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Biomedical subjects

J Old

Publications and source records attributed to J Old.

At least 19 recordsLinked to original sources
PubMed2000

Informed choice in genetic screening for thalassaemia during pregnancy: audit from a national confidential inquiry.

OBJECTIVE: National audit of informed choice in antenatal screening for thalassaemia. DESIGN: Audit from the UK Confidential Enquiry into Counselling for Genetic Disorders. SETTING: Thalassaemia module of the UK Confidential Enquiry into Counselling for Genetic Disorders. SUBJECTS: 138 of 156 couples who had had a pregnancy affected by a major beta thalassaemia from 1990 to 1994. MAIN OUTCOME MEASURES: How and when genetic risk was identified for each couple, and whether and when prenatal diagnosis was offered. RESULTS: Risk was detected by screening before or during the first pregnancy in 49% (68/138) of couples and by diagnosis of an affected child in 28% (38/138) of couples. Prenatal diagnosis was offered in 69% (274/400) of pregnancies, ranging from 94% (122/130) for British Cypriots to 54% (80/149) for British Pakistanis and from 90% in the south east of England to 39% in the West Midlands. Uptake of prenatal diagnosis was 80% (216/274), ranging from 98% (117/120) among British Cypriots in either the first or second trimester to 73% (35/48) among British Pakistanis in the first trimester and 39% (11/28) in the second trimester. A demonstrable service failure occurred in 28% (110/400) of pregnancies, including 110 of 126 where prenatal diagnosis was not offered and 48 of 93 that ended with an affected liveborn infant. CONCLUSION: Although antenatal screening and counselling for haemoglobin disorders are standard practices in the United Kingdom, they are delivered inadequately and inequitably. An explicit national policy is needed, aiming to make prenatal diagnosis in the first trimester available to all couples and including ongoing national audit.

Choice Behavior↗
PubMed2000

Beta-thalassaemia intermedia in Lebanon.

Approximately one third of thalassaemia patients on record in Lebanon have thalassaemia intermedia. We have analysed three factors in a panel of 73 patients with this less severe form of the disease in our population: mild beta-globin gene mutations, deletions in the alpha-globin gene and the presence of a polymorphism for the enzyme Xmn I in the Ggamma-promoter region. The results show that the most important contributing factor is the beta-genotype: 68% of patients have a mild beta+ mutation (IVSI-6, cd29, -88 or -87), while 26% of patients are positive for the Xmn I polymorphism associated with increased production of HbF, which showed strong linkage to particular mutations (IVSII-1, cd8 and cd30). However, the genotype phenotype correlation is difficult, because many patients were initially misdiagnosed as thalassaemia major and were started early on regular blood transfusions, which was stopped later on. This illustrates well the importance of an early accurate diagnosis of thalassaemia intermedia for appropriate clinical management.

Adolescent↗
PubMed2000

Jamaican Sbeta+-thalassaemia: mutations and haematology.

The sickling disorders are a common cause of morbidity and mortality in Jamaica. Sickle cell beta+-thalassaemia is the fourth commonest form, occurring in one in every 3000 births. This is a heterogeneous condition, producing HbS, HbF and HbA2 with variable amounts of HbA, depending on the mutation and, within a defined population, only a few beta-thalassaemia mutations occur at high frequency. This study establishes the frequency of beta-thalassaemia mutations in Sbeta+-thalassaemia patients in Jamaica. In addition, comparison of the haematological phenotypes is possible by looking at the 'average steady-state haematology' of the different mutational groups. Blood samples from 132 unrelated Sbeta+-thalassaemia patients attending the MRC Sickle Cell Unit at the University of the West Indies were analysed by amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) or sequencing to determine the nature and frequencies of the underlying beta-thalassaemia mutations. Ten mutations were identified, four of which accounted for 93% of patients studied. These were -29(A --> G) in 71 (54%), -88(C --> T) in 27 (20%), polyA(T --> C) in 17 (13%) and IVS1-5(G --> C) in nine (7%). The six remaining mutations found at low frequency were C24(T --> A) in two patients and one each of IVS2-848(C --> A), -90(C --> T), IVS1-5(G --> T), IVS1-5(G --> A) and IVS1-6 (T --> C). In one individual, no mutation was found. The three commonest mutations were all associated with haemoglobin levels of greater than 10 g/dl, whereas IVS1-5 (G --> C) had a more severe haematological phenotype. The predominance of -29(A --> G) and -88(C --> T) is in keeping with other studies on populations of African origin. IVS1-5(G --> C) is found chiefly in Indian populations, and all affected families acknowledged Indian ancestry, reflecting the prominent Indian community in Jamaica.

