Ammonia intoxication due to acongenital defect in urea synthesis

Ammonia intoxication due to acongenital defect in urea synthesis

Volume 65 Number 6 Part 2 logic entities or rather different manifestations of the same disease process. DISCUSSION DR. P. E. CONEN, Hospital for Sic...

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Volume 65 Number 6 Part 2

logic entities or rather different manifestations of the same disease process. DISCUSSION DR. P. E. CONEN, Hospital for Sick Children, Toronto, Ontario. This is indeed a most intriguing case, Dr. Zellweger. I wondered whether your reviews were not entirely complete. Last year, we published a case of nemaline myopathy with electron microscopic findings, and the actual bodies with light microscopy were much more twirled than were yours. It may have something to do with the fixation. I wondered with electron microscopy whether you had an opportunity to examine the periodicity of the rod bodies. They have a periodicity of about 140 A which makes them pretty similar to tropomyosin which forms part of the normal muscle. Its location has not been really identified. Perhaps it is in the C-band. I wondered whether you had had a chance to analyze any of the muscle to see whether the tropomyosin content was normal. These bodies are present in the human fetus. Another thing I notice is that in your summary you comment on increased satellite cells. Did you see these by the electron microscope? In your table in the abstract you say "increased satellite cells." Was this with the light microscope as described in 1941? The reason I am interested is that these are also present normally in the fetus. I think it is very interesting that you link these two diseases together. DR. JO~N W. GERRARD, University of Saskatch-

ewan, University Hospital, Saskatoon, Saskatchewan. I was very much interested, too, in Dr. Zellweger's paper because we in Saskatchewan have been following a very similar family. I am sorry to say we have not gotten such beautiful histologic studies of the muscles. But in this family of six children, two boys and a girl as well as the father have this disease. There is some degree of consanguinity between the father and the mother, so we were not certain whether the disease is recessive, being present in a homozygous father who has married a carrier and has three affected children on that account, or whether it is transmitted by dominant mode. All three children and the father have the same syndrome. All of them were floppy as infants, slow to sit up and stand and walk. They have a typical dystrophic waddle. The greatest weakness is in the proximal muscles. One additional factor which they all have is a very fine tremor which has been present from birth. The father of these three children is a farmer, so the disease is not incompatible with quite strenous activity.

DR. STANLEy J. GOLDBERG, University of Cati[ornia School of Medicine, Los Angeles, Call/. I wonder if you have had an opportunity to study the hearts of these patients or if you have any electrocardiographic observations. DR. ZELLWEOF.R. Dr. Goldberg, clinical findings, x-rays, and electrocardiogram were normal. Dr. Conen, the periodicity was somewhere in the neighborhood of 110 A. An increase of satellite ceils was seen in cases

Abstracts

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of congenital dystrophy but not in the cases presented here. The pictures of your case, Dr. Cohen, are very similar to those reported as nemaline myopathy by Shy and others. No biochemical studies were done in our case. Dr. Gerrard, I thank you for your comment. I am very interested in your observations. The fact that the disease involves the father as well as some of his children would suggest autosomal dominance.

18. A m m o n i a intoxication due to a congenital defect in urea synthesis John M. Freeman, M.D., ~ John F. Nicholson, M.D., ~- William S. Masland, M.D., ~ Lewis P. Rowland, M.D., "~ and Sidney Carter, M.D., ~ Departments of Neurology, Pediatrics, and Biochemistry, College of Physicians and Surgeons, Columbia University, New York, N. Y. Introduced by Edward C. Curnen, M.D. We have studied a child with a previously undescribed inherited metabolic disorder characterized by marked elevation of blood ammonia and alteration of neurologic status on a normal protein diet. A dramatic therapeutic response was obtained by restriction of protein intake. Product of a sixth pregnancy, this 3-month-old child is the only surviving offspring of unrelated parents. A maternal great aunt and maternal aunt died of neonatal convulsions. Three pregnancies ended in miscarriages. The fourth child died of neonatal convulsions. The fifth child died at 5 months of age with symptoms similar to those of the patient being described. Unexplained hyperbilirubinemia complicated the neonatal period, but subsided spontaneously on the fifth day of life. At 10 days of age vomiting, lethargy, dehydration, and flaccidity occurred, and required hospitalization. These symptoms recurred each time the child was fed proprietary milk formulas or casein hydrolysate. The symptoms subsided promptly following administration of protein-free fluids by the oral or intravenous route. On a low protein diet (1 Gm. per kilogram) the child continued to thrive and appeared developmentally normal. A laparotomy demonstrated fatty infiltration of the liver and a normal portal circulation. After operation, she developed severe ketosis, acidosis, and hyperlipemia, and died at 5 months of age. During the periods of lethargy, a marked increase in blood ammonia (480 y per 100 ml.) and cerebrospinal fluid ammonia (550 Y per 100 ml.) occurred. Ammonia levels returned to normal with restriction of protein intake, and there was concomitant improvement in the neurologic status of the patient. Plasma glycine was increased (3.4 to 5.1 mg. per 100 ml.). There was no elevation of other plasma amino acids. Glycine constituted

