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At least 1,315 records · Page 73Linked to original sources
PubMed1997

Thiopurine drugs in the treatment of childhood leukaemia: the influence of inherited thiopurine methyltransferase activity on drug metabolism and cytotoxicity.

AIMS: The response to 6-mercaptopurine (6MP) is highly variable. Its antileukaemic effect can be related to drug derived 6-thioguanine nucleotides (TGNs). The inherited level of thiopurine methyltransferase (TPMT) activity may be a major factor in the clinical response to 6MP because TPMT forms methylmercaptopurine metabolites (MeMPs) at the expense of TGNs. The aim of this study was to explore the clinical importance of TPMT phenotype. METHODS: Thiopurine metabolism was studied in a consecutive cohort of children with acute lymphoblastic leukaemia (ALL) treated according to the Medical Research Council trial UK ALL XI. TPMT phenotype was measured in 38 children at diagnosis, and thiopurine metabolites were measured at defined times during 2 years treatment in 29 of these children. RESULTS: TPMT activities at diagnosis ranged from 5.5 to 18.5 units ml(-1) packed RBCs, no different from the range of activities reported in healthy children. TGNs and MeMPs measured during the first 6MP cycle at 75 mg m(-2) ranged from 187 to 594 pmol 6TGNs, median 327, and 0.5 to 22.0 nmol MeMPs, median 4.5, per 8 x 10(8) RBCs. TPMT activity was not significantly related to the generation of MeMPs (r(s) = 0.06), but was negatively correlated to 6TGNs (r(s) = -0.44, P<0.025, n=29). TGNs were related to neutropenia at the point of dose reduction (r(s) = -0.5, P<0.01). TPMT activity was also inversely related to the duration of cytopenia driven 6MP withdrawal (r(s)= -0.41, P<0.05). CONCLUSIONS: These findings support the suggestion that the inherited activity of TPMT in a given individual can modulate the cytotoxic effect of 6MP, and this information may help in clinical management.

Antimetabolites, Antineoplastic↗
PubMed1999

Defining target antigens in linear IgA disease using skin from subjects with inherited epidermolysis bullosa as a substrate for indirect immunofluorescence microscopy.

Identification of target antigens in immunobullous disorders usually involves laborious techniques such as immunoblotting and immunoprecipitation, which do not always provide conclusive data. This is particularly true of linear IgA disease (LAD) in which the target antigen has often proved difficult to identify. As an alternative means of antigen identification in five adult patients with LAD, we performed indirect immunofluorescence (IIF) microscopy on a panel of skin samples taken from subjects with different forms of inherited epidermolysis bullosa (EB). Skin samples were selected that showed a complete absence of immunostaining for a specific basement membrane zone (BMZ) molecule (type VII collagen, laminin 5 or the 180-kDa bullous pemphigoid antigen BP180). In each case, the underlying genetic mutations had been defined and shown to consist of premature termination codons on both alleles of the particular gene, resulting in total ablation of the encoded protein. Two epidermal-binding LAD sera showed BMZ fluorescence on all substrates except BP180-deficient skin, suggesting that the target antigen was BP180, or a closely related molecule. In contrast, two dermal-binding LAD sera were positive on all substrates except the type VII collagen-deficient skin, suggesting that the target antigen was likely to be type VII collagen. One LAD serum sample, which showed combined dermal and epidermal fluorescence on normal salt-split skin, was also positive on all substrates tested, suggesting a target antigen other than type VII collagen, laminin 5 or BP180. The study confirms that LAD is a heterogeneous disorder and illustrates that IIF using a panel of skin samples which lack specific BMZ molecules, taken from subjects with inherited EB, is a relatively simple and useful tool to help identify target antigens in immunobullous disorders.

Adult↗
PubMed1999

Complement sensitivity of erythrocytes in a patient with inherited complete deficiency of CD59 or with the Inab phenotype.