Deoxyribonucleases, Type II Site-Specific↗
PubMed1997

Audit of prenatal diagnosis for haemoglobin disorders in the United Kingdom: the first 20 years.

OBJECTIVES: To audit services for prenatal diagnosis for haemoglobin disorders in the United Kingdom. DESIGN: Comparison of the annual number of cases recorded in a United Kingdom register of prenatal diagnoses for haemoglobin disorders, with the annual number of pregnancies at risk of these disorders, by ethnic group and regional health authority. The number of pregnancies at risk was estimated using data on ethnic group from the 1991 census and data from the United Kingdom thalassaemia register, which records the number of babies born with thalassaemia. SETTING: The three national prenatal diagnosis centres for haemoglobin disorders. SUBJECTS: 2068 cases of prenatal diagnosis for haemoglobin disorders in the United Kingdom from 1974 to 1994. MAIN OUTCOME MEASURES: Utilisation of prenatal diagnosis by risk, ethnic group, and regional health authority. Proportion of referrals in the first trimester and before the birth of any affected child. RESULTS: National utilisation of prenatal diagnosis for haemoglobin disorders was around 20%. During the past 10 years it has remained steady at about 50% for thalassaemias and risen from 7% to 13% for sickle cell disorders. Utilisation for sickle cell disorders varies regionally from 2% to 20%. Utilisation for thalassaemias varies by ethnic group. It is almost 90% for Cypriots and ranges regionally for British Pakistanis from 0% to over 60%. About 60% of first prenatal diagnoses are done for couples without an affected child. Less than 50% of first referrals are in the first trimester. CONCLUSIONS: National utilisation of prenatal diagnosis for haemoglobin disorders is far lower than expected, and there are wide regional variations. A high proportion of referrals are still in the second trimester and after the birth of an affected child. The findings point to serious shortcomings in present antenatal screening practice and in local screening policies and to inadequate counselling resources, especially for British Pakistanis.

Africa↗
PubMed1997

Incidence of endocrine complications and clinical disease severity related to genotype analysis and iron overload in patients with beta-thalassaemia.

The incidence of endocrine dysfunction in relation to the detailed genotype of beta-thalassaemia is investigated in this study. In addition, the association of genotype to specific clinical features of beta-thalassaemia is examined, together with the relationship between serum ferritin levels and endocrine complications. Ninety-seven patients were included, all with transfusion dependent beta-thalassaemia. Patients were divided into 2 categories; group 1 consisted of patients with a beta0/beta0 genotype with or without a concomitant alpha-globin gene deletion as well as patients with beta0/beta+ or beta+/beta+ genotype and normal alpha-globin chain synthesis. Group 2 included patients with beta+/beta+ or beta+/beta0 genotype and one alpha-globin chain deletion and those with a moderate amount of beta-globin chain synthesis (beta++) and normal alpha-globin chain synthesis. The results showed that group 1 patients were more likely to have severe clinical disease (p=0.005). Sixty-four patients (66%) had at least 1 endocrine disorder and 39 (40%) had multiple endocrinopathies; the most common abnormality was hypogonadotrophic hypogonadism (HH). There was a significant association between patients with group 1 genotypes and the presence of HH and impaired glucose tolerance or diabetes. A positive correlation was demonstrated between serum ferritin concentrations and the presence of thyroid or parathyroid dysfunction.

Adolescent↗
PubMed1996

Haemoglobinopathies.

