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PubMed2006

Sonographic diagnosis of SEDC and double heterozygote of SEDC and achondroplasia--a report of six pregnancies.

OBJECTIVE: To define the sonographic features of spondyloepiphyseal dysplasia congenita (SEDC) and the double heterozygote for SEDC and achondroplasia. METHODS: A retrospective review of 6 pregnancies in one family where one parent has achondroplasia and the other SEDC. RESULTS: There were 4 double heterozygote pregnancies and 2 where the fetus had SEDC. Shortening of long bones was evident in both conditions from around 16 weeks gestation. Other findings such as an increased nuchal translucency were more variable. CONCLUSIONS: Molecular analysis of the FGFR3 and COL2AI gene once mutations are known in a family such as reported here can inform prenatal diagnosis and help to distinguish between the double heterozygote and a fetus which has inherited a single mutation. The data presented here on the growth of the long bones and other sonographic features associated with SEDC may aid prenatal diagnosis in cases where the mutation is not known.

Achondroplasia↗
PubMed1997

Hyperandrogenism and manifesting heterozygotes for 21-hydroxylase deficiency.

Premature adrenarche and functional adolescent androgen excess are common disorders which may evolve into polycystic ovary syndrome (PCOS). In all three disorders, ACTH-stimulated 17-hydroxyprogesterone concentrations are often somewhat elevated. To determine the role of 21-hydroxylase (CYP21) gene mutations in these disorders, we performed molecular genotype analysis on 48 children and adolescents referred for evaluation of hyperandrogenic findings and diagnosed as having premature adrenarche or functional androgen excess. For comparison, DNA samples from 80 healthy adults were genotyped. Seventeen of the 48 hyperandrogenic patients were found to be heterozygotic carriers of CYP21 mutations. The frequency of heterozygosity was significantly greater among symptomatic patients (35%) than among the healthy controls (6%), P < 0.001. Seven mutation-positive patients (50%) and only one mutation-negative patient had ACTH-stimulated 17-hydroxyprogesterone concentrations typical for heterozygotic carriers of 21-hydroxylase deficiency, 400-1000 ng/dl. The significant difference in heterozygote frequency between symptomatic patients and healthy controls suggests that heterozygosity for 21-hydroxylase deficiency may be associated with premature adrenarche and functional adolescent hyperandrogenism. Longitudinal studies are necessary to determine if heterozygosity for 21-hydroxylase deficiency predicts risk for PCOS.

Adolescent↗
PubMed1981

A new approach to detection of heterozygotes for adenosine deaminase deficiency: a hypothetical method.

In a second and third families with ADA deficiency found in Japan, we tried a new approach to evaluate heterozygote detection. This is based on the hypothesis that ADA activity of red blood cell is the quantitative sum of the activities of ADA proteins expressed by two allelic genes at the ADA autosomal locus, and that these activities are not changed by the gene transmission from parents to children. We have detected red blood cell-ADA activities expressed by the one normal allelic gene in heterozygotes (including parents and paternal or maternal grandfather or grandmother) and from these values have determined combinations for the pair of ADA activities expressed by the two allelic genes of other family members. These combinations were consistently made in all relatives examined in the two families, and we conclude that several members of each family who were judged to have nil activity in the combinations were heterozygotes for ADA deficiency.

Adenosine Deaminase↗
PubMed1993

Improved identification of heterozygotes for phenylketonuria using blood neopterin and biopterin.

A novel approach that combines information provided by the metabolism of pteridines and that of phenylalanine has been applied to the detection of heterozygotes for phenylketonuria. Phenylalanine, tyrosine, biopterin and neopterin have been measured in serum from normal controls and heterozygotes for classical phenylketonuria, before and after a phenylalanine oral load. Significant differences in neopterin and biopterin mean values in fasting serum and in the mean increase of biopterin induced by the phenylalanine load were found between groups. Inclusion of pteridine data in the discriminant analysis significantly improved the resolution of the classical phenylalanine loading test for the detection of heterozygotes for phenylketonuria.

