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PubMed1995

Spleen size in beta-thalassaemia heterozygotes.

In 45 beta-thalassaemia heterozygotes and in 38 normal controls we determined by ultrasound tomography: (a) the surface of the projection of the spleen to thoracic and abdominal wall, (b) the maximum diameters of the organ, and (c) its volume. The volume of the spleen is significantly bigger in heterozygotes as opposed to normals (132.94 +/- 41.76 and 80.29 +/- 25.88, respectively). In 17.8% of heterozygotes a palpable spleen was found. The findings of this study lead to the hypothesis that in all heterozygotes the final volume of the organ is increased; however, in only 17.8% of them a palpable spleen is found.

Heterozygote↗
PubMed1996

Alterations in plasma lipoproteins and apolipoproteins before the age of 40 in heterozygotes for lipoprotein lipase deficiency.

We have assessed the expression of heterozygosity for lipoprotein lipase (LPL) deficiency by studying a single large French Canadian family comprising 92 persons including 21 carriers of the catalytically defective P207L mutation. Phenotypic changes distinguishing heterozygotes from controls were seen early, before the age of 40 and often before 20 years of age. In the total cohort these changes included an elevation in the mean very low density (VLDL) and intermediate density lipoprotein (IDL) triglyceride (+69%; P = 0.01 and +40%; P = 0.001) and cholesterol (+51%; P = 0.03 and +67%; P = 0.007) and apoB levels but decreased HDL2 and HDL3 cholesterol, (-32%; P = 0.01 and -15%; P = 0.002 respectively). While the lipid compositions of VLDL and IDL were similar between heterozygotes and controls, the low density (LDL) and high density lipoproteins (HDL) of carriers were triglyceride enriched. Heterozygotes also had a markedly lower apoC-III ratio (apoC-III in supernatant/apoC-III in heparin precipitate) (1.46 vs. 3.86 P = 1 x 10(-4)) indicating a substantial enrichment of VLDL and IDL with apoC-III and depletion of HDL apoC-III supporting this ratio as an effective index for efficiency of lipolysis. LpA-I was markedly reduced (0.34 vs. 0.43 P = 1 x 10(-5)) showing that levels of this particle are partly dependent on LPL catalytic activity. Heterozygotes manifest from an early age with a markedly reduced HDL, LpA-I, apoC-III ratio and an increased TC/HDLc ratio which would predict a relatively increased risk of premature coronary artery disease, compared to their normal siblings.

Adult↗
PubMed1983

Cytogenetic differentiation of Fanconi anemia, "idiopathic" aplastic anemia, and Fanconi anemia heterozygotes.

We have analyzed chromosome breaks in 8 patients with Fanconi anemia (FA), 42 with "idiopathic" aplastic anema (AA), 15 first-degree relatives of FA patients, and 13 controls. Their lymphocytes were treated in culture with three concentrations of mitomycin-C (MMC). A 60-fold increase in breaks was observed in FA patients as compared to AA patients, regardless of severity of clinical signs. The MMC-stress test was standardized to clearly differentiate FA from other pancytopenias in doubtful cases. Also, the effect of storage of MMC in solution was investigated. The data on SCEs of 12 subjects tested, 10 mo apart, showed an inverse relationship between length of storage of MMC and chromosome damage. The 10-month-old solution induced only one half as many SCEs as it induced at 4 months. Further, the usefulness and power of diepoxybutane (DEB) in detection of FA heterozygotes was investigated in 12 first-degree relatives of patients with Fanconi anemia and 12 healthy controls. The mean number of chromosome breaks per mitosis by DEB stress in obligate heterozygotes was 0.08 in comparison to 0.06 in controls. Four of twelve control subjects showed proportions of breaks almost identical to or higher than those of FA heterozygotes, ie, 0.12, 0.10, 0.10, and 0.11 breaks per mitosis. The responses of healthy controls to DEB could be separated into two groups: one with mean chromosome breaks of 0.11 per mitosis, and a second with mean breaks of 0.04 per mitosis. Thus, it appears that heterozygote detection by DEB stress of cultured lymphocytes is not unequivocal.

