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Biomedical subjects

D M Danks

Publications and source records attributed to D M Danks.

At least 55 records · Page 3Linked to original sources
PubMed1991

The importance of further cytogenetic and molecular investigation of acrocentric variants: justification by presentation of a case [t(8;14)(q24;p11)].

On routine chromosome analysis a moderately retarded 18-year-old man was found to have an unusual short arm on one chromosome 14. With GTL-banding this chromosome showed an enlarged short arm with no evident secondary constriction. Negative CBG-banding of the short arm suggested the possibility of a translocation involving euchromatin. Interpretation of the abnormality as an unbalanced translocation relied on chromosome analysis using GTL-, CBG-, and Ag-NOR-banding of the proband's phenotypically normal mother, who was found to be carrying a balanced translocation involving chromosomes 8 and 14. In situ hybridization of sequences known to map to the short arm of chromosome 14 confirmed the interpretation and established that the breakpoint was within p11. The patient, whose karyotype is 46,XY, -14, +der(14)t(8;14)(q24.1;p11), is trisomic for the terminal end of the long arm of chromosome 8. The patient's clinical features are described and compared with those reported in patients trisomic for this region. This study demonstrates the importance of using a number of different banding techniques in conjunction with in situ hybridization for the investigation of morphologically unusual acrocentric short arm variants seen at routine diagnosis.

Adolescent↗
PubMed1991

Copper and liver disease.

There has been some limited progress in the understanding of the basic defect in Wilson disease and the gene concerned has been located to the chromosome region 13q14. Treatment with zinc has emerged as a definite alternative to penicillamine administration and some shortcomings and/or hazards of both forms of therapy have emerged as their modes of action have been studied more carefully. Tetrathimolybdate may have a place in treatment, especially when rapid complexing of copper is important. Hepatic copper accumulation occurs in a number of cholestatic diseases and they play an important part in pathogenesis and can occasionally lead to neurologic toxic effects. Copper overload in the newborn period when biliary excretion of copper is inefficient may establish a vicious cycle of copper accumulation and liver damage in Indian childhood cirrhosis and less frequently in babies in other countries.

Adult↗
PubMed1991

A comparison of phenotype and copper distribution in blotchy and brindled mutant mice and in nutritionally copper deficient controls.

The murine mottled mutants brindled, Mo br, and blotchy, Mo blo, are valuable animal models for the study of mammalian copper metabolism. In this paper, we present data showing that a nutritionally copper deficient suckling mouse, Cu-, with strong phenotypic similarities to the brindled mutant can be produced by feeding genetically normal dams a copper deficient diet (0.1-0.4 ppm Cu2+) from the day of mating. Comparisons of copper distribution between the Cu- mice and brindled mutants indicate that when a small dose of copper (0.5-0.9 micrograms Cu2+) was administered by intracardiac injection, the copper was abnormally distributed, and that the pattern of tissue distribution was very similar in Cu- mice and brindled mutants 24 h after injection. When, however, a treatment dose (50 micrograms Cu2+) was injected subcutaneously, and tissues assayed 3 d after injection, copper distribution in Cu- mice and brindled mutants was clearly different. Copper deficiency in Cu- suckling mice is entirely derived from maternal effects. Evidence that maternal effects may also influence the survival and phenotype of the brindled and blotchy mutants was obtained by comparing the viability of mutants born to dams carrying mottled mutations on one or both X chromosomes.

Animals↗
PubMed1991

Hepatic ceruloplasmin gene expression is unaltered in the toxic milk mouse.

The toxic milk mutation in mice is an autosomal recessive condition that causes a marked hepatic accumulation of copper in the adults, but is also characterized by severe copper deficiency in the pups of toxic dams. To establish whether the mutation affects ceruloplasmin (CP) gene expression, we analyzed the steady state levels of CP mRNA in mutant and normal animals at various stages of development and following administration of copper and zinc. In fetal and neonatal animals, the expression of the CP gene is unaltered by the mutation or the copper deficiency in the pups of mutant dams. Copper and zinc administration to 7-d-old pups caused a significant increase (35%) in CP mRNA in all genotypes. In the adults that had accumulated 600-700 micrograms/g dry wt of copper in the liver, the CP mRNA level was normal, but pregnancy produced two-to fourfold elevation of the mRNA in both normal and mutant females. These results suggest that the toxic milk mutation does not affect the regulation of the CP gene and that the gene is not responsive to copper deficiency, copper administration or copper excess in the liver.