Adult↗
PubMed1986

Identification of cystic fibrosis homozygotes and heterozygotes by isoelectric focusing of serum proteins.

Screening of 44 cystic fibrosis homozygotes, 17 heterozygotes and 36 normal controls, by identification of cystic fibrosis protein (CFP), was performed on sera using an improved isoelectric focusing technique. CFP was observed in 91% of homozygotes, 88% of heterozygotes and 8% of normal controls tested. Partial purification of CFP by chromatofocussing indicates that CFP has a molecular weight of about 52,000 u. It is speculated that CFP is a normal serum protein that exhibits a quantitative difference in concentration between CF homozygotes, heterozygotes and normals.

Blood Proteins↗
PubMed1986

Protein-bound plasma homocyst(e)ine and identification of heterozygotes for cystathionine-synthase deficiency.

We measured protein-bound plasma homocyst(e)ine in 15 normal adult subjects and nine heterozygotes for homocystinuria due to cystathionine beta-synthase deficiency. The mean (+/- SD) concentrations obtained in the two groups of subjects were 4.35 +/- 1.50 and 9.16 +/- 3.40 mumoll-1, respectively. The mean values were significantly different, although the levels of three heterozygotes overlapped those of the control range. This method allows preliminary screening of the heterozygotes for homocystinuria and can be carried out by laboratories that have only facilities for amino acid analysis.

Adult↗
PubMed1982

Gaucher type I (Ashkenazi) disease: a new method for heterozygote detection using a novel fluorescent natural substrate.

A new acid beta-glucosidase assay for the detection of heterozygotes for Gaucher Type I disease has been developed using isolated lymphocytes as enzyme source and a novel fluorescent natural substrate, NBD-glucosyl ceramide. The procedure for optimal heterozygote discrimination was established by systematic evaluation of the effect of various solubilization techniques, detergent concentrations, pH, enzyme sources and artificial vs. natural substrates. A pilot screening study indicated the feasible application of this assay for heterozygote detection in the high-risk Ashkenazi Jewish population.

Clinical Enzyme Tests↗
PubMed1989

Use of 4-heptylumbelliferyl-beta-D-glucoside to identify Gaucher's disease heterozygotes.

Three fluorometric beta-glucosidase assays were compared for their ability to identify Gaucher's disease heterozygotes, using leukocytes as the source of enzyme: the pH 5.5-taurocholate assay of Peters et al.; the conduritol B epoxide dependent variation of that assay; and the newly developed method described herein. While the first two procedures utilize the standard substrate 4-methylumbelliferyl-beta-D-glucopyranoside to estimate beta-glucosidase activity, the new assay uses 4-heptylumbelliferyl-beta-D-glucoside as (C7UGlc) substrate. Use of this substrate enhances the specificity of the method for lysosomal glucocerebrosidase, thereby minimizing the contribution of the nonspecific cytosolic beta-glucosidase to estimates of substrate hydrolysis. Using Student's t test for the three assays examined, the C7UGlc assay procedure was determined to have the lowest p value (p less than 0.001) and highest t value (t = 4.95) for the discrimination between the mean glucocerebrosidase value of control and obligate Gaucher heterozygote samples. The high reliability and simplicity of the C7UGlc assay lends adequate reason to favor this assay for regular clinical diagnosis of Gaucher heterozygotes.

Brain↗
PubMed1981

Comparison of two methods for detecting translocation heterozygotes in mice.

An accurate estimate of the error of misclassifying male translocation heterozygotes as normals is essential for the proper evaluation of results of the heritable translocation test in mice. The size of this error may vary from one laboratory to another depending, primarily, on the method or variation of the method used in screening for translocation heterozygotes. This report shows a way to estimate for misclassification errors involved in two methods, sequential and direct cytological analysis, of screening for translocation heterozygotes. A positive correlation was found between the degree of partial sterility of a male and the frequency of cells with multivalent configurations among his diakinesis-metaphase I cells. We interpreted this to confirm that the length of translocated chromosome segments has some influence on the proportion of unbalanced gametes in the ejaculate, presumably reflecting the frequency with which adjacent-1 and adjacent-1 segregations and 3-1 misdivisions occur.

