eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Citrullinemia: Follow-up

Author: Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Contributor Information and Disclosures

Updated: Mar 26, 2009

Follow-up

Further Outpatient Care

  • Patients with citrullinemia must be under the ongoing care of a biochemical geneticist or metabolic disease specialist with expertise in the care of urea cycle disorders.
  • A trained nutritionist should monitor the low-protein diet, which is essential in treatment.
  • Frequent monitoring of growth and blood amino acid levels is imperative in order to make adjustments before essential amino acid levels fall below normal and the child becomes catabolic.
  • Under no circumstances should a primary care provider provide follow-up for a patient with citrullinemia without the frequent input of a specialist.

Transfer

  • Any infant or child noted to have hyperammonemia should be considered for transfer to a medical center for further evaluation.

Deterrence/Prevention

  • Prenatal diagnosis is possible and is available at academic centers. Molecular diagnosis is possible, using amniocytes or chorionic villi.

Complications

  • Complications are chiefly neurological, including mental retardation, acute hyperammonemic coma, and death.

Prognosis

  • Consistent with the course of most urea cycle disorders, the degree of intellectual impairment is roughly parallel to the severity of initial presentation and frequency of subsequent hyperammonemic episodes. Subsequent hyperammonemic episodes predictably recur with any intercurrent infection.
  • With appropriate treatment, survival into adulthood is possible and has been documented.

Patient Education

  • Both parents of an affected infant are assumed to be obligate heterozygotes because citrullinemia is an autosomal recessive trait; therefore, the recurrence rate in every subsequent pregnancy is 1 in 4, or 25%.
  • Genetic counseling is indicated.
  • Advise the parents to seek early medical care for the affected child at the earliest signs of infection.
  • Counsel the parents regarding strict adherence to the prescribed medical regimen.
  • Prenatal diagnosis is theoretically available, although it is not trivial.

Miscellaneous

Medicolegal Pitfalls

  • Suspect hyperammonemia in all infants and children with unexplained neurologically related symptoms and signs. Failure to do so may result in missed diagnosis of a treatable disorder.
  • Failure to establish a diagnosis in a proband may result in subsequent infants in the family with the same disease.

Special Concerns

  • Adults with hepatic cirrhosis unassociated with most common causes, such as long-term alcohol consumption, should be evaluated for the adult-onset form of citrullinemia.
  • This condition has been most frequently reported in Japan and was initially described in that country, probably leading to a heightened clinical awareness not shared in the United States. Thus, the disorder could be significantly more common than originally believed. 
 


More on Citrullinemia

Overview: Citrullinemia
Differential Diagnoses & Workup: Citrullinemia
Treatment & Medication: Citrullinemia
Follow-up: Citrullinemia
Multimedia: Citrullinemia
References
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References

  1. Prestes CC, Sgaravatti AM, Pederzolli CD, et al. Citrulline and ammonia accumulating in citrullinemia reduces antioxidant capacity of rat brain in vitro. Metab Brain Dis. Mar 2006;21(1):63-74. [Medline].

  2. Saheki T, Kobayashi K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet. 2002;47(7):333-41. [Medline].

  3. Noto D, Takahashi K, Hamaguchi T, et al. A case of adult onset type II citrullinemia with portal-systemic shunt. J Neurol Sci. Mar 12 2009;[Medline].

  4. Engel K, Hohne W, Haberle J. Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene. Hum Mutat. Mar 2009;30(3):300-7. [Medline].

  5. Nagasaka H, Okano Y, Tsukahara H, et al. Sustaining hypercitrullinemia, hypercholesterolemia and augmented oxidative stress in Japanese children with aspartate/glutamate carrier isoform 2-citrin-deficiency even during the silent period. Mol Genet Metab. Jan 25 2009;[Medline].

  6. Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr. Jan 2001;138(1 Pt 2):S56-S62. [Medline].

  7. Hayakawa M, Kato Y, Takahashi R, Tauchi N. Case of citrullinemia diagnosed by DNA analysis: including prenatal genetic diagnosis from amniocytes of next pregnancy. Pediatr Int. Apr 2003;45(2):196-8. [Medline].

  8. Issa AR, Yadav G, Teebi AS. Intrafamilial phenotypic variability in citrullinaemia: report of a family. J Inherit Metab Dis. 1988;11(3):306-7. [Medline].

  9. Kennaway NG, Harwood PJ, Ramberg DA, Koler RD, Buist NR. Citrullinemia: enzymatic evidence for genetic heterogeneity. Pediatr Res. Jun 1975;9(6):554-8. [Medline].

  10. Kuhara H, Wakabayashi T, Kishimoto H, et al. Neonatal type of argininosuccinate synthetase deficiency. Report of two cases with autopsy findings. Acta Pathol Jpn. Jul 1985;35(4):995-1006. [Medline].

  11. Matsuda I, Anakura M, Arashima S, Saito Y, Oka Y. A variant form of citrullinemia. J Pediatr. May 1976;88(5):824-6. [Medline].

  12. Morrow G 3rd, Barness LA, Efron ML. Citrullinemia with defective urea production. Pediatrics. Oct 1967;40(4):565-74. [Medline].

  13. Ohura T, Kobayashi K, Tazawa Y, et al. Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). J Inherit Metab Dis. Apr 2007;30(2):139-44. [Medline].

  14. Saheki T, Kobayashi K, Iijima M, et al. Metabolic derangements in deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier. Hepatol Res. Oct 2005;33(2):181-4. [Medline].

  15. Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr. Jan 2001;138(1 Suppl):S21-9. [Medline].

  16. Tamamori A, Fujimoto A, Okano Y, et al. Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency. Pediatr Res. Oct 2004;56(4):608-14. [Medline].

  17. Tazawa Y, Kobayashi K, Abukawa D, et al. Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients. Mol Genet Metab. Nov 2004;83(3):213-9. [Medline].

  18. Walter JH, Allen JT, Holton JB. Arginosuccinate synthetase deficiency: good outcome despite severe neonatal hyperammonemia. J Inherit Metab Dis. 1992;15(2):282-3. [Medline].

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Further Reading

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Keywords

citrullinemia, citrulline, argininosuccinic acid synthase deficiency, citrullinuria, aminoaciduria, ornithine transcarbamylase reaction, argininosuccinic acid, ASA, ASA synthase, carbamyl phosphate synthetase reaction, CPS reaction, waste nitrogen disposal, hyperammonemia, mental retardation, urea cycle defect, neonatal intrahepatic cholestasis, NICCD, hepatomegaly, treatment, diagnosis

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Contributor Information and Disclosures

Author

Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Co-Director: Pediatric and Child Health Research, Oregon Clinical and Translational Research Institute (CTSA).
Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research
Disclosure: Genzyme Honoraria Speaking and teaching; Genzyme Grant/research funds Other; Shire Honoraria Speaking and teaching; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Speaking and teaching; Biomarin Consulting fee Consulting

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Leonard G Feld, MD, PhD, MMM, FAAP, Sara H Bissell and Howard C Bissell Endowed Chair in Pediatrics, Chief Medical Officer, Levine Children's Hospital, Carolinas Medical Center
Leonard G Feld, MD, PhD, MMM, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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