We investigated the complement sensitivity of erythrocytes from three patients, one with inherited complete deficiency of CD59, one with the Inab phenotype, and one with paroxysmal nocturnal haemoglobinuria (PNH). The complement lysis sensitivity units on the erythrocytes were 11.7, 4.6, and 47.6 for inherited CD59 deficiency, Inab phenotype, and PNH, respectively. Two-colour flow cytometric analysis showed that the erythrocytes from the three patients consisted of a single population negative for CD59, negative for decay accelerating factor (DAF), and negative for both proteins, respectively. In addition, only the Inab phenotype patient had no haemolysis in vivo. These facts suggest that CD59 deficiency plays a more important role than DAF deficiency in complement-mediated haemolysis in vitro and in vivo, and that deficiency of both proteins, but not CD59 or DAF alone, causes complement sensitivity corresponding to that of PNH III erythrocytes in vitro.

Adult↗
PubMed2000

Liver biopsy in Irish hepatitis C-infected patients with inherited bleeding disorders.

The majority of patients receiving plasma-derived clotting factor concentrates between 1970s and the mid-1980s are now hepatitis C positive. The progression of hepatitis C is extremely variable and there is frequently a poor correlation among liver biochemistry, viral load and the stage of liver disease. Liver biopsy remains the only definitive way of staging fibrosis and grading necroinflammatory activity. Concerns have been expressed about the safety of the procedure; however, with modern regimes for the correction of coagulopathy in patients with inherited bleeding disorders, normal haemostasis may be maintained during the peribiopsy period. We performed 21 liver biopsies between 1984 and 1997 on patients with factor VIII (FVIII) or IX (FIX) deficiency and von Willebrand's Disease (VWD). Four had concomitant human immunodeficiency virus (HIV) infection, five were thrombocytopenic and one had a prolonged prothrombin time (PT). Haemostasis was achieved using an intermittent bolus of factor concentrate or continuous infusion regimens. One patient with VWD received Desmopressin (DDAVP). There were no bleeding episodes associated with biopsy. We suggest that liver biopsy is a safe procedure in patients with inherited bleeding disorders when the coagulopathy is fully corrected. It is the only definitive method of staging the extent of fibrosis associated with hepatitis C infection, and it is this that defines prognosis.

Adult↗
PubMed2002

Inherited factor VII deficiency and surgery: clinical data are the best criteria to predict the risk of bleeding.

Inherited factor VII (FVII) deficiency is a rare autosomal disorder characterized by a weak relationship between FVII activity (FVII:C) and operative bleeding risk. We report a retrospective study of 17 patients with a FVII:C below 0.1 IU/ml, in whom surgery was performed without any replacement therapy. Clinical and biological data were analysed to establish predictive criteria for bleeding tendency. We found that systematic preoperative replacement therapy may not be necessary for 'minor' surgical procedures, for patients suffering from inherited FVII deficiency, unless the clinical history includes severe haemorrhagic symptoms such as haemarthrosis, severe haematomas (even of soft tissue) or abundant epistaxis.

Adolescent↗
PubMed2002

A novel inherited mutation of the transcription factor RUNX1 causes thrombocytopenia and may predispose to acute myeloid leukaemia.

The RUNX1 (AML1, CBFA2) gene is a member of the runt transcription factor family, responsible for DNA binding and heterodimerization of other non-DNA binding transcription factors. RUNX1 plays an important part in regulating haematopoiesis and it is frequently disrupted by illegitimate somatic recombination in both acute myeloid and lymphoblastic leukaemia. Germline mutations of RUNX1 have also recently been described and are dominantly associated with inherited leukaemic conditions. We have identified a unique point mutation of the RUNX1 gene (A107P) in members of a family with autosomal dominant inheritance of thrombocytopenia. One member has developed acute myeloid leukaemia (AML).

Acute Disease↗
PubMed1998

Failure to increase insulin-like growth factor-I synthesis is involved in the mechanisms of growth retardation of children with inherited liver disorders.

