Journal of Pediatric Neurosciences
: 2019  |  Volume : 14  |  Issue : 3  |  Page : 133--136

Arginase deficiency presenting as acute encephalopathy

Leema Pauline Cornelius, Vivekasaravanan Raju, Asir Julin 
 Department of Paediatric Neurology, Institute of Child Health and Hospital for Children, Madras Medical College, Chennai, Tamil Nadu, India

Correspondence Address:
Dr. Leema Pauline Cornelius
Department of Paediatric Neurology, Institute of Child Health and Hospital for Children, Egmore, Chennai, Tamil Nadu.


Urea cycle disorders are rare metabolic disorders that present as encephalopathy with hyperammonemia. Arginase deficiency causing hyperargininemia is one among the urea cycle disorders, which usually presents as spastic diplegia. Hyperammonemic encephalopathy is rare in arginase deficiency. We present a rare case of arginase deficiency presenting as acute encephalopathy in a child.

How to cite this article:
Cornelius LP, Raju V, Julin A. Arginase deficiency presenting as acute encephalopathy.J Pediatr Neurosci 2019;14:133-136

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Cornelius LP, Raju V, Julin A. Arginase deficiency presenting as acute encephalopathy. J Pediatr Neurosci [serial online] 2019 [cited 2020 May 27 ];14:133-136
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Urea cycle disorders are a group of inborn errors of metabolism that are associated with hyperammonemic encephalopathy with an estimated prevalence of 1 per 14,000–70,000. Arginase deficiency is the least frequent of the urea cycle disorders with an estimated prevalence of 1 per 350,000.[1] Unlike the other urea cycle disorders, which usually present with an acute hyperammonemic crisis, arginase deficiency presents as progressive spastic diplegia in children. Though hyperammonemia can be observed infrequently, presentation as acute encephalopathy is rare. We report a rare case of hyperargininemia presenting as acute encephalopathy.

 Case Report

A 5-year-old girl, born second to second-degree consanguineous parents, presented with acute onset of lethargy and altered sensorium. No history of fever, loose stools, vomiting, respiratory distress, or seizures was reported. There was no history of trauma, ingestion of toxins either. Developmental milestones were delayed. Her perinatal period was unremarkable. She had a similar episode of drowsiness lasting for 2 days not associated with vomiting or fever 4 months ago. Her elder sibling is normal.

On examination, the child was drowsy, responding to painful stimuli with intact doll’s eye and reactive pupils. She was moving all four limbs to painful stimuli, with preserved deep tendon jerks and extensor plantars. She was afebrile, did not have organomegaly or any sting or bite marks. No meningeal signs were observed. Her blood pressure recordings were normal for her age.

Initial computed tomography (CT) of brain was normal and metabolic parameters including blood sugar, urea, creatinine, electrolytes, and liver enzymes were normal. She was started on ceftriaxone, acyclovir, and hypertonic saline. Cerebrospinal fluid (CSF) analysis was normal with no cells, normal biochemistry, and gram stain. CSF culture was sterile. As no improvement was reported in sensorium, magnetic resonance imaging (MRI) of brain was carried out, which showed hyperintense signals in frontal regions bilaterally with diffusion restriction [Figure 1] and [Figure 2]. Magnetic resonance angiography and magnetic resonance venography were normal. CSF was negative for Japanese Encephalitis virus, Herpes Simplex virus, varicella, Cytomegalovirus, and enteroviruses. No clinically overt seizures were reported. However, in view of persistent altered sensorium, electroencephalogram was performed to rule out Non convulsive status epilepticus and there was only background slowing and no epileptiform discharges. Having ruled out infective, vascular etiologies, a toxic or a metabolic cause was considered. Historical review did not suggest exposure to drug or toxins, and blood for ammonia and lactate was sent. To our surprise, serum ammonia level was elevated (465 µg/dL). Blood lactate level was normal. In view of hyperammonemia with no acidosis, urea cycle disorder was suspected and blood for tandem mass spectrometry was sent and urine for orotic acid was planned. Intravenous dextrose was started and sodium benzoate was added in the dose of 250mg/kg/day and her sensorium improved over the next 2 days and serum ammonia levels came down to 210 µg/dL. She was initiated on protein-restricted diet and sodium benzoate was continued. Tandem mass spectrometry report revealed elevated levels of arginine, 480 µmol/L (<50 µmol/L) suggestive of arginase deficiency. At discharge, she was conscious, oriented, and able to walk independently. However, she had spasticity in both lower limbs with brisk deep tendon reflexes. Red blood cell arginase activity or genetic studies could not be performed for want of facilities. Repeat MRI brain showed T2-weighted, Fluid attenuated inversion recovery hyperintensities in both frontal regions. On follow-up, she did not have any further episodes of vomiting or lethargy and her ammonia level was 141 µg/dL.{Figure 1}, {Figure 2}


