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R Gitzelmann

Publications and source records attributed to R Gitzelmann.

At least 73 records · Page 4Linked to original sources
PubMed1984

Cysteine in the triple-helical domain of one allelic product of the alpha 1(I) gene of type I collagen produces a lethal form of osteogenesis imperfecta.

We studied tissue and cultured skin fibroblasts from a newborn with the lethal perinatal form of osteogenesis imperfecta born to a mother with the Marfan syndrome and her unrelated husband. Dermis from the infant was thinner and fibril diameter smaller than control; dermal fibroblastic cells had dilated endoplasmic reticulum. His fibroblasts in culture synthesized two different species of pro alpha 1(I) chains in about equal quantity. One chain was normal, the other contained cysteine within the triple-helical portion of the COOH-terminal cyanogen bromide peptide alpha 1(I)CB6. Molecules which contained two copies of the mutant chain formed alpha 1(I)-dimers linked through interchain disulfide bonds. Molecules which contained either one or two mutant chains were delayed in secretion and underwent excessive lysyl hydroxylation and hydroxylysyl glycosylation of all chains in the molecule, probably as a result of delayed triple-helix formation. Molecules containing either one or two copies of the mutant chain melted at 38 degrees C instead of 41 degrees C. The most likely explanation for these findings is that a cysteine is substituted for a glycine in the triple-helical domain of the products of one of the alpha 1(I) alleles. Such a substitution would interfere with triple-helix formation and stability and thus explain 1) the decreased melting temperature, 2) the increased post-translational modification, 3) the altered rate of secretion and accumulation of intracellular material, 4) the increased intracellular degradation of newly synthesized collagen, and 5) the decreased collagen production. Since neither parental cell strain produced the same mutant chain, the findings are best explained by a new mutation in one of the alpha 1(I) genes. The role of the uncharacterized "Marfan" gene in modifying the phenotype in this patient is unclear.

Alleles↗
PubMed1984

Galactosemia: how does long-term treatment change the outcome?

In galactosemic subjects, treatment prevents liver and kidney failure, brain damage and cataracts, but total exclusion of galactose from the diet does not ensure the absence of all pathology. Early and well-treated children show satisfactory general health and growth, make reasonable though suboptimal intellectual progress, are prone to speech defects, and commonly experience visual perceptual difficulties and some social maladjustment. Two different metabolites are potentially toxic: galactitol is responsible for the cataracts while galactose-1-phosphate causes the rest of the pathology. As both metabolites are present in the fetus and in postnatal life, pathological changes may develop at any time in life, even when treatment is strict. Owing to UDP-galactose 4'-epimerase, man can generate galactose from glucose from early embryonic life on. Therefore, transferase-deficient individuals can form galactose-1-phosphate in the absence of exogenous galactose, a process for which UDP-glucose pyrophosphorylase is essential. Biosynthesis of galactose from glucose in well-treated galactosemics constitutes a mechanism of self-intoxication, not only in utero but also in adult life. The prognosis for some treated galactosemics may depend on their own ability to limit this process. Galactosemic girls, whether well-treated or not, run a considerable risk of developing ovarian dysfunction. Hypergonadotropinism has been diagnosed from 2 years of age to the third decade. Prenatal ovarian failure is not excluded but the observed facts suggest that ovarian failure is acquired after ovarian differentiation and initiation of folliculogenesis, at an individual rate and possibly through continuous self-intoxication with galactose-1-phosphate. Up to now, mild hypergonadotropinism has been documented in only 2 galactosemic males, but the male cohort of galactosemics studied for gonadal dysfunction is yet small.

Female↗
PubMed1984

Short communication. Glycogenosis Ib: neutrophil microbicidal defects due to impaired hexose monophosphate shunt.