OBJECTIVE: Growth retardation is a prominent secondary feature of chronic liver disease. We investigated the hypothalamic-pituitary-liver axis in six patients with inherited liver disease and growth failure. The objectives were to determine (1) whether there were any abnormalities in the GH/IGF-I/IGFBPs/GH binding protein (GHBP) axis, (2) whether any abnormalities were nutrition-dependent, and (3) whether recombinant human (rh) GH could be efficaciously and safely administered. MEASUREMENTS: The evaluation included two standard GH provocative tests, GHRH test, night-time GH secretion, GHBP; and IGF-I, IGFBP-3 and IGFBP-1 before and after 0.1 and 0.3 U/kg/day of rhGH given i.m., for 4 days. Two patients were enrolled for rhGH treatment. RESULTS: Quantitative nutritional assessment showed the patients' calorie and protein intake to be compatible with the recommended daily allowance in liver disease. The mean baseline GH level was higher in patients than in controls (8.4 +/- 3.8 vs 2.6 +/- 2.0 mU/l, P < 0.005) and the GH response to stimuli was normal; spontaneous GH secretion was apparently normal. The mean baseline IGF-I value in the patients was significantly below the mean of controls (31.6 +/- 16.4 vs 260 +/- 35.2 micrograms/l, P = 0.00001) and similar to that of children with GH-deficiency (40.8 +/- 18.4 micrograms/l). The mean peak IGF-I response after 0.1 U/kg/day of rhGH increased (84.9 +/- 28.2 micrograms/l, P = 0.009) but remained lower than the mean IGF-I response in GH-deficient patients and in controls (P = 0.00001). The mean peak IGF-I response after 0.3 U/kg/day (113.3 +/- 52.3 micrograms/l) was significantly higher than that after 0.1 U/kg/day (P = 0.002). The mean standard deviation score (SDS) peak for IGF-I response to 0.1 and 0.3 U/kg/day of rhGH decreased significantly from -1.7 to -1.0 (P = 0.02) and from -1.9 to -0.9 (P = 0.005), respectively. There was no difference between patients and controls in serum GHBP activity or in mean baseline IGFBP-3 and IGFBP-1 levels. IGFBP-3 levels did not change significantly in response to rhGH at either 0.1 or 0.3 U/kg/day, while IGFBP-1 significantly decreased after 0.3 U/kg/day (56.3 +/- 35.6 vs 45.9 +/- 33.1 micrograms/l, P = 0.04). A significant positive correlation was present between albumin and peak IGF-I responses to rhGH at the dose of 0.1 and 0.3 U/kg/day (R = 0.83, P = 0.03; R = 0.78, P = 0.03 respectively), as well as between height SDS and baseline or stimulated IGF-I after rhGH 0.1 U/kg/day (R = 0.81, P = 0.04; R = 0.88, P = 0.01 respectively). In the two patients treated with rhGH at 22-25 U/m2/week, the growth rate doubled in one and trebled in the other during the first year of treatment, and in both was maintained in the second year without acceleration of bone maturation or evidence of adverse effects. CONCLUSIONS: The underlying cause of growth retardation in patients with inherited liver disease seems to be a progressive failure to increase IGF-I synthesis (at the conventional rhGH dose) and the consequent lack of its growth-promoting effect. The moderate increase in baseline GH values, the greater IGF-I response to the higher rhGH dose and the improvement in growth rate following rhGH administration suggest at least a degree of sensitivity to rhGH which could be of therapeutic value.

Adolescent↗
PubMed1997

Glomus tumours and genomic imprinting: influence of inheritance along the paternal or maternal line.

