Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Female patients with congenital adrenal hyperplasia (CAH; N = 33; 11-41 years), simple-virilizing (SV) patients (N = 19), salt-wasting (SW) patients (N = 13), and sister controls (N = 14) were compared with regard to their body positions and movement patterns. Data collection comprised both self assessments and mothers' assessments using 20 sex-dimorphic items with corresponding "more masculine" and "more feminine" versions for each variable, represented in photographs (forced-choice approach). Primarily based on mothers' assessments, single-item results suggested slightly more masculine positions and patterns for female CAH patients compared to sisters, for SW patients more distinct than for SV patients. Results from an 11-item scale ("motor behavior", alpha = 0.59) revealed differences between SW (more masculine) and SV patients for self assessments (P, one-tailed, < 0.09); sisters were in an intermediate position closer to the SV patients. According to mothers' assessments, the CAH patient group as a whole differed (more masculine) from sisters (P < 0.06); this finding was mainly accounted for by the SW group (P < 0.04). Complex analyses on the relationship of motor behavior and intervening variables (e.g., postnatal androgenization, onset of puberty, menarche, height, weight, sexual orientation) revealed very few significant results. Findings rather suggested organizational hormonal effects on body positions and movements prenatally; they are in line with main results from the interview section of the Hamburg CAH study (e.g., "Gender-related behavior"). An approach of this kind seems to be justified for investigating motor behavior in future psychoendocrine studies.
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PMID:Body positions and movement patterns in female patients with congenital adrenal hyperplasia. 147 31

We have characterized mutations in the steroid 21-hydroxylase gene (CYP21) in salt-wasting congenital adrenal hyperplasia (SW-CAH) subjects, healthy control subjects, and affected sibling pairs with SW-CAH. To identify point mutations in CYP21, we have used an improved polymerase chain reaction methodology that allows analysis of the entire CYP21 gene. In addition, we have used polymerase chain reaction to search for abnormally spliced mRNAs resulting from putatively abnormal CYP21 genes transfected into COS1 cells. We found that all 26 SW-CAH subjects from whom DNA could be completely analyzed, had mutations that could account for the 21-hydroxylase enzyme deficiency. These mutations included CYP21 gene deletion, conversion to the inactive CYP21P form, point mutations leading to amino acid substitutions or stop codons, small gene deletions, and a point mutation in intron-2 that leads to an abnormally spliced mRNA. The point mutation in intron-2 was directly shown to activate a cryptic splice site 19 basepairs from exon-3 of CYP21 and thereby cause a reading frame mutation. This CYP21 mutation was frequently found in our white SW-CAH subjects, while the frequency of this mutation was extremely low in a racially matched control population. Furthermore, affected sibling pairs shared this mutation in all cases examined. The results presented should have important applications for the prenatal diagnosis of CAH.
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PMID:Salt-wasting congenital adrenal hyperplasia: detection and characterization of mutations in the steroid 21-hydroxylase gene, CYP21, using the polymerase chain reaction. 174 Apr 89

We studied a family in which one out of two children presented a non-salt wasting form of CAH. Genomic DNA of the patient, his brother, his parents and a normal control were digested by the Taq I and Bgl II restriction enzymes. The fragments were electrophoresed, transferred onto a nitrocellulose membrane and hybridized with two specific probes: pC21a for the CYP21 genes and pAT-A for the C4 genes. We performed simultaneous RFLP analyses of the CYP21 and C4 genes and determined the relative hybridization intensity of the genes using scanning densitometry of the X-ray films. The affected child had a CYP21B gene conversion in the CYP21A pseudogene on one chromosome inherited from his mother and a mutated CYP21B gene on the second chromosome inherited from his father. The second maternal chromosome, inherited by the unaffected brother, presented an unusual CYP21A gene deletion without a C4A or C4B gene deletion. Although CYP21A is a pseudogene, this type of complete CYP21A gene deletion associated with a CYP21B gene conversion has never been previously described.
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PMID:CYP21B gene conversion and complete CYP21A gene deletion in congenital adrenal hyperplasia. 197 31

Nutritional assessment factors (including dietary history, anthropometric and biochemical measurements, and evaluation of immunocompetence) were retrospectively reviewed in 74 patients undergoing an initial liver transplantation procedure. The patients were subdivided into four categories on the basis of type of liver disease: chronic active hepatitis (N = 24), primary sclerosing cholangitis (N = 22), primary biliary cirrhosis (N = 20), and acute or subacute hepatitis (N = 8). Our nutritional assessment data indicated that malnutrition was present preoperatively in all liver transplantation groups but that each group had distinct characteristics. The group with primary biliary cirrhosis seemed to have the best hepatic synthetic function despite extreme wasting of muscle and fat. On the basis of all criteria, the group with acute hepatitis was the most malnourished of the various disease groups. Aggressive nutritional support, which includes adequate intake of nutrients and supplementation of vitamins and trace minerals, should be encouraged for all potential liver transplant patients.
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PMID:Assessment of nutritional status of patients with end-stage liver disease undergoing liver transplantation. 249 64

