PubMed Health⌕ Search

Biomedical subjects

A Goodeve

Publications and source records attributed to A Goodeve.

At least 19 recordsLinked to original sources
PubMed2006

Genetic diagnosis of haemophilia and other inherited bleeding disorders.

Inherited deficiencies of plasma proteins involved in blood coagulation generally lead to lifelong bleeding disorders, whose severity is inversely proportional to the degree of factor deficiency. Haemophilia A and B, inherited as X-linked recessive traits, are the most common hereditary hemorrhagic disorders caused by a deficiency or dysfunction of blood coagulation factor VIII (FVIII) and factor IX (FIX). Together with von Willebrand's disease, a defect of primary haemostasis, these X-linked disorders include 95% to 97% of all the inherited deficiencies of coagulation factors. The remaining defects, generally transmitted as autosomal recessive traits, are rare with prevalence of the presumably homozygous forms in the general population of 1:500,000 for FVII deficiency and 1 in 2 million for prothrombin (FII) and factor XIII (FXIII) deficiency. Molecular characterization, carrier detection and prenatal diagnosis remain the key steps for the prevention of the birth of children affected by coagulation disorders in developing countries, where patients with these deficiencies rarely live beyond childhood and where management is still largely inadequate. These characterizations are possible by direct or indirect genetic analysis of genes involved in these diseases, and the choice of the strategy depends on the effective available budget and facilities to achieve a large benefit. In countries with more advanced molecular facilities and higher budget resources, the most appropriate choice in general is a direct strategy for mutation detection. However, in countries with limited facilities and low budget resources, carrier detection and prenatal diagnosis are usually performed by linkage analysis with genetic markers. This article reviews the genetic diagnosis of haemophilia, genetics and inhibitor development, genetics of von Willebrand's disease and of rare bleeding disorders.

Blood Coagulation Disorders, Inherited↗
PubMed2006

Linkage analysis in families diagnosed with type 1 von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 VWD.

BACKGROUND: von Willebrand disease (VWD) type 1 is a congenital bleeding disorder caused by genetic defects in the von Willebrand factor (VWF) gene and characterized by a reduction of structurally normal VWF. The diagnosis of type 1 VWD is difficult because of clinical and laboratory variability. Furthermore, inconsistency of linkage between type 1 VWD and the VWF locus has been reported. OBJECTIVES: To estimate the proportion of type 1 VWD that is linked to the VWF gene. PATIENTS AND METHODS: Type 1 VWD families and healthy control individuals were recruited. An extensive questionnaire on bleeding symptoms was completed and phenotypic tests were performed. Linkage between VWF gene haplotypes and the diagnosis of type 1 VWD, the plasma levels of VWF and the severity of bleeding symptoms was analyzed. RESULTS: Segregation analysis in 143 families diagnosed with type 1 VWD fitted a model of autosomal dominant inheritance. Linkage analysis under heterogeneity resulted in a summed lod score of 23.2 with an estimated proportion of linkage of 0.70. After exclusion of families with abnormal multimer patterns the linkage proportion was 0.46. LOD scores and linkage proportions were higher in families with more severe phenotypes and with phenotypes suggestive of qualitative VWF defects. About 40% of the total variation of VWF antigen could be attributed to the VWF gene. CONCLUSIONS: We conclude that the diagnosis of type 1 VWD is linked to the VWF gene in about 70% of families, however after exclusion of qualitative defects this is about 50%.

Adolescent↗
PubMed2006

A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD).

BACKGROUND: A quantitative description of bleeding symptoms in type 1 von Willebrand disease (VWD) has never been reported. OBJECTIVES: The aim was to quantitatively evaluate the severity of bleeding symptoms in type 1 VWD and its correlation with clinical and laboratory features. PATIENTS AND METHODS: Bleeding symptoms were retrospectively recorded in a European cohort of VWD type 1 families, and for each subject a quantitative bleeding score (BS) was obtained together with phenotypic tests. RESULTS: A total of 712 subjects belonging to 144 families and 195 controls were available for analysis. The BS was higher in index cases than in affected family members (BS 9 vs. 5, P < 0.0001) and in unaffected family members than in controls (BS 0 vs. -1, P < 0.0001). There was no effect of ABO blood group. BS showed a strong significant inverse relation with either von Willebrand ristocetin cofactor (VWF:RCo), von Willebrand antigen (VWF:Ag) or factor VIII procoagulant activity (FVIII:C) measured at time of enrollment, even after adjustment for age, sex and blood group (P < 0.001 for all the four upper quintiles of BS vs. the first quintile, for either VWF:RCo, VWF:Ag or FVIII:C). Higher BS was related with increasing likelihood of VWD, and a mucocutaneous BS (computed from spontaneous, mucocutaneous symptoms) was strongly associated with bleeding after surgery or tooth extraction. CONCLUSIONS: Quantitative analysis of bleeding symptoms is potentially useful for a more accurate diagnosis of type 1 VWD and to develop guidelines for its optimal treatment.