The inherited haemoglobinopathies are a heterogeneous group of recessive disorders that include the thalassaemias and sickle cell disease. Nearly a thousand mutant alleles have now been characterized. The mutations are regionally specific and in most cases the geographical and ethnic distributions have been determined providing the foundation for a programme of control through screening, genetic counselling and prenatal diagnosis. The main requirements for methodologies providing molecular diagnosis are speed, cost, convenience and the ability to test for multiple mutations simultaneously. For beta-thalassaemia mutations the procedures that meet these requirements are the amplification refractory mutation system and the reverse dot-blot hybridization system. For alpha-thalassaemia the technique of gap PCR is useful for targeting specific deletion mutations but Southern blotting remains the standard diagnostic test.

Female↗
PubMed1995

Optimisation and properties of a UHG for genotyping of hemoglobins S and C.

The use of universal heteroduplex generators (UHG) as an effective means of screening for specific mutations has been previously reported. Here, we report the optimisation of a UHG system used for the rapid and simple detection of sickle cell hemoglobinopathies, HbS and HbC. The test involves heteroduplex formation between between polymerase chain reaction (PCR)-amplified beta-globin gene first exon sequences, and a UHG. The UHG is a synthetic DNA molecule homologous to HbA but which contains a small deletion adjacent to the HbS and HbC mutation sites in codons 5 and 6. Heteroduplexes are resolved on nondenaturing polyacrylamide minigels and are diagnostic of HbS and HbC in homozygous and heterozygous individuals. A blind trial of UHG genotyping involving eleven previously sequenced DNAs showed complete concordance between methods. In addition, we identified a characteristic heteroduplex banding pattern for the H2H silent mutation (CAC-->CAT) in codon 2.

Anemia, Sickle Cell↗
PubMed1994

Mutational bias provides a model for the evolution of Huntington's disease and predicts a general increase in disease prevalence.

Huntington's disease (HD) correlates with abnormal expansion in a block of CAG repeats in the Huntington's disease gene. We have investigated HD evolution by typing CAG alleles in several human populations and in a variety of primates. We find that human alleles have expanded from a shorter ancestral state and exhibit unusual asymmetric length distributions. Computer simulations are used to show that the human state can be derived readily from a primate ancestor, without the need to invoke natural selection. The key element is a simple length-dependent mutational bias towards longer alleles. Our model can explain a number of empirical observations, and predicts an ever-increasing incidence of HD.

Alleles↗
PubMed1994

Effect of alpha thalassaemia trait and enhanced gamma chain production on disease severity in beta thalassaemia major and intermedia.

One hundred and twenty patients with homozygous beta thalassaemia were selected to determine the clinical effects of certain genetic factors which may modify disease severity. Genetic analysis defined specific beta thalassaemia mutations, the alpha thalassaemia genotype, and the presence of an XmnI restriction enzyme site, associated with increased fetal haemoglobin (HbF) production under certain conditions. Genotypic data with globin chain synthesis were related to the age when regular transfusions began and subsequent pubertal development. This study showed that the major determinants of disease severity in beta thalassaemia were the beta thalassaemia mutations, with co-inheritance of alpha thalassaemia trait and coinheritance of a high HbF determinant acting as ameliorating factors. The presence of an alpha thalassaemia deletion significantly reduced initial disease severity, although the effect on pubertal development was less clear. It is concluded that detailed genetic analysis should be performed in all newly diagnosed patients with thalassaemia. This, in conjunction with clinical assessment, will help to predict disease severity and prognosis.

Adolescent↗
PubMed1992

Alpha thalassaemia hydrops fetalis in the UK: the importance of screening pregnant women of Chinese, other South East Asian and Mediterranean extraction for alpha thalassaemia trait.