Impairment of 21-hydroxylation is the most common enzymatic deficiency resulting in the syndrome of CAH, which may present either in the classical form in infants or in the nonclassical form in older individuals. Variable signs and symptoms of androgen excess are common to both types of the disorder, which are transmitted as autosomal recessive traits linked to HLA. Virilization begins in the second month of gestational life in classical 21-OHD, but postnatally in the nonclassical form. Salt wasting is a feature of the disease in a large number of classical patients; in the simple virilizing form aldosterone biosynthesis, a function of the adrenal zona glomerulosa, is intact. Additionally, no patient with nonclassical 21-OHD has been found to have salt wasting. Levels of precursor hormones are less markedly elevated in nonclassical 21-OHD, reflecting a less severe enzyme deficiency; coordinates of basal and stimulated 17-OHP are plotted on a nomogram to ascertain diagnostic category within a family. Confirmatory evidence of heterozygosity within the family of an affected proband is found by performing HLA typing. Specific linkage disequilibria exist for the classical and nonclassical forms of 21-OHD. Frequency of the classical disease is 1/5,000-1/15,000 in Caucasians, whereas the nonclassical disease is found in approximately 1/100 individuals in the Caucasian population, placing the latter disorder among the most common autosomal recessive disorders in man. A deletion of the active 21-hydroxylase gene has been detected in some classical patients; further investigations are in progress to elucidate the molecular genetics of this disease.
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PMID:Genetics of adrenal steroid 21-hydroxylase deficiency. 352 88

HLA (human leucocyte antigens) alleles and plasma 17-hydroxyprogesterone levels after ACTH stimulation were studied in 134 German families of patients with salt-wasting (SW), simple virilizing (SV), and nonclassical (NC) late-onset forms of CAH. HLA typing revealed a genetic difference between the two classical disease forms. SW-CAH was strongly associated with Bw47 and SV-CAH was closely linked to B5. The nearly complete connection of NC-CAH with B14 was confirmed. Bw47 and B14 were mostly components of the normally rare haplotypes A3, Bw47, DR7 and Aw33, B14, DR1, respectively. They did not occur in the families' disease-unaffected haplotypes. The HLA linkage data were consistent with those obtained from the ACTH stimulation test which showed a higher 17-hydroxyprogesterone increase in the group of genetically defined heterozygous relatives of SW patients than in the groups of heterozygous members of SV and NC families.
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PMID:Different gene defects in the salt-wasting (SW), simple virilizing (SV), and nonclassical (NC) types of congenital adrenal hyperplasia (CAH). 387 33

We studied 95 patients and their relatives with the classical salt wasting (SW) and simple virilizing (SV) form of CAH. SSCP/heteroduplex analysis allowed fast and efficient screening for the most common 21-hydroxylase mutations (e.g. deletions, splice site mutation in intron 2 (bp 656), Ile172Asn mutation in exon 4) and determination of the relative intensities of CYP21A and CYP21B genes. The splice site mutation in intron 2 was found as the most frequent cause of 21-hydroxylase deficiency (35% of our patients). There is a strong genetic association between the mutation in intron 2 and the SW form of CAH. On the other hand, about 20% of our patients with the intron 2 mutation have the SV phenotype. Interestingly, homozygous splice site mutations in intron 2 were also detected in some parents or other relatives with no phenotypic changes typical for CAH (clinical evaluation, steroid hormone levels). In those patients with SV-CAH and especially in the relatives with the homozygous intron 2 mutation and an unaffected phenotype, the splice site mutation could be "leaky". mRNA-splicing in the adrenal cortex should result in a high degree of normal mRNA species. This is in contrast to in vitro expression studies of CYP21B genes containing the intron 2 mutation, performed by other groups. However, the results of in vitro expression studies are not always reflecting the in vivo conditions in the adrenal cortex. This situation is in good agreement with the variable degree of normal spliced mRNA and different phenotypic severity in intron mutations found in thalassemia.
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PMID:Divergence between genotype and phenotype in relatives of patients with the intron 2 mutation of steroid-21-hydroxylase. 758 99

Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) most commonly carry an A-G transition at nucleotide 656 (nt 656 A-->G), causing abnormal splicing of exons 2 and 3 in CYP21, the gene encoding active steroid 21-hydroxylase. Affected infants are severely deficient in cortisol and aldosterone, and usually come to medical attention during the neonatal period. We report on 2 affected boys, homozygous for the nt 656 mutation, who thrived in early infancy, but suffered salt-wasting crises unusually late in infancy, at 3.5 and 5.5 months, respectively. Laboratory studies at presentation showed hyponatremia, hyperkalemia, dehydration, and acidosis; serum aldosterone was low in spite of markedly elevated plasma renin activity. Basal 17-hydroxyprogesterone levels were only moderately elevated, yet the stimulated levels were more typical of severe, classic CAH due to 21-hydroxylase deficiency. Genomic DNA from the patients was analyzed. Southern blot showed no major deletions or rearrangements. CYP21-specific amplification by polymerase chain reaction, coupled with allele-specific hybridization using wild-type and mutant probes at each of 9 sites for recognized disease-causing mutations, revealed a single, homozygous mutation in each patient: nt 656 A-->G. These results were confirmed by sequence analysis. We conclude that the common nt 656 A-->G mutation is sometimes associated with delayed phenotypic expression of SW-CAH. We speculate that variable splicing of the mutant CYP21 may modify the clinical manifestations of this disease.
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PMID:Splicing mutation in CYP21 associated with delayed presentation of salt-wasting congenital adrenal hyperplasia. 767 50