Animals↗
PubMed1991

The natural history of untreated phenylketonuria over 20 years.

Fifty-one adults with untreated phenylketonuria (PKU), have been reviewed after a 20 year interval, at ages ranging from 28.8 to 71.8 years. Five died of causes unrelated to PKU. Three severely affected individuals had shown a progressive loss of motor function and three had developed epilepsy, bringing the total with this problem to 12. No loss of abilities was apparent in 41 patients. Other health problems, including cataracts, were not frequent. Serum phenylalanine levels had decreased over the 20 year period. Untreated PKU does not generally cause progressive loss of abilities during adult life.

Activities of Daily Living↗
PubMed1990

Geleophysic dysplasia.

We describe 2 children with geleophasic dysplasia. Prominent cardiac disease in one of the patients caused death at an early age. The history of consanguinity in one of the families supports autosomal recessive mode of inheritance. Histological and ultrastructural changes suggest that a disturbance in the relations between cell membrane and extracellular matrix may be involved in the pathogenesis.

Abnormalities, Multiple↗
PubMed1990

Unusual X chromosome inactivation in a mentally retarded girl with an interstitial deletion Xq27: implications for the fragile X syndrome.

A de novo interstitial deletion (X)(q27.1q27.3), between the loci DXS 105 and F8, has been found in a mentally retarded female. The deleted X chromosome is preferentially early replicating in fibroblasts, B cells and T cells, suggesting that the missing region plays a role in inactivation of the X chromosome. None of the available DNA probes except DXS 98 maps to the deleted region of about 10,000 kb. The locus FRAXA is either included in the deletion, or located close to the distal break point.

Blotting, Southern↗
PubMed1990

The effect of D-penicillamine on metallothionein mRNA levels and copper distribution in mouse hepatocytes.

Penicillamine increases the levels of metallothionein (MT) mRNA in a time and concentration dependent manner without altering either the rate of copper uptake or the amount of copper within the cell. The effect is dependent on the presence of intracellular copper, however, since depletion of copper by chelators blocks the effect, and does not alter the ability of dexamethasone to stimulate mRNA production. Penicillamine did not alter the distribution of 64Cu in the hepatocytes, as measured by fast protein liquid chromatography (FPLC), although the pattern may be affected by the amount of MT present. The data indicates that penicillamine removes copper from some intermediary ligand, thereby making it available to induce metallothionein. It is possible that this is part of the therapeutic action of the chelator in the treatment of Wilson's disease.

Animals↗
PubMed1990

Effects of cellular copper content on copper uptake and metallothionein and ceruloplasmin mRNA levels in mouse hepatocytes.

The intracellular copper content of mouse hepatocytes has been altered by incubating with either increasing amounts of extracellular copper or increasing amounts of diamsar, a copper chelator. Metallothionein 1 (MT1) and MT2 mRNA levels in the cells increased in proportion to the intracellular copper concentration. The degree of stimulation was similar for both MT1 and MT2, with mRNA levels increasing approximately fourfold for a six- to eightfold increase in intracellular copper levels. In contrast, neither copper uptake nor ceruloplasmin mRNA showed any response to intracellular copper levels. Unlike the situation in the rat, there was no clear evidence for saturation of copper uptake. Incubating cells with increasing amounts of 64Cu resulted in a linear increase in the amount taken up over 2 h. The amount of 64Cu accumulated was the same in control and copper-depleted cells, which suggests that neither ceruloplasmin production nor copper uptake is regulated by intracellular copper levels. However, other possibilities, such as the chelators not being able to deplete the pool(s) responsible for the control of ceruloplasmin production or copper uptake, must also be considered.

Animals↗
PubMed1990

Role of albumin's copper binding site in copper uptake by mouse hepatocytes.