Adolescent↗
PubMed1991

Statistical approaches for the detection of heterozygotes for biotinidase deficiency.

We applied and evaluated 3 statistical approaches for the detection of heterozygotes for biotinidase deficiency in a randomly selected population of French adults. The first method, which used a cutoff value to dichotomize the population, lacked sensitivity. The second approach calculated the probability of heterozygosity for a given enzyme activity through the application of Bayes theorem to the normal density functions of the enzyme distributions of the obligate heterozygote and the test populations. A priori values of the means and standard deviations (SDs) of the genotypic distributions were used. This method was sufficiently sensitive for both population screening and genetic counseling, but requires prior knowledge of the frequency of the deficient gene (q). The third approach was similar to the second, however, maximum likelihood estimates of the means and SDs of the genotypic distributions were calculated and used to determine the probability of heterozygosity for a given enzyme activity. This method was as sensitive as the second method and is appropriate for screening populations for which there is little prior information about the gene frequency and the genotypic distributions. This method can also be used to estimate the gene frequency of the disorder within a given ethnic or racial population. Using this method, we estimated the frequency of heterozygotes (2pq) in the French population to be 0.012, which was similar to that estimated from the results of neonatal screening for biotinidase deficiency. These methods can be used to detect heterozygotes and to estimate the gene frequency of other inherited enzyme deficiencies.

Amidohydrolases↗
PubMed1981

Heterozygote detection in MLD. allelic mutations at the ARA locus.

The detection of heterozygotes for MLD based on enzyme assays of a general population is highly unreliable. Twenty-three percent of controls and ARA activities below the levels found in some obligate heterozygotes for MLD. This serious overlap problem precludes the use of ARA determinations in large screening programs to assign individuals into specific genetic categories. On the other hand, intrafamily analysis of ARA activity offers the possibility of accurately determining heterozygotes for MLD. Sixteen children of parents heterozygous for MLD had ARA activities which clearly categorized them as either homozygous affected, heterozygous, or normal. The wide range of ARA activity found in controls and heterozygotes for MLD appeared to result from the presence of multiple allelic mutations at the ARA locus. One of these mutations leads to a low ARA activity and when present in an individual who is heterozygous for MLD may lead to overlap of his total activity with that of some homozygous affected individuals. This low ARA activity mutation can be recognized by alterations in the multiple molecular forms of ARA activity separated by analytical isoelectric focusing electrophoresis.

Adult↗
PubMed1985

Fructose-1,6-diphosphatase deficiency: diagnosis using leukocytes and detection of heterozygotes with radiochemical and spectrophotometric methods.

The first two cases of fructose-1,6-diphosphatase (FDPase) deficiency from the Middle East have been diagnosed on leukocytes using a spectrophotometric assay and a new radiochemical technique. The control mean for FDPase measured by the spectrophotometric assay was 178.2 nm mg-1 h-1 (n = 12), 66.8 nm mg-1 h-1 for obligate heterozygotes (n = 4) and non-detectable in the two patients. By the radiochemical assay the values were controls, 103.3; heterozygotes, 20.6; patients, 0.46 and 3.5 nm mg-1 h-1. Using both methods it was possible to identify two certain FDPase heterozygotes and three non-carriers in the family of one of the probands. The radiochemical method was found to be more effective in differentiating heterozygotes from controls than the spectrophotometric method. However, either technique may be conveniently used for the diagnosis of FDPase deficiency in leukocytes.

Adult↗
PubMed1981

The Hurler syndrome: detection of patients and heterozygotes using a microassay for alpha-L-iduronidase in fibroblasts.