ABO Blood-Group System↗
PubMed2005

The molecular analysis of haemophilia A: a guideline from the UK haemophilia centre doctors' organization haemophilia genetics laboratory network.

Haemophilia A is a common inherited bleeding disorder that has a well-understood pathophysiology. Our understanding of the molecular genetics of the disease has allowed the development of comprehensive carrier and prenatal diagnosis for this single gene defect. Continuing technological developments improve our ability to provide genetic analysis in a rapid and cost effective manner. This guideline aims to provide advice on current best laboratory practice when approaching genetic diagnosis of haemophilia A.

Base Sequence↗
PubMed2005

The molecular analysis of haemophilia B: a guideline from the UK haemophilia centre doctors' organization haemophilia genetics laboratory network.

Haemophilia B is one of the most common inherited bleeding disorders and has a well understood pathophysiology. Our understanding of the molecular genetics of the disease has allowed the development of comprehensive carrier and prenatal diagnosis for this single gene disorder. Continuing technological developments improve our ability to provide genetic analysis in a rapid and cost-effective manner. This guideline aims to provide advice on current best laboratory practice when approaching genetic diagnosis of haemophilia B.

Base Sequence↗
PubMed2001

Somatic mosaicism in hemophilia A: a fairly common event.

Mutations in the large gene of clotting factor VIII (FVIII) are the most common events leading to severe human bleeding disorder. The high proportion of de novo mutations observed in this gene raises the possibility that a significant proportion of such mutations does not derive from a single germ cell but instead should be attributed to a germline or somatic mosaic originating from a mutation during early embryogenesis. The present study explores this hypothesis by using allele-specific PCR to analyze 61 families that included members who had sporadic severe hemophilia A and known FVIII gene defects. The presence of somatic mosaicisms of varying degrees (0.2%-25%) could be shown in 8 (13%) of the 61 families and has been confirmed by a mutation-enrichment procedure. All mosaics were found in families with point mutations (8 [25%] of 32 families). In the subgroup of 8 families with CpG transitions, the percentage with mosaicism increased to 50% (4 of 8 families). In contrast, no mosaics were observed in 13 families with small deletions/insertions or in 16 families with intron 22 inversions. Our data suggest that mosaicism may represent a fairly common event in hemophilia A. As a consequence, risk assessment in genetic counseling should include consideration of the possibility of somatic mosaicism in families with apparently de novo mutations, especially families with the subtype of point mutations.

Alleles↗
PubMed2001

A standard nomenclature for von Willebrand factor gene mutations and polymorphisms.

Mutations in the von Willebrand factor gene responsible for von Willebrand disease, in particular those responsible for type 2 von Willebrand disease, are being increasingly identified. The plethora of mutation screening techniques now available and their enhanced sample throughput capability is also enabling an increasing number of investigations in patients with types 1 and 3 disease. An unambiguous von Willebrand factor nucleotide and amino acid nomenclature is now essential. In this paper, we present a uniform standard nomenclature for von Willebrand factor gene mutations and polymorphisms as approved and recommended by the International Society on Thrombosis and Haemostasis Scientific and Standardisation Committee subcommittee on von Willebrand factor.

DNA↗
PubMed2000

Haemophilias: advances towards genetic engineering replacement therapy.

Both haemophilia A and B are X-linked recessive disorders and therefore occur almost exclusively in males. The genes for both factors VIII and IX have been mapped to the distal end of the long arm of the X chromosome, bands Xq28 and Xq27.1, respectively. The Factor VIII gene comprises 186 kb DNA with 9 kb of exon of DNA which encodes an mRNA of nearly 9 kb. The Factor IX gene is 34 kb in length and the essential genetic information is present in eight exons which encode 1.6 kb mRNA. In gene therapy, genetic modification of the target cells can be either ex vivo or in vivo. The advantage of the ex vivo approach is that the genetic modification is strictly limited to the isolated cells. In the in vivo approach, the integrity of the target tissue is maintained but the major challenge is to deliver the gene to the target tissue. The use of improved retroviral and adenovirus-based vectors for gene therapy has produced clinically relevant levels of human factor VIII in mice and haemophilic dogs. If further improvements can increase the persistence of expression and decrease the immunological responses, phase I clinical trials in patients can be considered.

Animals↗
PubMed2000

Experience of a single Italian center in genetic counseling for hemophilia: from linkage analysis to molecular diagnosis.

