Citrullinemia Clinical Presentation

Author: Karl S Roth, MD; Chief Editor: Bruce Buehler, MD more...

Updated: Mar 13, 2012

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History
Physical
Causes
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History

At least one half of newborns with citrullinemia present in the first several days of life.

The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, vary in presentation, diagnostic features, and treatment. For these reasons, urea cycle defects are considered individually; however, the common denominator, hyperammonemia, can manifest clinically as some or all of the following:

Anorexia
Irritability
Heavy or rapid breathing
Lethargy
Vomiting
Disorientation
Somnolence
Asterixis (rare)
Combativeness
Obtundation
Coma
Cerebral edema
Death (if treatment is not forthcoming or effective)

The most striking clinical findings of each individual urea cycle disorder relate to this constellation of symptoms and rough temporal sequence of events.

No routine laboratory studies provide a diagnostic clue, and only a high index of suspicion can prompt the physician to obtain a blood ammonia measurement. The need for a high index of suspicion cannot be sufficiently emphasized.

In the face of intercurrent illness, other affected children experience delayed development from infancy with exaggerated lethargy and vomiting. Again, only a high index of suspicion based on a thorough history can lead to proper diagnosis.

The adult form of citrullinemia has been reported almost exclusively in Japan, and these cases are associated with unusual self-selection of diet.^{[4, 5]}These individuals have been shown by DNA studies to be affected by a mutation that impairs function of the mitochondrial malate-aspartate shuttle. The abnormal protein that affects this impairment is called citrin and is encoded by the SLC25A13 gene at locus 7q21.3. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is also due to a mutation in the same gene. Whether such infants will be affected by the adult form of citrullinemia later in life is unclear.

General

Signs of severe hyperammonemia may be present.
Poor growth may be evident.

Head, ears, eyes, nose, and throat (HEENT)

Papilledema may be present if cerebral edema and increased intracranial pressure have ensued.

Pulmonary

Tachypnea or hyperpnea may be present.
Apnea and respiratory failure may occur in later stages.

Abdominal

Hepatomegaly may be present and is usually mild.

Neurologic

Poor coordination
Dysdiadochokinesia
Hypotonia or hypertonia
Ataxia
Tremor
Seizures and hypothermia
Lethargy progressing to combativeness, obtundation, and coma
Decorticate or decerebrate posturing

Causes

Citrullinemia is an autosomal recessive genetic condition. The gene has been mapped to chromosome 9 and has a locus at band 9q34.^{[6, 7]}The adult-onset type is caused by mutation at locus 7q21.3 and, therefore, must be considered a separate disorder; the same mutation also causes NICCD. The etiologic connection between the 2 clinical entities remains problematic.

At least 20 distinct mutations have been reported. Most of them are single-base substitutions that cause missense mutations that result in an enzyme protein with abnormal kinetic properties.

Urea cycle defects with resulting hyperammonemia are due to deficiencies of the enzymes involved in the metabolism of waste nitrogen. The enzyme deficiencies lead to disorders with nearly identical clinical presentations. The exception is arginase, the last enzyme of the cycle; arginase deficiency causes a somewhat different set of signs and symptoms (see Arginase Deficiency).

Proceed to Differential Diagnoses

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.

Specialty Editor Board

Robert D Steiner, MD Credit Unions for Kids Professor of Pediatric Research, Professor of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Faculty, Program in Molecular and Cellular Biosciences, Oregon Health and Science University School of Medicine; Attending Physician, Doernbecher Children's Hospital; Staff Consultant, Director of Metabolic Bone Disease Clinic, Shriners Hospital Portland

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: Amicus Honoraria Consulting; Actelion Honoraria Consulting; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Consulting; Genzyme Honoraria Consulting; Shire Honoraria Consulting

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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.

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 and Genetics, Director RSA, 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.

References

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].
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].
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].
Yazaki M, Ikeda S, Kobayashi K, Saheki T. Therapeutic approaches for patients with adult-onset type II citrullinemia (CTLN2): effectiveness of treatment with low-carbohydrate diet and sodium pyruvate. Rinsho Shinkeigaku. Nov 2010;50(11):844-7. [Medline].
Nakamura M, Yazaki M, Kobayashi Y, Fukushima K, Ikeda S, Kobayashi K, et al. The characteristics of food intake in patients with type II citrullinemia. J Nutr Sci Vitaminol (Tokyo). 2011;57(3):239-45. [Medline].
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].
Marquis-Nicholson R, Glamuzina E, Prosser D, Wilson C, Love DR. Citrullinemia type I: molecular screening of the ASS1 gene by exonic sequencing and targeted mutation analysis. Genet Mol Res. Aug 3 2010;9(3):1483-9. [Medline].
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].
Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr. Jan 2001;138(1 Pt 2):S56-S62. [Medline].
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].
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].
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].
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].
Matsuda I, Anakura M, Arashima S, Saito Y, Oka Y. A variant form of citrullinemia. J Pediatr. May 1976;88(5):824-6. [Medline].
Morrow G 3rd, Barness LA, Efron ML. Citrullinemia with defective urea production. Pediatrics. Oct 1967;40(4):565-74. [Medline].
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].
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].
Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr. Jan 2001;138(1 Suppl):S21-9. [Medline].
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].
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].
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].

Urea cycle. Compounds that comprise the urea cycle are numbered sequentially, beginning with carbamyl phosphate. At the first step (1), the first waste nitrogen is incorporated into the cycle; also at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl phosphate synthetase (CPS). Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (4); the reaction is mediated by argininosuccinate (ASA) synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.

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