Correspondence

Persistent Pulmonary Hypertension of the Newborn

N Engl J Med 2002; 346:864March 14, 2002

Article

To the Editor:

I was pleased to see that the report by Pearson et al. (June 14 issue)1 supports the findings of my colleagues and me that nitric oxide synthesis and plasma arginine levels are reduced in infants with persistent pulmonary hypertension of the newborn.2 Pearson et al. propose that a variant carbamoyl-phosphate synthetase genotype is an important determinant of plasma arginine levels in these infants. As shown in Table 2 of the article, the AA genotype (homozygosity for the A-encoded Asn1405 variant) is absent in infants with persistent pulmonary hypertension of the newborn, but, as the authors noted, “only three infants in the control group had the AA genotype.” Why is the AC genotype (heterozygosity for the A-encoded Asn1405 variant and the C-encoded Thr1405 variant), which presumably leads to an intermediate level of carbamoyl-phosphate synthetase activity relative to that of the CC genotype (homozygosity for the C-encoded Thr1405 variant) and the AA genotype, overrepresented in all infants relative to its prevalence in the general population? Was the mother's carbamoyl-phosphate synthetase genotype considered, since the mother is the source of the fetal arginine? The prevalence of the CC genotype is 420 per 1000, and the prevalence of the CC genotype among newborns whose mothers had the same genotype is 370 per 1000. These values are vastly greater than the observed risk of persistent pulmonary hypertension of the newborn of 1.9 per 1000, thus implying that carbamoyl-phosphate synthetase genotype is only a small factor in the risk of this condition. The data support the existence of a multifactorial pattern of inheritance of persistent pulmonary hypertension of the newborn, which includes factors such as the initial consumption of intra–endothelial-cell arginine, which would contribute to the lower plasma levels of arginine in affected infants but would not affect nitrate levels measured at 36 hours of life, in addition to the carbamoyl-phosphate synthetase genotype.

Robert J. Vosatka, Ph.D., M.D.
Columbia University College of Physicians and Surgeons, New York, NY 10032
bob.v@bigfoot.com

2 References

1. 1

   Pearson DL, Dawling S, Walsh WF, et al. Neonatal pulmonary hypertension: urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med 2001;344:1832-1838
   Full Text | Web of Science | Medline

2. 2

   Vosatka RJ, Kashyap S, Trifiletti RR. Arginine deficiency accompanies persistent pulmonary hypertension of the newborn. Biol Neonate 1994;66:65-70
   CrossRef | Medline

Citing Articles (1)

Citing Articles

1. 1

   V. Ahuja, S. G. Powers-Lee. (2008) Human carbamoyl-phosphate synthetase: Insight into N-acetylglutamate interaction and the functional effects of a common single nucleotide polymorphism. Journal of Inherited Metabolic Disease 31:4, 481-491
   CrossRef