Maurice D. Kogut

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.

Studies of lactose absorption in patients with galactosemia.

Ten patients with galactosemia and six control subjects were given oral lactose loads. Only one child, a patient with galactosemia, failed to hydrolyze lactose and absorb its monosaccharide components. Nine of ten patients with galactosemia hydrolyzed lactose in spite of the fact that lactose had been excluded from their diet since early infancy, which suggested that intestinal lactase does not appear to be dependent upon lactose intake. The results of the sugar tolerance tests and of jejunal enzyme studies indicated that one of the children with galactosemia had an isolated lactase defect.

Carbohydrate Metabolism and Pancreatic Islet-cell Function in Thalassemia Major

To investigate the development of diabetes mellitus in patients with thalassemia major, plasma glucose and immunoreactive insulin (IRI) levels following oral glucose and intravenous tolbutamide and glucose disappearance rates following intravenous insulin were measured in 10 patients before and during five years on a high transfusion program (HTP). Plasma immunoreactive glucagon (IRG) levels following oral glucose, intravenous insulin, and arginine were measured during the sixth year. Serial percutaneous liver biopsies were performed on seven patients. The oral glucose tolerance tests (OGTT) and mean peak IRI levels were normal in nine of 10 patients before HTP. After HTP was begun a progressive deterioration of OGTT occurred despite normal IRI levels. Following tolbutamide, the mean per cent fall in plasma glucose in the patients before HTP was significantly less than in controls (p < 0.01) and similar to that of controls during five years of HTP in spite of higher than normal peak IRI levels. Of seven survivors after six years of HTP, three had normal OGTT and four had chemical diabetes; mean peak IRI levels were normal, but fasting IRG levels were significantly higher than in controls (p < 0.05). In all seven patients, plasma IRG failed to increase following insulin-induced hypoglycemia and was significantly higher than in controls after arginine (p < 0.01); after oral glucose, plasma IRG fell significantly below that of fasting only in the patients with chemical diabetes (p < 0.03). Following intravenous insulin, the mean per cent fall in glucose before and during HTP was significantly less than in controls (p < 0.01). Hemosiderosis and cirrhosis were present in all biopsied patients. Four patients died; two had chemical and two had nonketotic insulin-dependent diabetes. These data suggest that diabetes mellitus occurs frequently in patients with thalassemia on HTP and that insulin resistance and hyperglucagonemia, possibly due to cirrhosis, are important etiologic factors.

Effect of low-dose human growth hormone on carbohydrate metabolism in children with hypopituitarism+

Carbohydrate metabolism was studied in nine growth hormone-deficient children before and one year after treatment with human growth hormone (HGH). Before treatment the mean plasma immunoreactive insulin concentrations following administration of glucose and tolbutamide were significantly reduced. After one year of HGH therapy the mean plasma immunoreactive insulin levels in response to glucose and tolbutamide were greater than before treatment. The pattern of response of plasma free fatty acids, which was abnormal before treatment, returned to normal with therapy. The improvement in insulin responsiveness following HGH suggests that in the absence of growth hormone pancreatic beta cells have a decreased capacity to release insulin which improves following therapy. The effect of HGH on growth may be due, in part, to its insulinogenic activity.

Isoenzymes of hypoxanthine-guanine-phosphoribosyl transferase in a family with partial deficiency of the enzyme

The isoenzymes of hypoxanthine-guanine-phosphoribosyl transferase (HGPRT; E. C. 2.4.2.8) were studied by polyacrylamide gel disc electrophoresis in the erythrocytes of a family in which there was a partial deficiency of this X-linked enzyme. Hyperuricemic males, in whom HGPRT activity was 4% of normal, were found to have a variant enzyme which had altered kinetic and electrophoretic properties. In acrylamide gel, this variant migrated about 15% faster than the normal enzyme, and its Km for hypoxanthine was twice that of the normal. The sister of two patients had 34% of normal activity in her erythrocytes and was thought to be a heterozygote. Electrophoresis of her hemolysate yielded profiles in which there were two zones of HGPRT activity. The more slowly migrating isoenzyme behaved electrophoretically like the normal isoenzyme. The faster-migrating isoenzyme had a mobility identical to that of the variant enzyme found in hemolysates from her hyperuricemic siblings. However, in her profile the activity of the variant enzyme was three times greater than that of the HGPRT found in the boys. This increased activity appears to be due to an interaction of the variant enzyme with the normal enzyme. Electrophoresis of a mixture of normal enzyme and the variant from a hyperuricemic male yielded a profile similar to that observed in this girl and a dramatic increase in the amount of activity in the variant zone.

