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Mol Genet Metab. 2018 Mar;123(3):297-300. doi: 10.1016/j.ymgme.2018.01.004. Epub 2018 Jan 16.

Prenatal treatment of ornithine transcarbamylase deficiency.

Wilnai Y1, Blumenfeld YJ2, Cusmano K3, Hintz SR1, Alcorn D1, Benitz WE1, Berquist WE1, Bernstein JA1, Castillo RO4, Concepcion W5, Cowan TM6, Cox KL4, Lyell DJ2, Esquivel CO5, Homeyer M1, Hudgins L1, Hurwitz M4, Palma JP1, Schelley S1, Akula VP1, Summar ML3, Enns GM7.

Author information

1
Department of Pediatrics, Stanford University, CA, USA.
2
Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA.
3
Department of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA.
4
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Stanford University, CA, USA.
5
Division of Abdominal Transplantation, Stanford University, CA, USA.
6
Department of Pathology, Stanford University, CA, USA.
7
Department of Pediatrics, Stanford University, CA, USA. Electronic address: greg.enns@stanford.edu.

Abstract

PURPOSE OF STUDY:

Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor.

METHODS USED:

Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery.

SUMMARY OF RESULTS:

Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years.

CONCLUSION:

Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.

Copyright © 2018 Elsevier Inc. All rights reserved.

KEYWORDS:

Liver transplantation; Neurological outcome; Nitrogen-scavenging medication; OTC deficiency; Prenatal treatment

PMID:
29396029
DOI:
10.1016/j.ymgme.2018.01.004

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