Two new families with glomus tumours and two additions to earlier publications are presented. The pattern of inheritance is autosomal dominant. Familial glomus tumours are inherited almost exclusively via the paternal line, a finding inconsistent with autosomal dominant transmission. This can be explained by genomic imprinting. The maternally derived gene is inactivated during female oogenesis and can be reactivated only during spermatogenesis. Two different loci have been assigned, one to a 5 cM region of chromosome 11q13.1 and one to 11q22.3-q23.3. Genomic imprinting has already been found for the distal locus and here we demonstrate that the proximal locus is subject to genomic imprinting too. Genomic imprinting has considerable implications for genetic counselling in families with glomus tumours. In addition to this the sex ratio among affected offspring appears to be influenced by the paternal or maternal origin of the gene of the transmitting father.

Aged↗
PubMed1999

Counselling about diagnosis and inheritance of genetic bleeding disorders: haemophilia A and B.

Genetic counselling remains an important part of comprehensive haemophilia care despite the improved outlook and quality of life for those who can obtain factor replacement concentrates. Eighty per cent of the world's population with haemophilia have limited or no treatment. It is vital that information about inheritance is made available to them. Genetic bleeding disorders impact on the daily life and psychological health not only of the affected individual, but on carriers and close family. Informed decisions about childbearing (when there is a risk of haemophilia) require knowledge about inheritance, antenatal diagnosis possibilities and consideration of selective abortion. Genetic counselling touches on sensitive issues related to childbearing, handicap and continuation of the family. Guilt, resentment and blame can be reduced if couples are enabled to gain insight into each others views and wishes in a neutral setting. Counsellors need technical knowledge, skills and clarity of purpose to carry out this task.

Adult↗
PubMed1998

Inheritance of behavioural differences between two interfertile, sympatric species, Drosophila silvestris and D. heteroneura.

The Hawaiian fly species, Drosophila silvestris and D. heteroneura, are sympatric and interfertile but show strong behavioural isolation and major differences in male aggressive behaviour and the associated morphology. As a first step in elucidating the genetic control of the differences between these species, we examined the mating and aggressive behaviour of their reciprocal F1 hybrids. The latency to the first wing vibration and the latency to copulate did not differ significantly between the parental species. However, D. heteroneura females had a very low tendency to copulate with D. silvestris males, rarely mating during the observation period. The duration of copulation also differed significantly; same-species pairs of D. silvestris had copulations that lasted about 50% longer than those of same-species pairs of D. heteroneura. The hybrids were intermediate between the parental species for both the tendency to copulate with D. silvestris males and the duration of copulation, suggesting codominance or polygenic inheritance for those traits. The aggression traits that we scored were the leg posture and wing extension during early aggression, and the leg posture and head position during escalated aggression. The parental species showed clear differences for each of these traits. The F1 hybrids resembled one parent or the other, without showing intermediate values, suggesting single-gene dominance or threshold expression of many genes for those traits. None of the courtship or aggressive traits showed X-chromosomal effects, although the head shape of hybrids is influenced by genes on the X chromosome. It is difficult to reconcile the patterns of inheritance of aggressive behaviour and the lack of an X-chromosomal effect with the hypothesis that these traits are influenced by a coadapted gene complex.

Aggression↗
PubMed2000

Monogenic inheritance of apomixis in two Hieracium species with distinct developmental mechanisms.

Apomixis, the asexual formation of seed, has been known in angiosperms for more than a century yet the genetic mechanisms that control this trait remain poorly understood. Most members of the genus Hieracium are apomicts, forming predominantly asexual seed. Some purely sexual forms, however, also exist. In this paper we present a study of the inheritance of apomixis using two apomictic species of Hieracium which utilize very different forms of megagametogenesis. In both cases the progeny inherited apomixis as a monogenic, dominant trait that could be transferred by both haploid and diploid male gametes. In common with observations from other systems, no diploid apomictic progeny were recovered from these crosses. This appears to have been caused by selection against the survival of diploid zygotes, rather than against the mediation of haploid gametes as has been noted in other systems. Crosses between the two apomicts showed that the dominant determinants in the two forms examined were closely linked, possibly allelic. The significance of these data is discussed with respect to current theories on the associative link between gametophytic apomixis and polyploidy.