The activities of alpha-L-iduronidase (EC 3.2.1.76) were measured, by a microassay with phenyl-alpha-L-iduronide as the substrate, in cultured fibroblasts from patients with the Hurler syndrome (MPS IH) or the Scheie syndrome (MPS IS) and from heterozygotes.l The iduronidase activities in the cells from 44 MPS IH and 7 MPS IS patients were all strongly reduced and distinct from the activities in heterozygotes and normal controls. In a group of 24 obligate heterozygotes for MPS IH, 23 could be classified as heterozygotes when the average iduronidase activities of two independent assays were considered. The use of a standard enzyme preparation as a reference in the assays further improved the identification of heterozygosity. The testing of possible heterozygotes (relatives of patients) and their partners may be a valuable contribution in genetic counselling.

Fibroblasts↗
PubMed1989

Identification of ataxia telangiectasia heterozygotes by flow cytometric analysis of X-ray damage.

Flow cytometry was used to identify heterozygotes for the autosomal recessive DNA-repair deficiency disease ataxia telangiectasia (AT). Confluent G0/G1 fibroblasts from 4 homozygotes (at/at), 5 obligate heterozygotes (at/+) and 7 presumed normal controls (+/+) were X-irradiated with 200 Rad and subcultured immediately in medium containing 5-bromodeoxyuridine (BrdU). Cells were harvested 72 h later and stained with fluoresceinated anti-BrdU antibody to identify cells that had entered S phase. They were counterstained with propidium iodide to measure total DNA content. On the basis of relative release from G0/G1, the at/+ strains as a group (33 +/- 3% release) were distinguished from both the presumed +/+ strains (60 +/- 3%) and at/at strains (85 +/- 3%), although the individual values for some strains did show overlap between genotypes. When 10 cell strains were coded and analyzed in 'blind' experiments, all 4 heterozygotes were correctly assigned, although one poorly growing presumed normal line was incorrectly assigned as a heterozygote. By a similar assay in which exponentially growing cultures were pulsed briefly with BrdU 8 h after irradiation with 400 Rad and then harvested immediately, presumed +/+ cells as a group could be distinguished from at/at cells but not from at/- cells. This combination of assays assists in the identification of all 3 AT genotypes. This should be of both basic and diagnostic use, particularly in families known to segregate AT.

Adolescent↗
PubMed1996

Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer.

About 1.4% of the general population are heterozygous carriers of the gene for ataxiatelangiectasia (A-T), an autosomal recessive progressive neurologic syndrome in which cancer incidence of homozygotes is approximately 100-fold greater than the general population's rates. The hypothesis that A-T heterozygotes are predisposed to breast cancer was tested by the unbiased statistically powerful index-test method based on molecular genotyping. The A-T gene carrier status of 775 blood relatives in 99 A-T families was determined by tracing the A-T gene in each family through tightly linked flanking DNA markers. There were 33 women with breast cancer who could be genotyped; 25 of these were A-T heterozygotes, compared to an expected 14.9 (odds ratio 3.8, 95% confidence limits 1.7-8.4, one-sided p = .0001). This demonstrates that the A-T gene predisposes heterozygotes to breast cancer. For the 21 breast cancers with onset before age 60, the odds ratio was 2.9 (1.1-7.6, p = .009) and for the 12 cases with onset at age 60 or older, the odds ratio was 6.4 (1.4-28.8, p = .002). Thus the breast cancer risk for A-T heterozygous women is not limited to young women but appears even higher at older ages. Of all breast cancers in the United States, 6.6% may occur in women who are A-T heterozygotes. This proportion is several fold greater than the estimated proportion of carriers of BRCA1 mutations in breast cancer cases with onset at any age.

Adult↗
PubMed1999

Estimating the effective number of breeders from heterozygote excess in progeny.