It is possible, in vitro, to label albumin with copper either exclusively on the specific binding site or partly on the specific site and also on other sites by altering the pH at which the two ligands are mixed. Copper attached exclusively to the specific site is taken up more rapidly than copper attached to that site and others on albumin. The effect is proportional to the amount of copper on the specific site. Additional histidine stimulates uptake irrespective of the copper binding site on albumin. The effect is related to the histidine on position 3 of the albumin, since it is not seen when dog albumin is labeled under the same conditions. The data suggest that the cell recognizes and presumably binds the copper-albumin (CuAlb) complex but may preferentially recognize the ternary complex formed by CuAlb and histidine. We suggest that, in vivo, copper is bound mainly as the ternary complex and that the structure formed, presumably similar to that formed by a copper-histidine complex, is what is actually recognized by the cell. After binding, the albumin and histidine are released, possibly by a reduction step, and the copper is transported across the membrane. If the copper cannot be transported (as occurs when the cells are incubated at 4 degrees C), it blocks further binding of the ternary complex.

Animals↗
PubMed1990

Biochemical basis of prolidase deficiency. Polypeptide and RNA phenotypes and the relation to clinical phenotypes.

Cultured skin fibroblasts or lymphoblastoid cells from eight patients with clinical symptoms of prolidase deficiency were analyzed in terms of enzyme activity, presence of material crossreacting with specific antibodies, biosynthesis of the polypeptide, and mRNA corresponding to the enzyme. There are at least two enzymes that hydrolyze imidodipeptides in these cells and these two enzymes could be separated by an immunochemical procedure. The specific assay for prolidase showed that the enzyme activity was virtually absent in six cell strains and was markedly reduced in two (less than 3% of controls). The activities of the labile enzyme that did not immunoprecipitate with the anti-prolidase antibody were decreased in the cells (30-60% of controls). Cell strains with residual activities of prolidase had immunological polypeptides crossreacting with a Mr 56,000, similar to findings in the normal enzyme. The polypeptide biosynthesis in these cells and the controls was similar. Northern blot analyses revealed the presence of mRNA in the polypeptide-positive cells, yet it was absent in the polypeptide-negative cells. The substrate specificities analyzed in the partially purified enzymes from the polypeptide-positive cell strains differed, presumably due to different mutations. Thus, there seems to be a molecular heterogeneity in prolidase deficiency. There was no apparent relation between the clinical symptoms and the biochemical phenotypes, except that mental retardation was present in the polypeptide-negative patients. The activities of the labile enzyme may not be a major factor in modifying the clinical symptoms.

Adolescent↗
PubMed1989

Striatal degeneration in glutaric acidaemia type II.

A girl of first cousin parents presented in the 1st year of life with a progressive neurological disease with muscle weakness and hypotonia, accompanied later by dystonia. Investigations, including gas chromatography of urine, showed no abnormality. Autopsy showed marked neuronal loss and gliosis in the putamen and globus pallidus. The activity of glutaryl-CoA dehydrogenase in cultured fibroblasts was normal, but the activity of electron transfer flavoprotein was markedly diminished. Retrospective study of urine by capillary gas chromatography/mass spectrometry showed small amounts of glutaric and other organic acids. This is the first report of striatal degeneration in association with glutaric acidaemia type II. The neuropathological changes were milder than those in glutaric acidaemia type I.

Child, Preschool↗
PubMed1989

Cytochrome c oxidase deficiency in subacute necrotizing encephalopathy (Leigh syndrome).

Tissues and cultured fibroblasts from two patients with Leigh syndrome (subacute necrotizing encephalopathy) were examined. A systemic defect in cytochrome oxidase was identified by enzyme assay and estimation of cytochrome concentrations. Immunochemical analysis showed a reduction of most subunits of the cytochrome oxidase complex. The rate of synthesis of cytochrome oxidase subunits, determined by labelling experiments in cultured fibroblasts, was the same in the patients and normal controls. The reduced cytochrome oxidase content of the patients' tissues must therefore result from abnormal turnover of the protein subunits.

Animals↗