OBJECTIVE: Alpha zero (alpha 0 or alpha-1) thalassaemia is an important genetic risk for women originating from Hong Kong, Singapore, Vietnam, Thailand, the Philippines or South China. Cypriots are also at risk. Carriers of alpha zero thalassaemia trait can be detected by routine haemoglobinopathy screening. When a couple are both carriers, in each pregnancy there is a 25% risk that the fetus will have alpha thalassaemia hydrops fetalis; this is fatal for the fetus and carries serious obstetric and psychological risks for the mother. Most informed couples at risk request prenatal diagnosis and selective abortion. This study investigates the effectiveness of screening, counselling and prenatal diagnosis for alpha thalassaemia hydrops fetalis in the UK. DESIGN: Retrospective analysis of the notes. SUBJECTS: 18 couples attending University College Hospital London for prenatal diagnosis of alpha thalassaemia hydrops fetalis since 1982. RESULTS: The study shows underdiagnosis of both alpha zero thalassaemia trait and alpha thalassaemia hydrops fetalis leading to avoidable stillbirths and complications in pregnancy. CONCLUSION: We recommend early screening for alpha zero thalassaemia trait for all women of Southeast Asian or eastern Mediterranean origin and the offer of prenatal diagnosis when indicated. The diagnosis of alpha thalassaemia hydrops fetalis should be considered in women of the relevant ethnic origin who have a stillbirth, neonatal death, abnormal ultrasound findings at fetal anomaly scanning (especially a large placenta), or who develop pre-eclampsia.

Abortion, Spontaneous↗
PubMed1987

Two unusual cases of first trimester prenatal diagnosis of cystic fibrosis using DNA probes.

There are now several DNA probes which localize the cystic fibrosis mutation (CF) to chromosome 7q2.2-q3.1. The most tightly linked probes, pJ3.11 and met, are useful for first trimester prenatal diagnosis for many families provided that there is at least one living child affected by CF (Farrall et al., 1986). We describe here two families seeking prenatal diagnosis for CF which present unusual counselling problems. The first is an extended family in which there is no living affected member with CF; the second, a consanguinous marriage at risk both for cystic fibrosis and beta-thalassaemia. In both cases first trimester chorionic villus sampling and DNA haplotype analysis predicted that the fetus is a carrier for CF, and in the doubly affected family a carrier for beta-thalassaemia as well. Both pregnancies resulted in live births and subsequent immunoreactive trypsin estimations were both in the normal range.

Chorionic Villi↗
PubMed1979

The molecular basis of alpha-thalassemias: frequent occurrence of dysfunctional alpha loci among non-Asians with Hb H disease.

Study of Asians has previously indicated that deletion of alpha-globin structural genes is the predominant lesion in alpha-thalassemias and that Hb H disease occurs when three of four normal alpha loci per cell are deleted. To test the generality of this model, Hb H disease DNAs of both Asian and non-Asian origin were analyzed by restriction endonuclease mapping using the technique of Southern (1975). Whereas in normal DNA, alpha sequences are present in a single Eco Rl fragment of cellular DNA approximately 22.5 kb long, fragments of 22.5, 20 and 2.6 kb were found in various Hb H disease DNAs. The 20 kb Eco Rl fragment alone, in which a single alpha-globin structural locus resides, was found in Asian Hb H disease DNA. This finding is consistent with the deletion model of alpha-thalassemia. In contrast, seven of eight non-Asian Hb H disease DNAs displayed a more complex molecular composition. The fragment patterns observed were 22.5 kb alone, 22.5 plus 2.6 kb, 20 plus 2.6 kb and 20 kb alone. Non-Asian Hb H disease DNAs contained one, two or three alpha loci per cell in contrast to the one locus predicted by the simple deletion model of alpha-thalassemia. The data are best explained by the existence of defective alpha loci in certain individuals with alpha-thalassemia, particularly outside the Asian population. Restriction mapping of the 20 kb Eco Rl fragment found in Asian and some non-Asian Hb H disease DNAs demonstrated a striking similarity in the placement of restriction sites about the single alpha gene compared with sites about the two genes in the 22.5 kb Eco Rl fragment seen in normal DNA. These data are consistent with origin of the 20 kb fragment from the 22.5 kb normal Eco Rl fragment by either unequal crossing-over or a deletion event. The molecular heterogeneity and frequent occurrence of defective alpha loci in non-Asian Hb H disease DNAs described here may explain, in part, the clinical heterogeneity of alpha-thalassemias and the absence of the homozygous deletion state (hydrops fetalis) in non-Asians. Further study of cellular DNA fragments containing the defective alpha loci identified in this work may indicate the types of specific mutations responsible for abnormal globin gene expression and complement similar studies on abnormal beta genes in beta-thalassemias.

Asia↗