studies in S. cerevisiae have identified multiple genes involved in both iron-transport systems. Cell-surface reductases, FRE1 and FRE2, provide ferrous iron for both systems. A non-ATP-dependent transmembrane transporter (FET4) has been identified as the main component of low-affinity transport. One gene identified to date as part of the high-affinity transport system is FET3, which shows high sequence and functional homology to multicopper oxidases. Accessory genes required for the functioning of this transport system include a plasma-membrane copper transporter (CTR1), an intracellular copper transporter (CCC2), and a putative transcription factor (AFT1). The mechanism by which these genes act in concert to ensure iron accumulation in S. cerevisiae presents an intriguing picture, drawing parallels with observations made in the human system almost 40 years ago.
Ovarian cancer is the fifth most common malignancy in women in the UK. Patients with a family history including ovarian cancer make up nearly 15% of family cancer referrals to the Genetic Clinic in Aberdeen. To date, only one pedigree has been suitable for linkage studies, which has enabled us to target screening more accurately at those people at highest risk. Following discovery of a strong candidate for the BRCA1 gene, direct mutation testing may soon be possible. People who seek testing will require further counselling. Therefore we anticipate an increased demand on both clinical and laboratory resources, but more accurate ascertainment of high risk subjects should lead to more appropriate targeting of screening services.
Bazex-Dupre-Christol syndrome (BDCS) is an X linked dominant disorder of the hair follicle characterised by follicular atrophoderma, multiple basal cell carcinomas, hypotrichosis, milia, and localised hypohidrosis. Follicular atrophoderma (FA) are follicular funnel shaped depressions, "ice pick marks", seen most commonly on the dorsum of the hands. We describe the first known Scottish family with this syndrome, five affected members spanning three generations. They have hypohidrosis confined to the face, coarse hair, dry skin, milia, and follicular atrophoderma. All the adults have a history of multiple basal cell carcinomas. None of them has any skeletal feature suggestive of Gorlin's syndrome. The clinical features, skin histology, and scanning electron microscopic (SEM) examination of the hair are described and illustrated. The features are compared with 15 previous reports of BDCS and four reports in which this is a possible diagnosis are also reviewed. BDCS should be considered as a differential diagnosis in patients with early onset or familial basal cell carcinomas.
Breast cancer is a multifactorial disease with an inherited predisposition being implicated in around 5% of all cases. Using previous epidemiological data assessing risks for the relatives of women with breast cancer, we have identified 154 women (from a screened population of 35,505) and 289 of their relatives between 50 and 64 years who have more than twice the age related risk of developing breast cancer. This constitutes 1.24% of the breast screening population attending the North East Scotland NHSBSP. For each woman identified to be at high risk, we have found 1.87 female relatives between 50 and 64 years and 1.85 relatives under 50 years also to be at high risk. Around 78% of the women identified with a significant family history of breast or other cancer have attended for counselling about their risks. The breast screening programme can be used to identify women at high risk of breast cancer in order to offer them (and their relatives) access to genetic counselling and appropriate screening.