The heterozygote-excess method is a recently published method for estimating the effective population size (Ne). It is based on the following principle: When the effective number of breeders (Neb) in a population is small, the allele frequencies will (by chance) be different in males and females, which causes an excess of heterozygotes in the progeny with respect to Hardy-Weinberg equilibrium expectations. We evaluate the accuracy and precision of the heterozygote-excess method using empirical and simulated data sets from polygamous, polygynous, and monogamous mating systems and by using realistic sample sizes of individuals (15-120) and loci (5-30) with varying levels of polymorphism. The method gave nearly unbiased estimates of Neb under all three mating systems. However, the confidence intervals on the point estimates of Neb were sufficiently small (and hence the heterozygote-excess method useful) only in polygamous and polygynous populations that were produced by <10 effective breeders, unless samples included > approximately 60 individuals and 20 multiallelic loci.

Animals↗
PubMed1990

Molecular analysis of atypical beta-thalassemia heterozygotes.

This paper reviews the molecular pathology of a heterogeneous group of beta-thalassemia heterozygotes which may be referred to as atypical beta-thalassemia. This group includes four different categories of heterozygous beta-thalassemia, which are characterized, respectively, by (1) normal MCV and MCH; (2) normal Hb A2; (3) normal MCV, MCH, and Hb A2 and imbalanced globin chain synthesis only or, (4) the presence of clinical manifestations. The first group is represented by a limited proportion of double heterozygotes for alpha- and beta-thalassemia. The second group includes two categories. One category is double heterozygotes for delta- and beta-thalassemia with the delta-thalassemia mutation in cis or in trans to beta-thalassemia. A number of delta-thalassemia mutations which produce this phenotype by interacting with beta-thalassemia have been described. The other category within the second group is heterozygotes for some mild beta(+)-thalassemia mutations. Within the third group, conclusive evidence for a mutation within the beta-globin gene cluster producing the silent beta-thalassemia phenotype has been obtained solely for a C----T substitution at -101 within the CACCC box of the beta-globin gene. Possible candidates are the complex rearrangements (-T, +ATA; -T, +ATATA) found at position -530 from the cap site. In the group of thalassemic hemoglobinopathies, a series of mutations mostly located in the third exon and producing elongated or truncated molecules have been recently reported. Most of the mutations are silent at the protein level, produce inclusion bodies in peripheral erythrocytes, and show a dominant transmission pattern or occur sporadically.

Codon↗
PubMed1989

Heterozygotes for cystic fibrosis: models for study of airway and autonomic reactivity.

Airway reactivity to cold air and methacholine, alpha-adrenergic and cholinergic reactivity measured as pupillary responses to phenylephrine and carbachol, respectively, and beta-adrenergic reactivity assessed by lymphocyte adenosine 3',5'-cyclic monophosphate (cAMP) response to isoproterenol were compared in 108 parents of patients with cystic fibrosis (CF) and 133 healthy adult controls. No differences were found between CF parents and controls in airway response to cold air or methacholine or in lymphocyte cAMP response to isoproterenol. Significant differences were found, however, in the response of the pupils to both phenylephrine and carbachol. Heterozygotes for CF have more reactive pupils; i.e., they require smaller doses of agonist for a 10% change in pupil size. In control subjects, the response of the pupils to phenylephrine and carbachol is highly correlated (r = 0.45, P less than 0.001), whereas in CF heterozygotes, the correlation is not significantly different from zero (r = -0.02). In controls, the pupil response to carbachol has a significant negative correlation with cold air response (r = 0.39, P less than 0.05), indicating that those whose pupils were most sensitive to carbachol had the greatest airway reactivity to cold air, but in CF heterozygotes the correlation is not significant (r = 0.10). A significant correlation exists between lymphocyte cAMP response and airway cold air response in CF heterozygotes (r = -0.32, P less than 0.05) (those whose beta-adrenergic responsiveness is low have greater airway reactivity), but not in controls. The CF parents with the most reactive airways tend to have lower beta-adrenergic responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Steroid sulphatase deficiency: identification of heterozygotes using hydrolysis of dehydroepiandrosterone sulphate by peripheral leucocytes.

