Background
The finding of elevated Citrulline in a newborn screen dried blood spot suggests one of two metabolic defects: Argininosuccinic Acid Synthetase Deficiency or Argininosuccinate Lyase Deficiency. Both are disorders of the Urea Cycle and are associated with severe, episodic hyperammonemia. Argininosuccinic Acid Synthetase Deficiency (commonly called Citrullinemia) occurs in 1:57,000 births and causes a dramatic elevation of plasma Citrulline. Argininosuccinate Lyase Deficiency causes a less dramatic increase of plasma Citrulline, but is no less clinically devastating. It is found in 1:70,000 births.
Clinical
Both forms of Citrullinemia have a similar clinical presentation. With an early onset presentation, the newborn appears normal for the first 24 hours. Symptoms develop in association with worsening hyperammonemia. By 72 hours, lethargy, feeding difficulties and vomiting usually appear. The patient develops hypothermia, respiratory alkalosis and often requires ventilation. Seizures progressing to coma and death are typical in untreated patients. Physical examination reveals encephalopathy, which is due to brain edema and swollen astrocytes from glutamine accumulation and the resulting water retention. Patients with Argininosuccinate Lyase Deficiency may exhibit hepatomegaly. These patients are frequently mistaken for a case of sepsis. A key laboratory abnormality suggesting a Urea Cycle defect is low blood urea nitrogen, which should dictate measurement of ammonia. Patients who survive the newborn period may have a neurologic impairment. These neonatal onset patients have recurrent episodes of hyperammonemia associated with viral infections or increased dietary protein intake. Some patients with either disorder have a later onset with a less severe course making diagnosis difficult.
Testing
Newborn screening by tandem mass spectrometry using a dried blood spot can detect elevated levels of Citrulline with either disorder. The levels of Citrulline in Argininosuccinic Acid Synthetase Deficiency range up to 100 times the normal limit. Argininosuccinate Lyase Deficiency patients have measurable levels of Argininosuccinic acid in plasma, which is not normally detected. The activity of either enzyme can be measured from a liver biopsy. Both genes have been isolated and mutations identified. DNA studies can be performed for prenatal diagnosis when the mutation is known from both parents. Biochemical studies of cultured amniocytes and chorionic villus tissue are also informative. The presence of Argininosuccinic acid in the amniotic fluid of Argininosuccinate Lyase Deficiency patients has been used for prenatal diagnosis.
Treatment
The symptoms of Citrullinemia seem to originate from the hyperammonemia rather than Citrulline accumulation. Acute hyperammonemia may necessitate hemodialysis, which is more effective for lowering ammonia than peritoneal dialysis or arteriovenous hemofiltration. Sodium benzoate is given to conjugate Glycine, a major amino acid that contributes ammonia to the urea cycle, forming hippurate, which is subsequently excreted in the urine. Intravenous Arginine results in ammonia clearance by enhancing formation of Citrulline in Argininosuccinic Acid Synthetase Deficiency or Argininosuccinate in Argininosuccinate Lyase Deficiency. Both of these metabolites are excreted in the urine and draw off excess nitrogen from ammonia. Patients who survive the initial presentation are placed on protein restriction. Patients with either defect having onset in the newborn period face a poor outcome and significant risk of neurological damage or demise. Because the diagnosis and therapy of these metabolic disorders is complex, the pediatrician is strongly advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.
Inheritance
These disorders most often follow an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder. As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.
References Brusilow, S.W. and Horwich, A. Urea Cycle Enzymes. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 85, pg. 1909-1963. Maestri, N.E., Hauser, E.R., Bartholomew, D., et al. Prospective treatment of urea cycle disorders. J Pediatrics 119:923, 1992. Maestri, N.E., Clissold, D.B., Brusilow, S.W. Long-term survival of patients with Argininosuccinate Synthetase deficiency. J Pediatrics 127:929, 1995. Rutledge, S.L., Havens, P.L., Haymond, M.W., et al. Neonatal hemodialysis: Effective therapy for the encephalopathy of inborn errors of metabolism. J Pediatrics 116:125, 1990.
Web Sites Web Sites
SaveBabies.org
Site established and maintained by parents of newborns affected with a rare genetic defect, with information for parents and professionals and links to other informative sites.
National Newborn Screening and Genetics Resource Center
Provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.
National Urea Cycle Defects Foundation
Parent and professional website with information and links to other useful websites.
Disclaimers
The analyses conducted by PerkinElmer Genetics produce results that can be used by qualified physicians in the diagnosis of disorders described herein. Evidence of these conditions will be detected in the vast majority of affected individuals; however, due to genetic variability, age of the patient at the time of specimen collection, quality of the specimen, health status of the patient, and other variables, such conditions may not be detected in all affected patients. PerkinElmer Genetics makes no warranty whatsoever, express or implied, including any warranty as to accuracy, completeness or timeliness, concerning the information contained herein, and you should not assume that such information is complete or the most up-to-date information available. PerkinElmer Genetics shall not be liable for any loss, claim or damages caused in whole or in part by our provision of, or your use of, any of the information contained herein. As a general statement, this information was drawn from published literature and is not drawn from our patient population or screening experience. The information contained herein is not intended to be a substitute for professional medical advice and should not be used for the diagnosis or treatment of any medical condition. A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions.
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