Arginase deficiency is one of the distal urea cycle defects, which is caused by homozygous or compound heterozygous mutation of the arginase-1 gene (ARG1) on chromosome 6q23, which results in partial or complete deficiency of the enzyme arginase that catalyzes the hydrolysis of arginine to ornithine and urea. It is inherited as an autosomal-recessive disorder, which usually manifests as progressive spastic diplegia, cognitive deficits, and epilepsy.[2]

The first documented cases of this condition were published in 1969 describing two sisters born to consanguineous parents who showed periodic vomiting, anorexia, lethargy, cognitive impairment, and a seizure disorder.[3]

ARG1D markedly differs from other Urea cycle disorders (UCDs) because it usually does not present during the neonatal period and first symptoms occur between 2 and 4 years of age.[4],[5] Hyperammonemia is less frequent than in other UCDs but patients can have neonatal and/or recurrent hyperammonemic crises.[6] The classical biochemical finding is significant elevation of plasma arginine level. In addition, urine orotic acid and guanidine compounds are elevated. Definitive testing is by red blood cell arginase activity.

Arginase exists in two isoforms, arginase I (ARG1), which is expressed in the liver, erythrocytes, and salivary glands,[4] and arginase II (ARG2), which is found predominantly in the renal tissues.[7] It is believed that the comparatively mild presentation of ARG1 deficiency may be the result of overexpression of ARG2. It has also been postulated that mitochondrial arginase activity becomes upregulated when the cytosolic ARG1 activity in the liver is deficient.[6] In some cases, mitochondrial arginase can increase up to 40-fold.[4]

The exact mechanism that causes spasticity in argininemia is unknown. However, it has been postulated that arginine and its guanidino compounds rather than ammonia act as neurotoxins by inhibiting transketolase activity causing demyelination and pyramidal signs as well as inhibit GABAergic neurotransmission.[8] Products of alternate pathways of arginine metabolism, such as nitric oxide and glutamate, have also been implicated.

MRI brain findings in hyperargininemia are usually nonspecific, such as cerebral atrophy.[9] They may also show symmetric involvement of cingulate gyrus and insular cortex. Maramattom et al.[10] have reported the involvement of precentral gyrus, cerebral peduncles, dorsal midbrain, periaqueductal grey matter, and superior cerebellar peduncles in an adult with hyperargininemia, presenting as acute encephalopathy. Our patient had hyperintense signals in frontal regions bilaterally, which has not been reported so far.

Acute management of hyperammonemic crises include stopping protein intake, providing calories by intravenous dextrose with or without insulin to prevent catabolism, and using nitrogen scavengers such as sodium benzoate or sodium phenyl butyrate. If ammonia levels are high >250 µmol/L, hemodialysis is recommended to bring down the ammonia levels. Long-term management comprises protein-restricted diet, ammonia detoxifiers, supplementation of vitamins and minerals, and prompt treatment of intercurrent infections.


Urea cycle disorders must be included in the differential diagnosis of any acute unexplained encephalopathy, and urgent estimation of plasma ammonia level must be indicated.

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Conflicts of interest

There are no conflicts of interest.


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