What are the respective places for prenatal treatment and neonatal screening in 21 hydroxylase deficiency, (21OHD) CAH? Current diagnostic procedures for 21OHD CAH do not prevent potential or actual morbidity and mortality from salt wasting and hypoglycaemia, ambiguous genitalia and late diagnosis. Presentation is with life-threatening illness or virilisation with long-term physical, psychological and psychosexual sequelae. Screening the whole newborn population would add only a very small additional unit cost in the screening laboratory already measuring TSH and phenylalanine. There are still few data on which to base an assessment of the efficacy of neonatal screening in reducing morbidity and mortality. Screening should now be adopted on a regional, or national, basis to assess both efficacy and cost-effectiveness. Although more (uncontrolled) data are now available concerning prenatal dexamethasone therapy, the degree of benefit in terms of reduced virilisation in relation to potentially significant maternal side effects is unclear and possible long term childhood side effects have not been studied. At present, therefore, there is insufficient evidence regarding the safety of mother and fetus to recommend the general use of dexamethasone outwith the context of controlled scientific studies. There is an urgent need for prospective controlled studies to be undertaken which would, in time, resolve both questions.
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PMID:Congenital adrenal hyperplasia (CAH)--the place for prenatal treatment and neonatal screening. 814 71

Classical 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase (3betaHSD) deficiency is a form of congenital adrenal hyperplasia that impairs steroidogenesis in both the adrenals and gonads resulting from mutations in the HSD3B2 gene and causing various degrees of salt-wasting in both sexes and incomplete masculinization of the external genitalia in genetic males. To identify the molecular lesion(s) in the HSD3B2 gene in the 11 patients from the seven new families suffering from classical 3betaHSD deficiency, the complete nucleotide sequence of the whole coding region and exon-intron splicing boundaries of this gene was determined by direct sequencing. Five of these families were referred to Morel's molecular diagnostics laboratory in France, whereas the two other families were investigated by Peter's group in Germany. Functional characterization studies were performed by Simard's group in Canada. Following transient expression in 293 cells of each of the mutant recombinant proteins generated by site-directed mutagenesis, the effect of the 25 mutations on enzyme activity was assessed by incubating intact cells in culture with 10 nM [14C]-DHEA as substrate. The stability of the mutant proteins has been investigated using a combination of Northern and Western blot analyses, as well as an in vitro transcription/translation assay using rabbit reticulocyte lysates. The present report describes the identification of 8 mutations, in seven new families with individuals suffering from classical 3betaHSD deficiency, thus increasing the number of known HSD3B2 mutations involved in this autosomal recessive disorder to 31 (1 splicing, 1 in-frame deletion, 3 nonsense, 4 frameshift and 22 missense mutations). In addition to the mutations reported here in these new families, we have also investigated for the first time the functional significance of previously reported missense mutations and or sequence variants namely, A82T, A167V, L173R, L205P, S213G and K216E, P222H, T259M, and T259R, which have not previously been functionally characterized. Furthermore, their effects have been compared with those of the 10 previously reported mutant enzymes to provide a more consistent and comprehensive study. The present results are in accordance with the prediction that no functional 3betaHSD type 2 isoenzyme is expressed in the adrenals and gonads of the patients suffering from a severe salt-wasting form of CAH due to classical 3betaHSD deficiency. Whereas the nonsalt-losing form also results from missense mutation(s) in the HSD3B2 gene, which cause an incomplete loss in enzyme activity, thus leaving sufficient enzymatic activity to prevent salt wasting. The functional data described in the present study concerning the sequence variants A167V, S213G, K216E and L236S, which were detected with premature pubarche or hyperandrogenic adolescent girls suspected to be affected from nonclassical 3betaHSD deficiency, coupled with the previous studies reporting that no mutations were found in both HSD3B1 and/or HSD3B2 genes in such patients strongly support the conclusion that this disorder does not result from a mutant 3betaHSD isoenzyme. The present study provides biochemical evidence supporting the involvement of a new molecular mechanism in classical 3betaHSD deficiency involving protein instability and further illustrates the complexity of the genotype-phenotype relationships of this disease, in addition to providing further valuable information concerning the structure-function relationships of the 3betaHSD superfamily.
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PMID:New insight into the molecular basis of 3beta-hydroxysteroid dehydrogenase deficiency: identification of eight mutations in the HSD3B2 gene eleven patients from seven new families and comparison of the functional properties of twenty-five mutant enzymes. 1059 96


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