Diagnosis of X-linked recessive ichthyosis, which is expressed only in males, can readily be made by measurement of leucocyte steroid sulphatase activity. However, because the gene for steroid sulphatase activity partly escapes from the process of X-chromosome inactivation associated with gene dosage compensation, identification of heterozygotes (females) is more difficult. We have measured the steroid sulphatase (by hydrolysis of dehydroepiandrosterone sulphate) and beta-glucuronidase (by hydrolysis of methylumbelliferyl glucuronide) activities in leucocytes from 18 heterozygotes, 100 normal females, 100 normal males and 11 affected subjects. When the ratio of the activities of steroid sulphatase and beta-glucuronidase in mixed leucocytes was plotted as a function of the steroid sulphatase activity, 85% heterozygotes were distinguished from normal females. Measurement of steroid sulphatase activity alone with these cells enabled identification of 78% heterozygotes. Measurements on mononuclear leucocytes were much less effective. Thrombocytes showed 1% of the steroid sulphatase activity of leucocytes. In females, leucocyte steroid sulphatase activity was independent of the stage of the ovarian cycle at which the cells were collected.

Adolescent↗
PubMed1988

Enhanced enzyme activity after incubation with zinc can be used to distinguish heterozygotes of Pompe's disease.

In an attempt to identify heterozygotes for Pompe's disease, the acid alpha-D-glucosidase activity at pH 4 in phytohemagglutinin-stimulated lymphocytes was measured. In the standard assay an overlap in the enzyme activity between normal controls and obligate heterozygotes was demonstrated. When the assay was modified by adding zinc chloride into the incubation mixture, the enzyme activity of the lymphocyte homogenates did not change. However, the enzyme activity increased dramatically after intact lymphocytes were preincubated with zinc chloride. There was no more overlap in the acid alpha-D-glucosidase activity between normal controls and obligate heterozygotes when lymphocytes were incubated 1 h with 10(-4) mol/liter zinc chloride or 2 h with 10(-3) or 10(-4) mol/liter zinc chloride. This modified enzyme activity should facilitate improved heterozygote detection.

Chlorides↗
PubMed1993

Biochemical and immunochemical study of seven families with 3-ketothiolase deficiency: diagnosis of heterozygotes using immunochemical determination of the ratio of mitochondrial acetoacetyl-CoA thiolase and 3-ketoacyl-CoA thiolase proteins.

The possibility of identifying heterozygotes of 3-ketothiolase deficiency, an inborn error of metabolism caused by a defect of mitochondrial acetoacetyl-CoA thiolase (T2), was tested in seven unrelated families by using enzymatic assay of thiolase activity and immunoblot analysis. The ratio of acetoacetyl-CoA thiolase activities, in the presence and absence of K+ ion (+K/-K ratio), in fibroblasts from 15 normal controls was around 2.0 (1.8 to 2.4), whereas the +K/-K ratio in eight patients was always 1.0. The ratio for the 13 obligate carriers ranged from 1.4 to 1.9, causing a minor overlap with control. Identification of heterozygote cells by immunoblot analysis, using anti-T2 antibody alone as a probe, was difficult, as previously reported. We therefore carried out immunoblot analysis, using as probes a mixture of anti-T2 antibody and the antibody against mitochondrial 3-ketoacyl-CoA thiolase (T1), another mitochondrial thiolase, and determined the ratio of the intensities of the T2 and T1 bands (T2/T1 ratio) using a densitometer. When the T2/T1 ratio was calculated, there was no overlap between the heterozygotes and normal controls. Hence, the heterozygotes can be unambiguously identified using this method. The thiolase activities and T2/T1 proteins in immunoblotting were detectable in peripheral lymphocytes, rectal mucosa, amniocytes, and liver. Thus, the postnatal diagnosis of 3-ketothiolase deficiency can be readily made using lymphocytes or rectal mucosa. The applicability of these methods in amniocytes indicates that prenatal diagnosis of this disease should be possible.