Animals↗
PubMed1989

HLA-D typing of heterozygotes using restriction fragment length polymorphism in the HLA-DQ gene region on the basis of standard band patterns derived from HLA homozygotes.

Genomic DNAs from 37 Epstein-Barr virus-transformed HLA-D homozygous cell lines with different Dw specificities, Dw1-Dw23, and DKT2 were digested with four different restriction endonucleases (EcoRI, PstI, TaqI, and MspI) and hybridized to DQ alpha and DQ beta cDNA probes. Polymorphic patterns of multiple fragments correlating with Dw, DQ, and DR haplotypes were detected, and the restriction fragment length polymorphism standard pattern specific for each Dw, DQ, and DR specificity could be defined. The polymorphic fragment patterns of HLA-D heterozygotes were predicted simply by the summation of two standard patterns of HLA-D homozygotes and utilized to identify HLA-D specificities of 25 normal individuals, who are HLA heterozygotes in most cases. The HLA-D, -DR, and -DQ specificities defined by this DNA typing were compared with those assigned by serologic and cellular typing. There was good correlation, allowing the application of accurate genotyping by DQ alpha and DQ beta cDNA probes to HLA class II typing of HLA heterozygotes.

Base Sequence↗
PubMed1983

Inherited purine enzyme deficiencies: prenatal diagnosis and heterozygote detection.

A number of genetically determined enzyme defects leading to disturbances of purine metabolism can prenatally be monitored, and heterozygote detection is possible in several cases. In severe hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency, associated with a neurological disease known as the Lesch-Nyhan Syndrome, rapid prenatal diagnosis can be performed by means of a simple quantitative radiochemical enzyme assay at the single cell level. In this X-linked recessive disease, the female heterozygotes can be detected by using cultured skin fibroblasts, but alternatively single hair root enzymes can directly be assayed. Two other genetic purine enzyme defects lead to deranged immune function: in adenosine deaminase (ADA) deficiency both T- and B-lymphocyte function are severely impaired. In purine nucleoside phosphorylase (PNP) deficiency, only certain T-cell abnormalities have been observed, with apparently normal B-cell function. Both diseases are transmitted as autosomal recessive traits. Prenatal diagnosis is possible, e.g. by means of the above mentioned microtechniques. Heterozygote detection can be done using blood cells or cultured fibroblasts. Microchemical methods offer the possibility to perform enzyme characterisation even when a very limited amount of material is available. In the case of HGPRT, ADA, and PNP, for a substrate affinity curve and pH optimum curve a few hundred cells are sufficient. These and other possibilities illustrate the general usefulness of simple microtechniques in clinical enzymology.

Adenosine Deaminase↗
PubMed2001

Ornithine carbamoyltransferase deficiency: improved sensitivity of testing for protein tolerance in the diagnosis of heterozygotes.

The most direct test of functional capacity of the liver in nitrogen disposal is to stress the urea cycle with a high protein load. This has been used in the diagnosis of heterozygosity for ornithine carbamoyltransferase deficiency for many years by measuring the subsequent excretion of orotic acid in urine. Reports have shown some ambiguity in both this and the more recent allopurinol test. We investigated the effects of different foods as the protein load and of different analytical methods. A standardized protocol was developed, giving 35 g protein per m2 surface area as steamed fat-free chicken breast to be eaten within 30 min. Urine was collected at zero time and over 0-2, 2-4 and 4-6 h. Compliance was checked by assessing excretion of amino acids. Diagnostic sensitivity was improved by reference to the change in excretion, i.e. the ratio of excretions 2-4 h/0-2 h. Extension of the test to 6 h gave no diagnostic advantage over a 4 h test. Comparison of the analysis of total orotic acids by the photometric method of Harris and Oberholtzer, the reference method for this study, with that by the method of Goldstein and colleagues showed that the latter gave erratic results with some false positives. However, comparison of the method of Harris and Oberholtzer with specific orotic acid analysis by a modification of the stable-isotope internal standard method of Rimoldi and colleagues yielded the same diagnoses. The improved protein load test gave a clearly positive result in all 16 obligate heterozygotes and 2 possible heterozygotes tested from 14 kindred, and a clearly negative result in all 18 control subjects and all 6 of the possible heterozygotes who were later shown by DNA studies not to carry the family mutation. The test appears at least as sensitive and specific as the allopurinol test, and is more convenient because of the short period of sample collection.

