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Case Report
 
Recurrent Abdominal Pain: An Unusual Presentation of Urea Cycle Disorder
Keywords :
Ashok Goyal1, Ujjal Poddar1, Vignesh Vinayagamoorthy1, Moinak Sen Sarma1, Zafar Neyaz2, Jayanti Kalita3, Anshu Srivastava1
Department of 1Pediatrics Gastroenterology, 2Radiology and 3Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.


Corresponding Author
:
Dr Ujjal Poddar
Email: ujjalpoddar@hotmail.com


DOI: http://dx.doi.org/10.7869/tg.633

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Hyperammonemia is the hallmark of urea cycle disorders. Toxic ammonia is produced by amino acid metabolism and is converted to harmless urea in the liver through a series of enzymatic steps, known as urea cycle. Citrullinemia type I (CTLN1) is a rare disorder of urea cycle (UCD) with autosomal recessive inheritance pattern, caused by a deficiency of the argininosuccinate synthetase (ASS) enzyme due to mutations in the ASS1 gene. CTLN1 commonly presents in neonatal period with acute life-threatening hyperammonemia related encephalopathy with high mortality rate. Uncommonly, milder late-onset, childhood or adult-onset form may be seen with behavioral abnormalities, incoordination, recurrent vomiting episodes, sometimes only as incidentally detected hyperammonemia during metabolic screening.1 Recurrent abdominal pain with vomiting is an uncommon presentation of UCD.2 Here we report a child who presented with gastrointestinal symptoms instead of usual neurological manifestations.

Case Report

Six and half-year-old boy presented to pediatric gastroenterology department with two months history of recurrent episodes of periumbilical abdominal pain and vomiting. On further reviewing the history, the child was also noticed by parents and teachers to have stubbornness, hyperactive, inattentive, aggressive behavior, sleep disturbances, frequent falls and learning disability for two years. He was born out of a non-consanguineous marriage, 4th in birth order with history of a male sibling death at day 5 of life due to refusal to feed, vomiting and lethargy. Other two female siblings are alive and healthy. Development quotient was 66% in all domains. 
General physical examinations and growth parameters were unremarkable. Abdominal examination revealed only soft hepatomegaly. Neurological examination revealed ataxia, grade 1 encephalopathy, exaggerated deep tendon reflexes. Complete hemogram, renal function, arterial blood gas and blood glucose were normal. Liver function tests showed SGOT: 49, SGPT: 176 (ULN: 40) u/Lwith normal synthetic functions and bilirubin. Blood ammonia was >286 µmol/L (normal range, 10-54 µmol/L). CSF analysis was unremarkable. Ultrasound abdomen showed enlarged liver with grade 1 fatty changes. With the above clinical features and elevated ammonia levels with no jaundice, possibility of UCD was considered.
EEG showed generalized slowing. Magnetic resonance imaging (MRI) revealed gyral swelling with T2/FLAIR hyperintensity showing diffusion restriction and glutamate/glutamine peak on MRS (Figure 1) involving the cortex of bilateral posterior temporal and occipital lobe. Also, there was discrete as well as confluent T2/FLAIR hyper intensities involving bilateral periventricular white matter with focal cystic changes,supporting the diagnosis of urea cycle disorder. 




Blood tandem mass spectroscopy (TMS) and urine gas chromatography (GCMS) showed elevated citrulline level 2101.56 (Normal:3.31 to 51.5), and orotic acid level 14.93% (normal:0-1.5%)suggestive of citrullinemia most likely type 1 due to arginosuccinate synthetase deficiency (ASSD) and was later confirmed by targeted gene sequencing showing homozygous mutation in (Exon 12c.793C>T (p.Arg265Cys)  of argininosuccinate synthetase (ASS) gene. The child was managed with nil per oral, dextrose containing IV fluid, ammonia scavengers (sodium benzoate at a dose of 250 mg/kg/day, 1.5g three times a day) and (L-arginine at a dose of 250 mg/kg/day, 1g three times a day).  After which his serum ammonia levels started decreasing, protein restricted diet was started at 1 gm/kg/day. After 10 days of therapy, ammonia level decreased to 111µmol/L. During hospital stay he showed significant improvement in symptoms with no reoccurrence of vomiting and pain abdomen. On follow-up (3 months) the child is asymptomatic with ammonia level 21 µmol /L.