BACKGROUND AND OBJECTIVE: We describe our three year experience in genetic counseling at the Castelfranco Veneto Hemophilia Center, Italy. DESIGN AND METHODS: A total of 258 individuals were involved in the study of 142 females. These formed 40 families with hemophilia A and 6 families with hemophilia B. Following pedigree analysis, the FVIII inversion was first examined in severe hemophilia A patients by polymerase chain reaction (PCR) analysis. DNA polymorphisms were used to track the affected gene through the remaining families. In uninformative cases, we initiated analysis of the FVIII or FIX gene coding region by conformation sensitive gel electrophoresis and DNA sequencing to identify the mutation responsible for the disease. RESULTS: The FVIII gene inversion was present in 16 of the 32 patients (50%) affected by severe hemophilia A and was informative for 44 females. For hemophilia A, 45 cases (55%) were informative by linkage analysis, however 37 (45%) were uninformative because of lack of key individuals, homozygosity, or sporadic disease. Information from extragenic linked polymorphisms alone was present in 9 cases (6%). For hemophilia B, linkage analysis was informative in only 50% of females (8 out of 16). To date, nine mutations have been identified in patients with hemophilia A and three in patients with hemophilia B. Six novel missense mutations in hemophilia A are discussed briefly. INTERPRETATION AND CONCLUSIONS: Using this approach we are now able to offer accurate genetic analysis to virtually all families with hemophilia.

Chromosome Inversion↗
PubMed1999

A study of Wilson disease mutations in Britain.

Wilson disease (WD) is an autosomal recessive disease of copper transport. The disease is caused by a large number of mutations in the ATP7B gene, some of which appear to be population specific, whereas others are found in probands from a variety of different ethnic backgrounds. This study presents the results of screening the ATP7B gene by SSCP and sequencing in order to define the spectrum of mutations seen in British referrals for WD. The 52 patients screened included 10 with a non-British mixed ethnicity origin. This study identified 19 novel mutations and 18 mutations that had been previously described. The novel mutations included seven nonconservative missense mutations, eight small insertions, or deletions causing frameshift, two nonsense mutations, and two splice-site mutations. Seven of the 10 mixed ethnicity patients harboured homozygous mutations, whereas only four of the larger British group were homozygotes. The detection rate by SSCP analysis in the British group of 42 consecutive unrelated WD probands was 70%. However, SSCP screening of just three exons (exons 8, 14, and 18) is predicted to identify 60% of mutations present in WD referrals.

Adenosine Triphosphatases↗
PubMed1999

c-kit proto-oncogene exon 8 in-frame deletion plus insertion mutations in acute myeloid leukaemia.

Genomic DNA from 60 cases of acute myeloid leukaemia (AML) was screened for mutations in the c-kit gene. DNA from all 21 exons was subjected to polymerase chain reaction (PCR) amplification and analysis by conformation sensitive gel electrophoresis (CSGE); exons showing altered CSGE patterns were then sequenced. Mutations were identified only in those patients with inv(16) (3/7 cases) or t(8;21) (1/2 cases) and comprised three in-frame deletion plus insertion mutations (exon 8) and one point mutation (exon 10, GTA --> ATA, Val530Ile). Exons 8 and 10 were then analysed in 31 further cases of inv(16) (n = 14) and t(8;21) (n = 17), revealing four additional exon 8 in-frame deletion plus insertion mutations, all of which were in cases of inv(16). All exon 8 in-frame deletion plus insertion mutations (n = 7) involved the loss or replacement of the codon for Asp419 which is highly conserved cross species and is located in the receptor's extracellular domain. The high frequency of the c-kit proto-oncogene exon 8 deletion plus insertion mutations in AML suggests an essential role for this region of the receptor's extracellular domain. The association with inv(16) invites speculation as to the link between these two changes in the pathogenesis of AML.

Acute Disease↗
PubMed1998

Late relapsing childhood lymphoblastic leukemia.