Adolescent↗
PubMed1983

Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes.

In subject with heterozygous familial hypercholesterolemia (FH), a 50% deficiency of receptors for plasma low density lipoprotein (LDL) impairs the removal of LDL from plasma and produces hypercholesterolemia. In these patients mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, blocks cholesterol synthesis and lowers plasma LDL levels. To determine the mechanism for the LDL-lowering effect, we administered 131I-labeled LDL intravenously to six FH heterozygotes before and during treatment with mevinolin and calculated the apparent fractional catabolic rate (FCR) and synthetic rate for LDL. After mevinolin treatment, the mean plasma LDL-cholesterol level declined from 262 to 191 mg/dl (27% decrease), the mean FCR for 131I-labeled LDL increased from 0.30 to 0.41 pools per day (37% increase), and the mean calculated synthetic rate for LDL-protein did not change significantly. In one of FH heterozygote with an ileal bypass and in another who received colestipol, the addition of mevinolin caused, respectively, a 41% and 60% decrease in plasma LDL levels and a 60% and 100% increase in the FCR for plasma LDL. The contribution of receptor-dependent pathways to the FCR for plasma LDL was estimated in three FH heterozygotes by simultaneous measurements of the FCR for native 131I-labeled LDL and 125I-labeled glucosylated LDL, which does not bind to LDL receptors. Whereas the removal rate for native LDL increased after mevinolin treatment, the removal rate for glucosylated LDL did not change. The current data suggest that mevinolin alone or mevinolin plus bile acid depletion (i.e., ileal bypass or colestipol therapy) decreases plasma LDL levels primarily by raising the number of LDL receptors and, thus, enhancing the removal of LDL from plasma.

Anticholesteremic Agents↗
PubMed2002

Assessment of a difference in ALDH2 heterozygotes and alcoholic liver injury.

We have speculated that the degree of liver dysfunction in alcoholic liver disease with ALDH2*1/2*2 may be less pronounced than that with ALDH2*1/2*1. In the present study, outpatients with alcoholic liver injury were examined for ALDH2 genotype and biochemical data. The number of patients was 29 cases of nonspecific changes, 16 cases of fatty liver, 5 cases of liver fibrosis, and 44 cases of liver cirrhosis. Biochemical data were evaluated with ALDH2 heterozygotes data obtained by PCR-SSCP. The ALDH2*1/2*1 and ALDH2*1/2*1 genotypes accounted for 90% and 10%, respectively. As for ALDH2*1/2*2, there were three patients with nonspecific changes, three with fatty liver, one with liver fibrosis, and two with liver cirrhosis. In alcoholic liver disease patients, when the ALDH2*1/2*2 genotype was compared with the ALDH2*1/2*1 genotype with biochemical data, the gamma-GTP value in patients with ALDH2*1/2*2 was significantly higher than with ALDH2*1/2*1 ( < 0.005). When the frequency of ALDH2 genotype was determined in patients with alcoholic liver injury, ALDH2 heterozygotes accounted for 15% for the non-cirrhosis group, and 5% for the cirrhotic group. When a relationship between the amount of ethanol intake and biochemical data were determined in patients with alcoholic liver injury who have ALDH2 heterozygotes, the glutamic oxaloacetic transaminase (GOT) and gamma-GTP values were significantly higher at an ethanol intake amount of ethanol more than 100 g per day than intake less than 100 g per day ( < 0.05). The alcoholic patients with ALDH2*1/2*2 drink a slight amount of ethanol, the liver injury is found to be stronger than those with ALDH2*1/2*1 when they drink more than 100 g ethanol per day.