Discussion

Citrullinemia type I is a rare urea cycle defect with estimated prevalence of 1 to 9 per 100,000.1  A biochemical diagnosis of UCD is made on the basis of high ammonia and blood amino acids profile by TMS and urinary orotic acid by GCMS and confirmed by genetic testing. Our patient fulfilled all criteria to be labelled as citrullinemia1. Our patient had homozygous mutation in c.793C>T (p.Arg265Cys) which is one of the common mutations found in patients with classical citrullinemia2 and is the 3rd common mutation found in Indian patients.3 While ornithine transcarbamylase (OTC) deficiency is reported to be the commonest UCD in Europe,4 argininosuccinate synthetase deficiency1 (ASS1) is found to be the commonest in India.3
In a study of 123 cases of UCD, 61 had citrullinemia 1. The majority of citrullinemia 1 present at birth or in the first year of life (50 of 61) with encephalopathy or seizures (51 of 61), but none presented with behavioural abnormalities, spasticity or ataxia in that series.3 Outcome was invariably bad with 44 of 54 died, most of them (52/54) died during neonatal period during the first episode of illness, 10 survived (7/10 survived with neurological disability, 3/10 without any disability, 2 of which after liver transplantation).3
Usual presentation of late onset type of citrullinemia1 includes growth failure, behavioral abnormalities, motor in-coordination, sleep disorders, vomiting, ataxia. Encephalopathy usually precipitated by infections and medications in the majority of cases.1 In our case, the child presented with recurrent colicky abdominal pain and vomiting as a primary complaint to a pediatric gastroenterology center, though one of the manifestations of urea cycle defect, is infrequently reported in the literature.5 Mhanni et al,5 reported a 3-year-old girl who presented with multiple episodes of abdominal pain, lethargy and sleep disturbances with ornithine transcarbamylase deficiency (OTC), a type of UCD similar to our child. 
High index of suspicion is required for the diagnosis as in our case, as certain inborn errors of metabolism (IEM) like acute intermittent porphyria, UCD and organic acidemias can present with recurrent episodes of vomiting and abdominal pain. In our case associated neurological symptoms led us to consider IEM as one of the differential diagnosis and with high ammonia levels and normal liver functions further supported the possibility of UCD.6 MRI findings of diffuse cortical signal changes has been reported in children with hyperammonemia7 and MRS showing glutamine peak suggestive of hyperammonemia has been used both for diagnosis and therapeutic monitoring purpose in hyperammonemic states.8
Hemodiafiltration is the therapy of choice and should be instituted in severe hyperammonemic encephalopathy to prevent permanent neurological sequelae as plasma ammonia concentration exceeding 300 µmol/l has poor cognitive outcome.1,6 Though liver transplant is curative in citrullinemia, medical management along with strict dietary adherence to be tried especially in resource limited settings before proceeding for liver transplantation. Multiple such cases has been reported worldwide who showed remarkable response only with medical management. This may be due to genotype-phenotype variations in disease manifestation.1,6

Conclusion

Recurrent abdominal pain may be the presentation of urea cycle disorders. Associated subtle neurological features and high serum ammonia are clues to diagnosis. Timely recognition and initiation of strict dietary adherence  (protein restricted diet) and anti-ammonia medication (sodium benzoate) gives gratifying response.

References
  1. Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis 2019;42:1192–230.  
  2. Berning C, Bieger I, Pauli S, Vermeulen T, Vogl T, Rummel T, et al. Investigation of citrullinemia type I variants by in vitro expression studies. Hum Mutat 2008;29:1222-7.
  3. Bijarnia-Mahai S, Haberle J, Jalan AB, Puri RD, Kohli S, Kudalkar K, et al. Urea cycle disorders in India: Clinical course, biochemical and genetic investigations and prenatal testing. Orphanet J Rare Dis  2018;13:174.
  4. Summar ML, Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, Kirmse B. The incidence of urea cycle disorders.Mol Genet Metab 2013;110:179–80.
  5. Mhanni AA, Prasad C, Rockman-Greenberg C. Ornithine Transcarbamylase Deficiency Presenting as Recurrent Abdominal Pain in Childhood. Pediatr Emerg Care 2011;27:850–853.
  6. Häberle J, Pauli S, Schmidt E, Schulze-Eilfing B, Berning C, Koch HG. Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1). Mol Genet Metab 2003;80:302–6. 
  7. Bindu PS, Sinha S, Taly AB, Christopher R, Kovoor.Cranial MRI in acute hyperammonemic encephalopathy. Pediatr Neurol 2009;41:139-42.
  8. O’Donnell-Luria AH, Lin  AP, Merugumala SK, Rohr F, Waisbren SE, Lynch R, et al. Brain MRS glutamine as a biomarker to guide therapy of hyperammonemic coma.Mol Genet Metab. 2017;121:9-15.