Alleles↗
PubMed2002

Antigen-specific dose-dependent system for the study of an inheritable and reversible phenotype in mouse CD4+ T cells.

The transgenic T-cell receptor in mouse TEa CD4+ lymphocytes recognizes an endogenous peptide, Ealpha52-68, presented in the context of the major histocompatibility complex class II molecule I-Ab. In response to an optimal peptide concentration TEa cells enter the cell cycle and proliferate. However, a single exposure to high doses of the specific peptide diminished cell expansion upon subsequent restimulation. This hyporesponsive, or anergic, phenotype can still be detected after multiple restimulations indicating that the hyporesponsiveness persists despite cell division and it was inherited by daughter cells. Furthermore, we demonstrated that this hypoproliferative response is associated with high p27Kip1 and cyclin E protein levels, and reduced intracellular interleukin-2 (IL-2) expression. Addition of exogenous IL-2 was required to reset p27Kip1 levels in the progeny derived from hyporesponsive TEa cells. Thus, we have established antigen dose-dependent induction of a reversible, inheritable (i.e. epigenetic) phenotype and we have identified at least three components of the network of interactions: p27Kip1 cyclin E, and IL-2 expression.

Animals↗
PubMed1998

Carney complex and the familial lentiginosis syndromes: link to inherited neoplasias and developmental disorders, and genetic loci.

Lentigines, synonymous but not identical to freckles or ephelides, are common skin lesions. In a small number of patients, however, these lesions constitute part of genetic syndromes that are associated with inherited forms of neoplasias or other pathologic processes of the cardiovascular, endocrine, and gastrointestinal systems. The familial lentiginoses, as these syndromes are collectively known, include Carney complex, the LEOPARD and Peutz-Jeghers syndromes, and the newly described 'syndrome of arterial dissections with lentiginosis'; isolated, familial lentiginosis has also been described. In the majority of the reported kindreds with these syndromes, the lesions were inherited in an autosomal dominant manner. The specific genes that are responsible for these disorders have remained elusive, but the genetic loci of Carney complex and Peutz-Jeghers syndromes were recently identified on chromosomes 2p 16 and distal 19p, respectively. Cytogenetic studies of tumours from patients with Carney complex suggest that the gene responsible for most patients with this syndrome may not have a tumour suppression function. We suggest that the genes responsible for the lentiginosis syndromes are important regulators of melanocyte function, they participate in the pleiotropy of human pigmentation, and are involved in the function, growth and proliferation of neural crest and mesenchymal cells.

Diagnosis, Differential↗
PubMed2003

Phylogeography of maritime pine inferred with organelle markers having contrasted inheritance.

Range-wide variation of maritime pine was studied at maternally inherited and paternally inherited markers (mitochondrial DNA and chloroplast DNA). While chloroplast DNA exhibits the highest diversity, phylogeographic inferences from this marker are blurred by homoplasy and extensive pollen flow. In contrast, the only three mitochondrial haplotypes found provide a clear picture of nonoverlapping areas colonized from different refugia, with no single population having a mixed composition (GST = 1). Comparison of the genetic structure inferred from both organelle genomes allows the investigation of differential seed and pollen dispersal, pointing to pollen, but not seed, dispersal across the Strait of Gibraltar (from Morocco into Iberia). A comparison with already available genetic information, especially that of one of the maritime pine's most threatening insect pests, the bast scale Matsucoccus feytaudi, further completes the picture.

DNA Primers↗
PubMed1998

Screening and controlling canine inherited ocular diseases in Finland: epidemiological, economical and health promotional aspect.

