PEDIATRICS (ISSN 0031 4005). Copyright © 1981 by the American Academy of Pediatrics.
Summarizing
Remarks
Vivian
E. Shih,
MD
From the Amino Acid Disorder Laboratory, Massachusetts General Hospital, Boston
The foregoing presentations have been most in-formative. Snodgrass, who has developed microas-says of the urea cycle enzymes and has been instru-mental in the study of a number of patients with
urea cycle disorders, reviewed the biochemistry of the urea cycle in normal and in diseased states. He, as well as the others, has drawn our attention to acetylglutamate synthetase and its important role in the regulation of the urea cycle. Although the mechanism is not entirely clear, acetyiglutamate
synthesis seems to be a critical step in governing the entry of ammonia into the urea cycle. Perhaps it may also regulate the overall functioning of the urea cycle. The reason that patients with a defect of this enzyme have not been described is most likely due to our ignorance.
Another important message from Snodgrass is that at physiologic conditions, the urea cycle en-zymes do not function at maximum rates and the ratio of enzyme activity as obtained by in vitro
studies does not exist in vivo. Rather, the enzyme activities are limited in vivo by the availability of substrates that are present at Km levels. Therefore,
small changes in concentration cause large changes
in velocity.
Ornithine transcarbamylase (OTC) deficiency and argininosuccinate lyase deficiency are the two most common of the five urea cycle disorders. En-zyme studies have revealed several variants (or mutants) in each disorder including defects in al-tered enzyme kinetics and the absence of enzyme proteins. There has been no satisfactory explana-tion for the cause of hyperammonemia found in all five urea cycle disorders.
Snyderman described the clinical manifestations of the urea cycle disorders. The pathogenesis of brain dysfunction is largely attributable to ammo-ma accumulation. Onset may be acute in the neo-natal period or more insidious later in infancy. OTC
deficiency is a X-linked disorder and affected males
seldom survive beyond the neonatal period. Clinical history, metabolite screening, and loading tests (protein or ammonia) are often adequate in making a diagnosis of these disorders.
Naylor presented an update on the development of new bacterial screening tests. Of the several tests described, the bacterial inhibition assay for pyrim-idine metabolites appears promising, as it will de-tect most of the hyperammonemic syndromes ex-cept carbamylphosphate synthetase (CPS) defi-ciency. This test seems to fit the criteria of a good screening test in terms of nonspecificity and sim-plicity. I hope that Naylor
will
give us a follow-up next year on the results of pilot studies usingthis
technique for newborn urine screening. For those who would consider embarking on such a new urine
screening program, I would like to remind you of Levy’s cautionary note regarding the justification and the cost effectiveness of such screening. It
should
also
be pointed out that patients with neo-natal onset of the disease will become ill in the firstfew days of life and be missed by routine urine screening which is currently performed at 3 to 4 weeks of age.
Goodman told us that prenatal diagnosis for ci-trullinemia and argininosuccinic aciduria is possible and has been accomplished. Fetuses affected with these disorders have been correctly identified by determining the respective enzyme activity in cul-tured amniotic fluid cells. The detection of abnor-mal metabolites in the amniotic fluid is an impor-tant ancifiary test that will greatly facilitate diag-nosis. For prenatal diagnosis of the other three urea cycle disorders, we await the development of new techniques.
As
ammonia
has been incriminated as annitro-gen (or ammonia) in the body. Shaw, using data from patients at the Children’s Hospital of
Los
Angeles, illustrated the effectiveness of a low pro-tein diet and a semisynthetic diet with a mixture of
essential amino acids as the major source of mtro-gen. Arginine, a semiessential amino acid, is given because of the low levels of plasma arginine
concen-tration in these patients whose endogenous arginine synthesis is reduced. This compound also stimu-lates the synthesis of acetylgiutamate. In severely affected infants, especially newborns, the response to simple dietary alteration is often inadequate. Brusiow and Batshaw along with Walser at The Johns Hopkins University began to use ketoacid analogues of essential amino acids as a way to recycle endogenous nitrogen. In principle, this seems to be a logical approach. However, Brusiow and Batshaw informed us of the disappointingly high casualty rate of patients so treated, and new forms of therapy have been sought. Through their ingenuity, alternative methods of increasing “waste nitrogen” disposal have been developed. They ad-vocate the use of arginine, sodium benzoate, and phenylacetate as vehicles for nitrogen excretion. Although preliminary results of these therapies ap-pear encouraging, carefully controlled studies will be necessary to determine their long-term effects.
Ng reviewed his experiences with heterozygote
detection of OTC deficiency and citrullinemia by protein loading tests. Increased urinary orotic acid excretion after loading is a more sensitive parame-ter than hyperammonemia in detecting heterozy-gotes. Interestingly, in the obligate heterozygotes for CPS deficiency he studied, the blood ammonia did not increase after protein loading. The normal urinary orotic acid excretion by these individuals was expected. I have not seen comparable studies on heterozygotes for argininosuccinate lyase defi-ciency. In our own experience, the majority of ob-ligate heterozygotes for this disorder have had re-duced argininosuccinate lyase activity in
erythro-cytes.
Although much progress in urea cycle disorders has been made in the past ten years, many questions
remain unanswered, eg, “What is the mechanism of hyperammonemia in citrullinemia, argininosuccinic
aciduria, and hyperargininemia?” “Wifi the treat-ment promoting waste nitrogen disposal be effective in preventing the development of clinical
symp-toms?” and “How many of the hyperammonemic
patients with normal activity of the five urea cycle enzymes have a defect in acetylglutamate
synthe-sis?”
The true incidence of urea cycle disorders is not known, but may not be all that rare. The clinical significance of these disorders is well recognized,
potential treatment is available, and simple
screen-ing tests have been developed. It seems that we are now at the stage with urea cycle disorders that we were with PKU in the early 1960s. Perhaps we are heading for an era of newborn screening for urea cycle disorders.
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WOMEN’S
‘LIB’
Men’s refusal to do “women’s work” around the house-at a time when women in most countries increasingly are doing men’s work-is an issue at the eye of a storm. So says Kathleen Newland, senior researcher at Washington’s Woridwatch Institute. Her new paper on the sexual division oflabor cites studies from a number of countries underscoring the problem.
One study of 12 countries concluded that employed women worked 70.2 hours a week, including housework and child care, while employed men worked only 60 hours. Communist countries that theoretically provide more day-care and other services are in fact no exception to the trend, the researcher argues.
If the problem isn’t solved, “equal opportunity for women will turn out to be a recipe for overwork,” she maintains.