Aldehyde Dehydrogenase↗
PubMed1985

Detection of heterozygotes of X-linked ichthyosis by measuring steroid sulphatase activity of lymphocytes. Mode of inheritance in three families.

Steroid sulphatase activity in peripheral blood lymphocytes was assayed in all available members of three families in which cases of X-linked ichthyosis were frequently seen. Lymphocytes from all the patients with this disease lacked steroid sulphatase activity and some female members who were probably heterozygotes, showed significantly lower enzyme activity compared with other healthy family members and normal controls. This suggest that females heterozygous for X-linked ichthyosis in these families could be traced enzymatically. Three childless females in these families were found to be possible heterozygotes in view of their lower enzyme levels. It was found that polyacrylamide gel electrophoretic mobility of serum low-density lipoproteins was increased in X-linked ichthyosis patients but was not changed in the probable heterozygotes. The detection of individuals heterozygous for X-linked ichthyosis, for the purpose of precise genetic counselling, may be possible by measuring steroid sulphatase activity of peripheral blood lymphocytes.

Female↗
PubMed1983

Diagnosis of cystic fibrosis homozygotes and heterozygotes from plasma and fibroblast cultures. A three-generation family study.

The diagnosis of cystic fibrosis (CF) homozygotes and heterozygotes and of individuals without the CF gene, based on differences in the thermal stability of acid phosphatase and alpha-mannosidase, is reported. The residual activities at 36.5 degrees C and 41.3 degrees C were below 10% of the activity in unheated samples for homozygotes, 40-50% for heterozygotes and above 90% for normals. The intracellular alkaline phosphatase and extracellular beta-hexosaminidase activities after treatment with heparin and gammaglobulin were 500% and 200%, respectively, of the activities without this treatment in CF homozygotes, whereas for heterozygotes and normals the values were the same after treatment as before. Pedigrees of four CF families, covering 2-3 generations, are presented. The possible use of these tests as diagnostic tools is further discussed.

Acid Phosphatase↗
PubMed1997

Evaluation of an aspartame loading test for the detection of heterozygotes for classical phenylketonuria.

Classical phenylketonuria (PKU) is an inborn error of metabolism of autosomal recessive inheritance characterized by the accumulation of phenylalanine (Phe) in tissues due to Phe-4-hydroxylase deficiency. Several methods have been developed for the detection of PKU heterozygotes based on the determination of plasma Phe and tyrosine (Tyr) levels, on the analysis of the Phe/Tyr and Phe2/Tyr ratios and on the use of discriminant functions. The objective of the present study was to test the value of loading with aspartame (a sweetener consisting of Phe, aspartate and methanol) for the identification of PKU carriers. The study was conducted on 22 obligate heterozygotes and 27 controls. Two blood samples were collected (under fasting conditions and 30 min after the loading) for fluorometric determination of Phe and Tyr. Phe, Phe/Tyr and Phe2/Tyr values were higher in heterozygotes, whereas Tyr was higher in controls in both situations investigated. Linear discriminant function was considered to be the best parameter for differentiation of the individuals in the two groups. Under the conditions employed in the present study, aspartame loading did not show any advantages in discriminating between PKU carriers and normal individuals when compared to the same analysis performed under fasting conditions.

Aspartame↗
PubMed1981

An improved method for heterozygote identification in feline and human mucopolysaccharidosis VI, arylsulfatase-B deficiency.

An improved method has been developed for the detection of heterozygotes for feline and human mucopolysaccharidosis VI. Arylsulfatase-A and -B activities were assayed in leukocyte extracts following separation of the enzymes by batch chromatography on DEAE cellulose. Determination of arylsulfatase-B specific activities did not permit accurate heterozygote identification, whereas the arylsulfatase-A to arylsulfatase-B activity ratio discriminated all 16 obligate heterozygotes for the feline and human disorders.

Animals↗