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American Pediatric Society

a disproportionate part of the otherwise normal urinary amino acids, but was not absolutely increased. Blood urea nitrogen and total urea excretion were normal on a normal protein diet, as was uric acid and creatine excretion. Liver chemistry determinations were normal. Following the oral administration of Nl~-glycine and NIS-ammonium chloride the rates of incorporation of this stable isotope into urinary ammonia and urea were determined. There was little incorporation of N ~5 into urea, and prolonged elevation of ammonia N aS, indicative of a defect in urea synthesis. N15-citrulline was rapidly converted to urea. Enzyme analysis of liver biopsy material revealed a reduction in carbamyl phosphate synthetase. The other urea cycle enzymes were normal. The in vivo demonstration of an incomplete block in citrulline synthesis was thus confirmed. Intermittent block in glucose utilization, elevation of blood glycine, and cyclic neutropenia remain unexplained. DISCUSSION DERRICK LOXSDALE, Cleveland Clinic, Cleveland, Ohio. I wondered whether you had DR.

an opportunity to test the use of arginine, glutamic acid, or neomycin in bringing down the level of the ammonia. DR. W. L. NVnAN, Department o[ Pediatrics,

University of Miami School of Medicine, Coral Gables, Fla. This is indeed a scholarly work-up of a new problem, and we are interested in the very thorough comparison given of the similarities between this condition and hyperglycinemia. As I listened to the presentation, I was particularly struck by the nature of the ketosis which, as you point out, is one of the most striking and devastating features of hyperglycinemia. I wonder, therefore, why you tend to exclude the possibility that the ketoses might result from the sequestration of alpha-ketoglutarate by the excess of ammonia. Certainly the most beautiful demonstration that I know of for the experimental production of ketosis is given by the experiments by Recknagel and Potter which indicate that one can regularly produce accumulations of acetoacetate simply by the addition of ammonium chloride in vitro, which will, by depleting the citric acid cycle, result in acetoacetate formation. I have privately thought that the most likely. simple explanation for the ketosis that one sees in hyperglycinemia is that this might be a confirmation for the cycle of Shemin in which deltaamino-levulinic acid is formed from succinyI-CoA and glycine. One might think of the production of ketosis in hyperglycinemia as being due to the drainage of succinyl-CoA simply by the metabolism of excess amounts of glycine. It seems to me, then, that there is the possibility now of considering the existence of two syndromes unrelated to carbohydrate metabolism, which would provide a better argument for ketosis produced in this manner. De. FREE~AN. In answer to Dr. Lonsdale's question, we did not have an opportunity to test

December 1964

the effects of arginine or glutamic acid on reduction of blood ammonia. In view of the defect in converting ornithine to citrulline, we would not have expected arginine to stimulate the conversion of ammonia to urea. Since we were able to reduce the blood ammonia by restriction of dietary protein, we did not attempt to sterilize the intestine with neomycin. This was a chronic situation, and we were wary of the effects of prolonged neomycin administration. Dr. Nyhan's question touches one of the central and least understood problems of this condition and of hyperglycinemia: the mechanism of the ketosis which was the cause of death in our patient. Although sequestration of alpha-ketoglutarate has been postulated as the mechanism of hepatic coma, there has been little in vivo experimental evidence to support this thesis. Ammonia intoxication in vivo is not associated with ketosis. In our patient the ketosis was not related to the level of blood ammonia, or to the duration of ammonia elevation. While there would appear to be a blockage of the citric acid cycle both in this condition and in hyperglycinemia, whether this bIockage is secondary to depletion of one of the cycle intermediates or to some inhibiting substance is at present unclear. However, as Dr. Nyhan stated, a major manifestation of both of these conditions involves interference with carbohydrate metabolism, although the primary defect is in a different system.

19. The e]]ect of low doses of x-ray (diagnostic procedures) on the chromosomes of human infants Barbara Ruben Migeon, M.D., ~ and Timothy Merz, Ph.D., ~ Departments of Pediatrics and Radiological Sciences, Johns Hopkins University, Baltimore, Md. Introduced by Barton Childs, M.D. To determine the in vivo radiosensitivity of the chromosomes of infants, we examined metaphase chromosomes from leukocyte cultures of 4 infants less than 3 months of age following diagnostic x-ray procedures and of 5 unirradiated newborn controls. Replicate specimens were examined whenever possible and studies were repeated on the same subject at various times following irradiation. Chromosome preparations were analyzed in respect to number of cells containing chromosomal aberrations and the type of aberration, chromosome or chrmnatid. Diagnostic procedures included chest films, intravenous pyelograin, cinecystourethrogram, upper gastrointestinal series, aortogram, and cineangiocardiogram. Frequencies of abnormal cells in the infant control group ranged from 1.6 to 8 per cent. The irradiated infants showed an aberration frequency of approximately 20 to 24 per cent. Two infants were examined before and after diagnostic doses