We studied neutrophil microbicidal function and oxidative metabolic activity in a patient with glycogenosis Ib. The intracellular killing defect and the respiratory burst abnormality in gycogenosis Ib neutrophils were confirmed. The impaired oxygen-dependent microbicidal activity was shown to result from impaired hexose monophosphate shunt activity (impaired endogenous NADPH synthesis) and could be corrected by homogenization of the cells, followed by the addition of exogenous NADPH. Our data are thus consistent with a possible role for glucose-6-phosphate transport in neutrophil microbicidal function. We recommend a continuous prophylaxis with co-trimoxazole in patients with glycogen storage disease Ib.

Adolescent↗
PubMed1984

Presence and absence of the microsomal beta-glucuronidase in mice correlates with differences in the processing of the lysosomal enzyme.

In some tissues such as liver and kidney, beta-glucuronidase is present not only in the lysosomes but also in the microsomes. Both enzymes are coded by the same structural gene. The function of the microsomal enzyme is still unclear. We have observed in primary cultures of mouse hepatocytes that the microsomal enzyme disappeared to a trace within 5 days after plating cells. This change of intracellular localization coincided with a change of the isoelectric focusing pattern of the lysosomal beta-glucuronidase. Within the multiple banding pattern of the lysosomal enzyme, a faintly staining group of bands in the more acidic range (mean pI 5.4) became more pronounced while a major group (mean pI 5.9) faded slightly. The correlation between the presence or absence of the microsomal beta-glucuronidase and distinct proportions of the two lysosomal enzyme forms was confirmed in vivo. The less acidic form (pI 5.9) prevailed in the presence (kidney, liver), the more acidic form (pI 5.4) in the absence of the microsomal enzyme (spleen). The two lysosomal forms differed also in their apparent molecular weight by approx. 1500 (Mr 71 500 versus 73 000). In order to elucidate the biosynthetic relationship between the microsomal enzyme and the two lysosomal enzyme forms we interfered with their processing in cultured hepatocytes. The addition of the protease/esterase inhibitor phenyl-methyl-sulfonyl-fluoride caused the disappearance of the microsomal and the appearance of the acidic pI 5.4 lysosomal enzyme within 24 h; with chloroquine, the microsomal enzyme remained nd no lysosomal pI 5.4 enzyme appeared.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Zonal differences of alpha-glucosidases in human kidney: studies in controls and in patients with glycogenosis type II.

In the kidneys of two infants who died from glycogenosis type II (deficiency of lysosomal acid alpha-glucosidase) the activity of alpha-glucosidase at acid pH was absent only from the medulla but not the cortex. This prompted an investigation of acid and neutral alpha-glucosidases of the two zones of normal human kidney and of liver. In the kidney medulla, a single, fast migrating electrophoretic band was active at neutral but not at acid pH. In the cortex, three additional bands were detected at neutral pH and two in the liver. One slowly migrating band was unique to the cortex and active over a broad pH range. It had comparatively high sensitivity to the inhibitor turanose and high heat stability. Its properties suggested a close relationship or identity to glucoamylase of the intestinal brush border membrane and to alpha-glucosidase in leukocytes and amniotic fluid and cells.

Child↗
PubMed1983

[Infusion-associated kidney and liver failure in undiagnosed hereditary fructose intolerance].

Appendectomy was performed in a 14 1/2-year-old boy with undiagnosed hereditary fructose intolerance because of chronic recurrent abdominal pain. During and after operation fructose containing solutions were infused. The patient received a total of 250 g fructose intravenously over 30 hours. Hours after onset of infusion he became soporous, hypoglycaemic and acidotic and was anuric after one day. Although the diagnosis was suspected by the end of the first postoperative day and fructose had been cancelled and haemodialysis been started, the boy died after a further 3 days with signs of acute kidney and liver failure. The diagnosis of hereditary fructose intolerance was biochemically established in post mortem liver tissue. This case recalls the fact that fructose, sorbitol or invert sugars should not be added to infusion solutions as they may be toxic for healthy persons and imply a lethal risk for patients with undiagnosed hereditary fructose intolerance, even well beyond the baby and infant period.