Official eye examination records of 18 146 dogs in 17 breeds were analyzed in order to evaluate the Finnish Kennel Club's eye examination scheme. The most common inherited ocular diseases were the Collie eye anomaly (CEA) in the Rough Collie and the persistent hyperplastic tunica vasculosa lentis (PHTVL) in the Doberman. In both diseases the prevalence has also increased during the study period 1988-1997. The most likely reason for the increase is the change in examination routines that now makes it easier to find milder disease forms that were previously classified as normal. The prevalences of other inherited diseases are so low that no conclusions about the trends can be made. Also, the data have some defects that can cause biased estimations of prevalences. The costs of screening programs are very high and no direct economical benefits can be shown. Methods of improving the screening and effectiveness of the program are also presented.

Journal Article↗
PubMed1996

Migraine without aura and migraine with aura are inherited disorders.

The familial occurrence and mode of inheritance were analysed in families with migraine without aura (MO) and migraine with aura (MA). The probands were found among 4000 persons from the general population. All persons with MA were included as probands, and an equivalent number of probands with MO was selected as a random sample among those with MO. Spouses and first-degree relatives were blindly interviewed. All interviews were performed by one neurological research fellow. The distinct familial patterns indicate that MO and MA have a different aetiology. Compared with the general population, the first-degree relatives of probands with MO had a 1.9-fold increased risk of MO while spouses had a 1.5-fold increased risk of MO, indicating that both genetic and environmental factors are important in MO. The first-degree relatives of probands with MA had a four-fold increased risk of MA while spouses had no increased risk of MA, indicating that MA is determined largely by genetic factors. The complex segregation analysis indicated that both MO and MA have multifactorial inheritance without generational difference.

Adolescent↗
PubMed2002

Role of immune cells in animal models for inherited neuropathies: facts and visions.

Mice heterozygously deficient in the peripheral myelin adhesion molecule P0 (P0+/- mice) are models for some forms of Charcot-Marie-Tooth (CMT) neuropathies. In addition to the characteristic hallmarks of demyelination, elevated numbers of CD8-positive T-lymphocytes and F4/80-positive macrophages are striking features in the nerves of these mice. These immune cells increase in number with age and progress of demyelination, suggesting that they might be functionally related to myelin damage. In order to investigate the pathogenetic role of lymphocytes, the myelin mutants were cross-bred with recombination activating gene 1 (RAG-1)-deficient mice, which lack mature T- and B-lymphocytes. The immunodeficient myelin mutants showed a less severe myelin degeneration. The beneficial effect of lymphocyte-deficiency was reversible, since demyelination worsened in immunodeficient myelin-mutants when reconstituted with bone marrow from wild-type mice. Ultrastructural analysis revealed macrophages in close apposition to myelin and demyelinated axons. We therefore cross-bred the P0+/- mice with spontaneous osteopetrotic (op) mutants deficient in the macrophage colony-stimulating factor (M-CSF), hence displaying impaired macrophage activation. In the corresponding double mutants the numbers of macrophages were not elevated in the peripheral nerves, and the demyelinating phenotype was less severe than in the genuine P0+/- mice, demonstrating that macrophages are also functionally involved in the pathogenesis of genetically mediated demyelination. We also examined other models for inherited neuropathies for a possible involvement of immune cells. We chose mice deficient in the gap junction component connexin 32, a model for the X-linked form of CMT. Similar to P0-deficient mice, T-lymphocytes and macrophages were elevated and macrophages showed a close apposition to degenerating myelin. We conclude that the involvement of T-lymphocytes and macrophages is a common pathogenetic feature in various forms of slowly progressive inherited neuropathies.

Animals↗
PubMed1998

A locus for inherited focal segmental glomerulosclerosis maps to chromosome 19q13.

We performed a genome-wide linkage analysis search for a genetic locus responsible for kidney dysfunction in a large family. This inherited condition, characterized by proteinuria, progressive renal insufficiency, and focal segmental glomerulosclerosis, follows autosomal dominant inheritance. We show with a high degree of certainty (maximum 2-point lod score 12.28) that the gene responsible for this condition is located on chromosome 19q13.

Chromosome Mapping↗