The role of molecular testing and enzyme analysis in the management of hypomorphic citrullinemia.

Abstract

Expanded newborn screening detects patients with modest elevations in citrulline; however it is currently unclear how to treat these patients and how to counsel their parents. In order to begin to address these issues, we compared the clinical, biochemical, and molecular features of 10 patients with mildly elevated citrulline levels. Three patients presented with clinical illness whereas seven came to attention as a result of expanded newborn screening. One patient presented during pregnancy and responded promptly to IV sodium phenylacetate/sodium benzoate and arginine therapy with no long-term adverse effects on mother or fetus. Two children presented with neurocognitive dysfunction, one of these responded dramatically to dietary protein reduction. ASS enzyme activity was not deficient in all patients with biallelic mutations suggesting this test cannot exclude the ASS1 locus in patients with mildly elevated plasma citrulline. Conversely, all symptomatic patients who were tested had deficient activity. We describe four unreported mutations (p.Y291S, p.R272H, p.F72L, and p.L88I), as well as the common p.W179R mutation. In silico algorithms were inconsistent in predicting the pathogenicity of mutations. The cognitive benefit in one patient of protein restriction and the lack of adverse outcome in seven others restricted from birth, suggest a role for protein restriction and continued monitoring to prevent neurocognitive dysfunction.

• Authors: David P Dimmock, Pamela Trapane, Annette Feigenbaum, Catherine E Keegan, Stephen Cederbaum, James Gibson, Michael J Gambello, Keith Vaux, Patricia Ward, Gregory M Rice, Jon A Wolff, William E O'Brien, Ping Fang
• Journal: American journal of medical genetics. Part A (Am J Med Genet A) Vol. 146A Issue 22 Pg. 2885-90 (Nov 15 2008) ISSN: 1552-4833 [Electronic] United States
• PMID: 18925679 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: (c) 2008 Wiley-Liss, Inc.

Chemical References

• Citrulline
• Argininosuccinate Synthase

Topics

• Adolescent
• Argininosuccinate Synthase (blood, genetics)
• Child
• Child, Preschool
• Citrulline (blood)
• Citrullinemia (diagnosis, enzymology, genetics, therapy)
• DNA Mutational Analysis
• Female
• Humans
• Infant
• Infant, Newborn
• Male
• Neonatal Screening
• Pregnancy
• Pregnancy Complications (enzymology, genetics, therapy)