Childhood lymphoblastic leukemia (ALL) is usually assumed to have been permanently eradicated in patients in long-term remission, but occasionally can recur after many years. To learn more about the problem, we studied a group of children whose leukemia had been in remission for 10 or more years before relapse and tried to determine whether they had true recurrences or second malignancies. We studied children treated on Medical Research Council ALL protocols between 1970 and 1984 and followed up by the Clinical Trial Service Unit in Oxford. Detailed clinical and laboratory data was collected from the centers concerned on all who were reported to have had a recurrence of their leukemia after 10 or more years from the time of achieving first complete remission (CR1). To prove that the relapse was a true recurrence rather than a second or secondary leukemia, DNA extracted from archived marrow smears was subjected to polymerase chain reaction (PCR) analysis for the presence of an identical Ig heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement at initial diagnosis and subsequent relapse. A total of 1,134 of 2,746 children had survived 10 years or more (range, 10 to 24 years) in CR1 and of those, 12 (approximately 1%) had subsequently relapsed. Relapse blast cells were shown to express the common ALL antigen (CD 10) in all cases and an identical clonal IgH or TCR gene rearrangement was found on PCR analysis of DNA from diagnosis and relapse in all eight cases where DNA extraction was successful. A further program of therapy was successful in inducing a second CR in all patients, four of whom have succumbed to a second relapse after 12 to 27 months. The remaining eight are in continuing CR2 at a follow-up of 12 to 108 months (median, 52) from relapse. Although the risk of relapse of childhood ALL after 10 years in remission appears to be small (around 1%), it persists. This raises questions about how blasts can survive quiescent for so long and when we can truly be confident of cure, if ever.

Adult↗
PubMed1998

Rapid genotypic diagnosis of type 2A von Willebrand's disease by heteroduplex analysis.

We have previously reported a rapid heteroduplex-based technique which is able to identify at least 10 recurrent mutations associated with type 2A von Willebrand's disease. Thirteen patients with this disorder were genotyped by this method and a specific mutation was identified in nine cases. This simple DNA based approach can provide useful information to support data derived from phenotype tests in the initial assessment of such patients.

DNA↗
PubMed1997

Clonal stability in late-relapsing childhood lymphoblastic leukaemia.

We report stability of a clonal immunoglobulin heavy chain (IgH) gene rearrangement in a case of childhood acute lymphoblastic leukaemia (ALL) relapsing 17 years after completion of first-line therapy. Clonal stability was shown by polymerase chain reaction amplification of the hypervariable CDRIII region of IgH gene. Identically sized products from the original diagnostic and the second presentation samples were obtained and direct sequencing confirmed complete sequence homology. Absence of clonal evolution together with recent reports of persistent minimal residual disease in patients in long-term complete remission, suggests that 'cure' of childhood ALL may be critically dependent on effective immune surveillance to keep such disease below clinically significant levels.

Adult↗
PubMed1995

Factor VIII gene inversions in severe hemophilia A: results of an international consortium study.

Twenty-two molecular diagnostic laboratories from 14 countries participated in a consortium study to estimate the impact of Factor VIII gene inversions in severe hemophilia A. A total of 2,093 patients with severe hemophilia A were studied; of those, 740 (35%) had a type 1 (distal) factor VIII inversion, and 140 (7%) showed a type 2 (proximal) inversion. In 25 cases, the molecular analysis showed additional abnormal or polymorphic patterns. Ninety-eight percent of 532 mothers of patients with inversions were carriers of the abnormal factor VIII gene; when only mothers of nonfamilial cases were studied, 9 de novo inversions in maternal germ cells were observed among 225 cases (approximately 1 de novo maternal origin of the inversion in 25 mothers of sporadic cases). When the maternal grandparental origin was examined, the inversions occurred de novo in male germ cells in 69 cases and female germ cells in 1 case. The presence of factor VIII inversions is not a major predisposing factor for the development of factor VIII inhibitors; however, slightly more patients with severe hemophilia A and factor VIII inversions develop inhibitors (130 of 642 [20%]) than patients with severe hemophilia A without inversions (131 of 821 [16%]).

Blotting, Southern↗
PubMed1995

DNA polymorphisms for carrier detection of hemophilia in Thailand.

The assessment of carrier state based on the pedigree and laboratory testing in 55 females from 34 Thai hemophilia families (24 affected by hemophilia A, 10 by hemophilia B) was studied. The laboratory testing included phenotypic analysis (FVIII:C/vWF: Ag ratio, FIX:C) and two types of DNA polymorphisms, restriction fragment length polymorphisms (RFLP) and variable number tandem repeats (VNTR) in/and close to the factor VIII genes (Bcl I, Xba I RFLP, St 14 VNTR) and factor IX genes (Mse I, Dde I RFLP). Fifteen out of seventeen (88%) obligate hemophilia A carriers and one out of five (20%) obligate hemophilia B carriers were diagnosed by phenotypic analysis. All hemophilia A carriers were informative for at least one polymorphism (Bcl I, Xba I or St 14) while 42% of hemophilia B carriers were informative for Mse I RFLP only. DNA polymorphism analysis has advantage over phenotypic analysis since it generally gives an absolute diagnosis when informative. Most DNA polymorphism analyses are performed by PCR technique which is a simple, inexpensive and quick procedure. However, it is limited by non-informativeness and high incidence of new mutations.

Factor IX↗