Acetyl-CoA C-Acetyltransferase↗
PubMed1988

Prenatal diagnosis of a heterozygote of salt wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency by genetic linkage analysis.

For the purpose of prenatal diagnosis of CAH, genetic linkage analysis by HLA genotyping with lymphocytes and cultured amniotic cells were performed in a family at risk in which two consecutive children had been affected with SW CAH. In addition, the response of serum 17-OHP to intravenous ACTH was determined in obligate carrier parents, and 17-OHP concentration of amniotic fluid was also measured at 16 weeks of gestation. As might be expected, the baseline levels of 17-OHP in obligate parents were significantly higher than that of normal control. Although the post stimulation response of 17-OHP to ACTH in the mother (I-2) was significantly higher than that of normal control, the post stimulation levels of 17-OHP were in normal range in the father (I-1). The 17-OHP level (5.7 ng/ml) in the amniotic fluid showed intermediate value compared to Pang's report (normal less than 30 ng/ml, CAH greater than 12.0 ng/ml) suggesting heterozygote of the fetus. Genetic linkage analysis by HLA genotyping with cultured amniotic cells revealed heterozygote in their fetus (II-3) who has received one chromosome No,6 containing HLA haplotype A24, B40, Cw3 (normal allele for 21-OH) from the father and the other chromosome No,6 containing HLA haplotype A2, Bw62, Cw4 (mutant allele for 21-OH D) from the mother. In conclusion, attempts to detect heterozygote for 21-OH deficiency by ACTH stimulation test were partially successful and prenatal diagnosis of CAH by the hormone studies in ammiotic fluid requires reliable values in normal, heterozygotes and patients group, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Hyperplasia, Congenital↗
PubMed2000

Detection of ornithine transcarbamylase deficiency heterozygotes by measuring of urinary uracil.

The importance of detecting heterozygosity for X-linked ornithine transcarbamylase deficiency is well known. Although the DNA analysis and the allopurinol loading tests are commonly used for this purpose, both methods require complicated procedures. In order to establish a simple test for detecting female heterozygotes, we examined the uracil and orotic acid in single-voided urine samples from 70 healthy women, and from 12 asymptomatic females with ornithine transcarbamylase deficiency. Based on the results of healthy women, we were able to determine a screening cut-off line of 11.9 micromol/mmol creatinine (mean +/- 1SD in logarithmic form) for uracil. Using this cut-off line, the sensitivity of OCT heterozygotes was 100%. We were also able to establish a second cut-off line of 28.9 micromol/mmol creatinine (mean +/- 3SD in logarithmic form) for diagnosis. Using this second cut-off line, the specificity of OCT heterozygotes was 100%. Our study has shown that the measurement of urinary uracil is a relatively simple and effective method for detecting female heterozygotes.

Female↗
PubMedDate not supplied

[Evaluation of the phenylalanine tolerance test in detection of heterozygote carriers of phenylketonuria gene].

The study aimed at identifying heterozygotic phenylketonuria gene carriers with phenylalanine tolerance test performed in Lublin region. Serum phenylalanine concentration has been assayed during fasting and 1 and 2 hours following oral phenylalanine load in the dose of 0.1 g per 1 kg body weight. The study involved 203 individuals of the general population and 29 heterozygotes with phenylketonuria gene. Blood serum phenylalanine was assayed with Guthrie' technique. Statistical analysis has shown that hyperphenylalaninemia is relatively frequent in fasting individuals of the general population (59.1%). The same was demonstrated in 5 heterozygotes. Phenylalanine tolerance test did not allow to identify heterozygotic carries of phenylketonuria gene in the general population though fasting and after phenylalanine load increased blood serum levels of this amino acid are a criterium of hyperphenylalaninemia in the group of tested individuals (29%).

Administration, Oral↗