Ravindra Arya, Rajneesh Nema, Maya Chansoria
Department of Pediatrics, Smt. Patel Centre for Child Health, N.S.C.B. Medical College, Jabalpur , M.P.
Address for Correspondence
Dr. Ravindra Arya, Block Q, House no. 4, Malkaganj, Delhi - 110007.
Urea cycle is a series of reactions involving six enzymes meant to detoxify ammonia generated by catabolism of amino acids. Urea cycle defects are the commonest genetic causes of hyperammonemia in infancy with overall prevalence of 1 in 30000 live births. Argininosuccinicate lyase deficiency (argininosuccinic aciduria) is an autosomal recessive trait with a prevalence of about 1 in 70000 live births.(1) Following case report illustrates the importance of a high index of suspicion for these metabolic disorders in a presentation overlapping with or simulating neonatal sepsis.
Case Report
A 1 month 18 days old female, first born of non consanguineous marriage with uneventful pregnancy, delivered at term by cesarean section having normal early neonatal course was admitted with vomiting, refusal to feed and lethargy alternating with irritability of sudden onset since 3 days. She had many episodes of abnormal movements suggestive of multi - focal clonic seizures each lasting 1 - 3 minutes. On admission, she was febrile (99.4°F), pale, icteric, tachypneic and hypertensive with non-invasive blood pressure of 138/ 70 mmHg. Systemic examination revealed firm hepatomegaly (span of 6 cm) and tense anterior fontanelle with intermittent hypertonia. There were no other significant findings on physical examination.

Laboratory studies demonstrated anemia with normal coagulation profile, CSF consistent with pyogenic meningitis (glucose of 20 mg/dl against concurrent blood glucose of 96 mg/dl, proteins 150 mg/dl and 90 cells/cumm with a differential of 92%), cerebral edema on USG brain and metabolic acidosis with base excess of -9 and bicarbonate of 12 mEq/L with normal serum electrolytes. Total serum bilirubin was 17.3 mg/dl with direct component of 12.9 mg/dl. SGPT was 269.3 IU/L. Other investigations for cause of conjugated hyperbilirubinemia were normal including thyroid profile, TORCH serology and HIV testing.

A diagnosis of neonatal sepsis, pyogenic meningitis with idiopathic neonatal hepatitis was made and baby started on parenteral fluids, antibiotics, phenobarbitone and oral ursodeoxycholic acid. Hospital stay was characterized by episodes of cyanosis along with hypoxemia and temperature instability. The baby was stabilized by 10 th day of admission and discharged subsequently with a bilirubin level of 11.2 mg/dl (total) and 8.9 mg/dl (direct).

On 15 th day after discharge patient was readmitted with sudden onset of numerous episodes of vomiting (>40 times/ 24 hours) and a right sided focal seizure lasting 5 - 7 minutes. CSF was normal but peripheral blood white cell count was raised (24,600/ with polymorphonuclear predominance (84%). Facility for serum ammonia estimation is not available in this city. Patient was again started on intravenous fluids, antibiotics and phenobarbitone but inspite had increasing frequency of multifocal clonic seizures, irritability, episodic cyanosis and hypoxemia. Phenytoin was added to control seizures and cardio - vascular examination including Color Doppler for cyanosis was normal. CT scan brain showed areas of intracerebral hemorrhage in left frontal lobe and basal region of left temporal lobe with mass effect. Also seen were intraventricular and subarachnoid hemorrhage throughout the left peripheral hemispheric region and in parafalcine region on right side. Widespread areas of infarction were seen on both sides. Plasma amino acid profile by electrospray ionization - tandem mass spectrometry showed elevated levels of citrulline and argininosuccinic acid. Hence a diagnosis of argininosuccinic aciduria due to argininosuccinate lyase deficiency was established.
We report this case not merely for its rarity but also to emphasize the importance of keeping these metabolic disorders in the differential diagnosis of common neonatal presentations like vomiting, seizures, refusal to feed and altered level of consciousness. These disorders can present as or co - exist with neonatal sepsis.

Argininosuccinic aciduria has a varied clinical spectrum. Besides the severe neonatal form with high mortality, seen in our patient, it has a subacute or late form manifesting as mental retardation, failure to thrive, hepatomegaly, dry and brittle hair with trichorrhexis nodosa, occasional gall stones with acute severe hyperammonemia during intercurrent illness. Biochemically, these variants are characterized by residual enzyme activity as measured by the incorporation of (14C) citrulline into proteins which is completely blocked in classical argininosuccinic aciduria and only partially reduced in fibroblasts of these patients.(2) It has been described that patients with argininosuccinic aciduria due to a deficiency of argininosuccinic acid lyase are uniquely prone to chronic hepatitis, potentially leading to cirrhosis and hypertension,(3) two features observed in our case.

We did not have facilities for genetic analysis but conventional genetic locus has been traced to 7q.(1) Linnebank and co - workers have recently characterized the complete sequence of the human Argininosuccinicate lyase (ASL) gene and a complete ASL homologue on chromosome 22 correlating with an immunoglobulin-lambda-like mRNA. On the basis of the novel sequence data, a polymerase reaction chain system for mutation-screening in all 16 coding exons of the ASL gene has been established and applied to the analysis of the ASL-deficient patients.(4) A novel missense mutation which results in the exchange of a stop codon to tyrosine at amino acid position 465 (X465Y) has been reported from Japan is likely related to a milder phenotype compared with previously reported mutations.(5)

Prenatal diagnosis is based on measuring the enzyme activity in cultured amniotic cells or amniotic fluid argininosuccinic acid levels for screening.(6)
References :
  1. Rezvani I. Defects in metabolism of amino acids. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics. 17 th edn. Philadelphia , Saunders; 2004: 424 - 429.
  2. Kleijer WJ, Garritsen VH, Linnebank M, et al. Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in five unrelated families. J Inherit Metab Dis. 2002 Sep; 25(5):399-410.
  3. Scaglia F, Brunetti-Pierri N, Kleppe S, et al. Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. J Nutr. 2004 Oct; 134(10 Suppl):2775S-2782S; discussion 2796S-2797S.
  4. Linnebank M, Tschiedel E, Haberle J, et al. Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. Hum Genet. 2002 Oct; 111(4-5):350-9.
  5. Tanaka T, Nagao M, Mori T, Tsutsumi H. A novel stop codon mutation (X465Y) in the argininosuccinate lyase gene in a patient with argininosuccinic aciduria. Tohoku J Exp Med. 2002 Oct;198(2):119-24.
  6. Mandell R, Packman S, Laframboise R, et al. Use of amniotic fluid amino acids in prenatal testing for argininosuccinic aciduria and citrullinaemia. Prenat Diagn. 1996 May; 16(5):419-24.
Last Updated : Sunday, April 01, 2007 Vol 4 Issue 4 Art #15
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Arya R, Nema R, Chansoria M. ARGININOSUCCINIC ACIDURIA. Pediatric Oncall [serial online] 2007[cited 2007 January 1];4. Art #15. Available From :
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