Idiopathic hypoglycemia: A study of twenty-six children*

Twenty-six children with idiopathic hypoglycemia were studied. Thirteen children had ketotic hypoglycemia, 5 had leucine sensitivity, 3 had transient neonatal hypoglycemia, and 5 could not be classified. Of 24 patients followed, neurologic impairment was noted in more than one third. An exaggerated insulin response was the principal metabolic abnormality in patients with leucine sensivitity. An important mechanism for hypoglycemia in children with ketotic hypoglycemia appears to be a failure to secrete insulin necessary to preserve liver glycogen. A specific and highly successful therapy for idiopathic hypoglycemia is not avialable.

Cadaver renal transplantation in children with cystinosis.

Five children with end-stage renal disease resulting from cystinosis received seven cadaver renal allografts. Four recipients have functioning grafts eight to 55 months after receiving the transplant and one recipient lost two grafts at 17 and 26 months after the transplant. There was no florid recurrence of the Fanconi syndrome although proximal renal tubular dysfunction developed in two patients, in one in association with chronic rejection and in one without apparent etiology. Free cystine content of white blood cells, cultured skin fibroblasts and allograft tissue was significantly increased. Cystine crystals were observed in the mesangium of two grafts and in the interstitial tissue of all grafts; however, no cystine crystals were found in the tubules. The location of the cystine crystals, as well as the fact that the highest free level of cystine of allograft tissue was observed in the graft undergoing chronic rejection. led to the hypothesis that recipient cells infiltrating the graft were the source of cystine deposition. The data indicate that successful cadaveric transplantation does not correct the primary metabolic defect in cystinosis, thereby explaining the persistence of the extrarenal clinical manifestations, such as photophobia and hypothyroidism, after renal transplantation in cystinosis.

Adrenocorticotropic hormone unresponsiveness: Report of a girl with excessive growth and review of 16 reported cases

A 4 9/12-year-old girl is described who developed vomiting, obtundation, convulsions, hypoglycemia, hyperpigmentation, and excessive growth after 11 months of age. She failed to elaborate cortisol following ACTH stimulation but could conserve salt and increase aldosterone production following salt deprivation. Secretory rates of desoxycorticosterone and corticosterone were normal on a normal salt diet. An explanation for her excessive growth was not evident. A sister, who had hypoglycemia and hyperpigmentation, died suddenly at age 2 1/2 years. The disorder is probably due to a failure in utero of the adrenal glands to respond to ACTH and to differentiate into the normal zones of the adrenal cortex. The clinical features of 16 reported pediatric cases are summarized. Evidence concerning the pathogenesis of this disease is reviewed.

Systemic manifestations of neurogenic tumors.

Summary 1. Patients with neurogenic tumors (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma) may secrete catecholamines and/or their degradation products in the urine. These patients may also exhibit symptoms and signs presumably ascribable to effects of the catecholamines. It is not known how many patients with these tumors elaborate catecholamines or how often these symptoms and signs are present. 2. The occurrence of adrenergic symptoms and signs and increased secretion of catecholamines is of practical importance in the diagnosis and management of this group of common and highly malignant tumors. 3. Increased elaboration of catecholamines may be detected either by measuring epinephrine or norepinephrine in the urine or their degradation products. VMA which is an important degradation product is measured with greater ease than its precursors. Excessive quantities in the urine are indicative that the tumor is elaborating catecholamines. 4. Hypertension, diarrhea, excessive sweating, flushing, pallor, rash, polyuria, and polydipsia are findings most characteristically associated with these tumors. 5. Considerable variation exists in thesymptomatology of patients with these tumors, possibly because of variability in the predominant metabolite of the catecholamine secreted by the tumor.