Acute Kidney Injury↗
PubMed1983

Hepatic glycogen synthetase deficiency not expressed in cultured skin fibroblasts.

Cultured skin fibroblasts from two siblings with hepatic glycogen synthetase deficiency and from their parents contained glycogen synthetase activity which was within the range of the controls. The mutation was thus not expressed in fibroblasts, a finding further documenting the presumed existence of genetically different forms of glycogen synthetase.

Adult↗
PubMed1982

A new high performance liquid chromatography (HPLC) method for the quantitation of strychnine in urine and tissue extracts.

A high performance liquid chromatography (HPLC) method was developed for the quantitation of strychnine in urine of children with nonketotic hyperglycinaemia and other developmental disorders treated with the alkaloid. Mobile and stationary phases were polar, i.e. methanol-water-330 g/kg ammonia (volumes, 85 ml + 14.2 ml + 0.8 ml) and LiChrosorb Si-60, 7 microns. Brucine was the internal standard. Extraction was performed by the Extrelut technique. At strychnine nitrate concentrations in urine of 21, 126, and 70 micrograms/l, recovery was 92.1 +/- 8.7, 98.1 +/- 2.7, and 102.5 +/- 2.7%. A child with nonketotic hyperglycinaemia under continued strychnine treatment excreted 1 to 13.6% of the daily dose unmetabolized in urine. The method was also suitable for the estimation of unreacted strychnine in tissue extracts. The fast disappearance in vitro of strychnine from a guinea pig liver preparation was confirmed.

Amino Acid Metabolism, Inborn Errors↗
PubMed1981

The diagnosis of hereditary fructose intolerance.

Hereditary fructose intolerance (HFI) is a potentially life-threatening disorder and can be suspected from a detailed nutritional history. The usefulness of 2 diagnostic procedures, fructose tolerance test (FTT) and aldolase assay on biopsied liver, was studied. A standardized intravenous FTT with 200 mg/kg b.w. was done on 11 children with HFI, 17 age-matched contrast children, 6 adults with HFI and 6 adult controls. Blood glucose, phosphorus, urate, magnesium and fructose were followed for 2 hours. By the FTT, each HFI individual was reliably distinguished from controls and contrasts and even from those with acute liver disease other than HFI. Both children with non-HFI hepatopathy examined by both procedures had a normal FTT in spite of reduced liver fructaldolase activity. HFI children responded to the FTT by earlier and more pronounced hypoglycemia than adults, and one girl converted to an adult type response between the ages 12 and 181/2 years. Responses of two HFI sibling pairs and of one set of monozygotic twins were typical for age, but resemblance was no greater than within the unrelated HFI probands. The intravenous FTT is judged a reliable diagnostic tool, simple and harmless if done in hospital. Essential fructosuria is readily diagnosed by the FTT, but fructose-1,6-diphosphatase deficiency and HFI are not differentiated with certainty. Liver biopsies were obtained from 35 children with HFI, 14 contrast persons and 10 controls (of which 9 organ donors) and examined enzymatically. Deficiency of fructaldolase was observed in all HFI children but also in some contrast children suffering from acute liver disease other than HFI. In these, HFI could only be excluded when the reduced activity of reference enzymes such as fructose-1,6-diphosphatase and glucose-6-phosphatase and liver histology were included in the evaluation. In one deceased HFI infant, fructaldolase was deficient in both, liver and kidney cortex. Extent of antibody activation and of heat inactivation of residual fructaldolase varied between unrelated HFI patients but not within families. These results did not contribute to diagnosis but further documented genetic heterogeneity of HFI. For diagnosis of HFI we recommend 1. immediate elimination of fructose from the diet, 2. the intravenous FTT after several weeks of fructose withdrawal, and 3., should diagnosis still be uncertain, laparoscopic liver biopsy for assay of fructaldose and of reference enzymes and for histology.

Adult↗