George N. Donnell

Hypergonadotropic Hypogonadism in Female Patients with Galactosemia

Abstract We evaluated gonadal function in 18 female and eight male patients with galactosemia due to transferase deficiency; it was normal in the males, but 12 females had signs of hypergonadotropi...

Disorder of purine metabolism due to partial deficiency of hypoxanthine-guanine phosphoribosyltransferase: A study of a family

Abstract Four patients in a kindred who have had hyperuricemia, uric acid crystalluria and stones, were found to have partial deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity. The pattern of inheritance is consistent with the observation that the activity of HGPRT is determined by a gene on the X chromosome. The patients have normal intelligence, do not display self-mutilation and do not have gouty arthritis. In two patients, both children, confirmatory evidence of overproduction of uric acid was obtained following the administration of isotopically labeled uric acid and glycine. In both of these patients cerebrospinal fluid levels of hypoxanthine were two to three times those of normal controls. In all patients the administration of allopurinol reduced the amount of uric acid in blood and urine, but a concomitant increase in the levels of hypoxanthine and xanthine occurred in two patients. This observation is consistent with the hypothesis that the HGPRT enzyme is necessary for the reutilization of hypoxanthine. In both of the affected children persistent acidity of the urine and a reduction in urinary ammonium excretion were noted before therapy was initiated. Renal function, histology of the renal cortex and renal glutaminase enzyme activities were normal in these two patients. In both patients urinary ammonium excretion increased following allopurinol therapy. This suggests that a high urate load presented to the kidney may alter ammonia production or excretion.

Galactose Metabolism in Human Ovarian Tissue

ABSTRACT: Galactose metabolism was studied in human ovarian tissue obtained from 14 women controls between 21 and 72 y of age, and one 21-y-old galactosemic patient with hypergonadotrophic hypogonadism. Tissue slices were incubated with l-14C-galactose, and labeled intermediates were analyzed by anion-exchange column chromatography. Activities of enzymes related to the galactose pathway: galactokinase, transferase, epimerase, uridine diphosphoglucose (UDPGlc) and uridine diphosphogalactose pyrophosphorylases, and UDPGlc and uridine diphosphogalactose pyrophosphatases were measured in ovarian homogenates using radioisotopic, spectrophotometric, and fluorometric techniques. Incorporation of carbon label from l-14C-galactose into various galactose and glycolytic intermediates, as well as carbon dioxide and TCA-insoluble materials was demonstrated in samples from non-galactosemic controls. In tissue from the galactosemic individual, no labeled carbon dioxide was produced and very little incorporation into TCA-insoluble material was found. Labeled galactose-1-phosphate was elevated. In normal ovarian tissue, specific activities of galactokinase, transferase, epimerase, and UDPGlc pyrophosphorylase are much higher than those found in the red cells and in testes. UDPGlc pyrophosphorylase activity is about 50 times that of transferase, suggesting that uridine nucleotide sugars have an important role in the normal development and function of the ovary. It is hypothesized that premature ovarian failure, often observed in patients with galactosemia, is due to interference with nucleotide sugar metabolism and the synthesis of galactose containing glycoproteins and glycolipids consequent to the enzymatic defect in the major pathway of galactose metabolism.

Partial Trisomy of the Long Arm of Chromosome No. 7

A case report on an infant with trisomy of the distal third of the long arm of chromosome No. 7 is presented.

Childbearing by a galactosemic woman.

A Negro woman with galactosemia, maintained on a galactose-restricted diet since infancy, had an uncomplicated pregnancy and delivered an apparently healthy infant who was shown to be heterozygous for galactosemia. The father was normal with respect to galactose-1-phosphate uridyl transferase. Maternal blood, urine, and amniotic fluid were monitored during the pregnancy. Following delivery the mothers milk and the infants urine were studied. The present study shows for the first time that a woman, homozygous for galactosemia, can produce a clinically normal infant.

The Oxidation of Glycine and Propionic Acid in Propionic Acidemia with Ketotic Hyperglycinemia

Extract: Ketotic hyperglycinemia is a syndrome in which elevated concentrations of glycine occur in body fluids of patients who manifest life-threatening episodes of ketoacidosis very early in life. The disorder originally described under this heading is now known to be more reliably categorized by propionic acidemia than by hyperglycinemia. Studies of the metabolism of glycine and of propionate in this condition have been undertaken. Conversion of glycine-1-14C and of propionate-1-14C to 14CO2 has been studied both in vivo and in vitro. Conversion of glycine-2-14C to serine-3-14C has been studied in vivo. It was found that the conversion of glycine-1-14C to CO2 in vivo was defective in all three of the patients with ketotic hyperglycinemia. At the earliest time points, the specific activities of expired CO2 in control subjects varied from 25 to more than 60 dpm/

Urinary galactitol in galactosemic patients

mUmole, whereas in patients these values did not exceed 10 and were less than 5 in two patients. Conversion of the second carbon of glycine to the third carbon of serine was normal. The relative specific activity of the third carbon was 20. This value was 2–10 times the values found previously in patients with nonketotic hyperglycinemia where this conversion is defective. Conversion of propionate-1-14C to CO2 was defective both in vivo and in vitro in patients with ketotic hyperglycinemia and with methylmalonic acidemia. In control subjects, specific activities of the CO2 expired following injection of propionate-1-14C approximated 200 dpm/

Results of a survey of carrier women for the galactosemia gene.

mUmole at the earliest time points, whereas in VB the comparable specific activity was close to 0. Activity of propionyl-coenzyme A (CoA) carboxylase was absent in the fibroblasts of a patient with ketotic hyperglycinemia. Values of 15—30 dpm/5 mg protein obtained in the patient do not seem to differ significantly from 0, whereas in control subjects the values ranged from 985 to 2655 dpm/5 mg protein. These observations indicate that there are defects in the metabolism of both glycine and propionate in patients with ketotic hyperglycinemia.Speculation: In propionic acidemia with ketotic hyperglycinemia there is a defect in the oxidation of both propionate and glycine in vivo. Propionate carboxylation has been demonstrated to be defective in vitro. The abnormality of propionate metabolism seems to be primary; that of glycine metabolism may be secondary, or both could reflect a defect in synthesis of a common cofactor.

A Short, Retarded Child with a Deletion of the Short Arm of Chromosome 18 (18p-)

Abstract The possibility was explored of using the measurement of urinary galactitol to monitor the galactose-restricted diet of patients with galactosemia. The response to the addition of graded doses of galactose to the galactose-restricted diet was measured. It was found that urinary galactitol excretion is a relatively insensitive index of galactose intake and that it is of limited value in diet monitoring. Unexpectedly, galactitol was found in the urine of all patients receiving a galactose-restricted diet, and it was postulated that this sugar alcohol has its origin in part from endogenously produced galactose.

Pitfalls in the diagnosis of galactosemia

A survey of 108 heterozygote women for the classic galactosemia gene, GALT, did not reveal that the carrier state was associated with premature ovarian failure or ovarian cancer. This survey did not support previous epidemiologic studies suggesting an increased risk for ovarian dysfunction in women with deficiency of the GALT enzyme.